HIV Infection and AIDS 

Updated: Jul 01, 2019
Author: Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP; Chief Editor: Michael Stuart Bronze, MD 

Overview

Practice Essentials

Human immunodeficiency virus (HIV) is a blood-borne virus typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding. HIV disease is caused by infection with HIV-1 or HIV-2, which are retroviruses in the Retroviridae family, Lentivirus genus. See the image below.

Electron microscopy of human immunodeficiency viru Electron microscopy of human immunodeficiency virus (HIV)–1 virions. Courtesy of CDC (Dr Edwin P Ewing, Jr).

Signs and symptoms

The patient with HIV may present with signs and symptoms of any of the stages of HIV infection. No physical findings are specific to HIV infection; the physical findings are those of the presenting infection or illness. Manifestations include the following:

  • Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash

  • The asymptomatic phase is generally benign

  • Generalized lymphadenopathy is common and may be a presenting symptom

  • AIDS manifests as recurrent, severe, and occasionally life-threatening infections or opportunistic malignancies

  • HIV infection can cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause)

The history should address risk factors for possible exposure to HIV, including the following:

  • Unprotected sexual intercourse, especially receptive anal intercourse

  • A large number of sexual partners

  • Previous or current sexually transmitted diseases (STDs)

  • Sharing of intravenous (IV) drug paraphernalia

  • Receipt of blood products (before 1985 in the United States)

  • Mucosal contact with infected blood or needle-stick injuries

  • Maternal HIV infection (for newborns, infants, and children)

See Clinical Presentation for more detail.

Diagnosis

HIV screening recommendations include the following:

  • The US Preventive Services Task Force (USPSTF) strongly recommends that clinicians screen for HIV in all adolescents and adults at increased risk for HIV infection, and all pregnant women[1]

  • The Centers for Disease Control and Prevention (CDC) recommends opt-out HIV screening for patients in all health-care settings; persons at high risk for HIV infection should be screened at least annually[2]

  • The American College of Physicians (ACP) recommends that clinicians adopt routine screening for HIV and encourage all patients to be tested[3]

  • A high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) should be used for screening; a positive result should be followed with confirmatory testing (eg, Western blot assays or similar specific assay); HIV-2 should be tested for in patients from an HIV-2 endemic area or those with indeterminate results on HIV-1 Western blot testing; early detection using combination screens may be more effective than simply using serology

The CD4 T-cell count reliably reflects the current risk of acquiring opportunistic infections, as follows:

  • Reference range, 500-2000 cells/μL

  • Because CD4 counts vary, serial counts are generally a better measure of significant changes

  • After seroconversion, CD4 counts tend to decrease (~700/μL) and continue to decline over time

  • For surveillance, a CD4 count below 200/μL is considered AIDS-defining in the United States

  • In children younger than 5 years, the CD4 T-cell percentage is considered more important than the absolute count (< 25% is considered to warrant therapy)

  • In adults with chronic hepatitis C and low absolute CD4 T-cells, the CD4 percentage may also be more useful[4]

Viral load in peripheral blood is used as a surrogate marker of viral replication rate; however, quantitative viral-load assays should not be used as a diagnostic tool. Clinical relevance is as follows:

  • Rate of progression to AIDS and death is related to the viral load; patients with viral loads greater than 30,000/μL are 18.5 times more likely to die of AIDS than those with undetectable viral loads.

  • With therapy, viral loads can often be suppressed to an undetectable level (< 20-75 copies/mL; optimal viral suppression); complete inhibition of viral replication appears impossible and may be unnecessary

  • Successfully treated patients may demonstrate intermittent low-level viremia (eg, < 400 copies/mL), but this is not thought to represent viral replication or to predict virologic failure (defined as a confirmed viral load of > 200 copies/mL[5]

In August 2013, the FDA approved Alere Determine HIV-1/2 Ag/Ab Combo test (Orgenics, Ltd) as the first rapid HIV test for the simultaneous detection of HIV-1 p24 antigen as well as antibodies to both HIV-1 and HIV-2 in human serum, plasma, and venous or fingerstick whole blood specimens.[6, 7] The test does not distinguish between antibodies to HIV-1 and HIV-2, and is not intended to be used for screening of blood donors.[6, 7]

Baseline studies for other infections that are important in the initial workup of a patient with newly diagnosed HIV infection include the following:

  • Purified protein derivative (PPD) skin testing for tuberculosis

  • Cytomegalovirus (CMV) testing

  • Syphilis testing

  • Rapid amplification testing for gonococcal and chlamydial infection

  • Hepatitis A, B, and C serology

  • Anti-Toxoplasma antibody

  • Ophthalmologic examination

The CDC classifies HIV infection into 3 categories, as follows[8] :

  • Category A: Asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions

  • Category B: HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection

  • Category C: HIV infection with AIDS-defining opportunistic infections

These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:

  • > 500/µL: Categories A1, B1, C1

  • 200-400/µL: Categories A2, B2, C2

  • < 200/µL: Categories A3, B3, C3

See Workup for more detail.

Management

Current Department of Health and Human Services (DHHS) guidelines on the timing of initiation of antiretroviral therapy are as follows[5] :

  • Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness or with a CD4 count below 350/µL

  • Antiretroviral therapy should be initiated regardless of CD4 count in pregnant patients, patients with HIV-associated nephropathy, and those with hepatitis B virus (HBV) coinfection when treatment of HBV infection is indicated

  • Panel divided on initiation of therapy with CD4 counts of 350-500/µL; 55% considered this a strong recommendation, 45% considered it a moderate recommendation

  • Panel also divided on initiation of therapy with CD4 counts above 500/µL: half favored initiation in this setting, and half considered treatment initiation optional

Highly active antiretroviral therapy (HAART) is the principal method for preventing immune deterioration. Classes of antiretroviral agents include the following:

  • Nucleoside reverse transcriptase inhibitors (NRTIs)

  • Protease inhibitors (PIs)

  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

  • Fusion inhibitors

  • CCR5 co-receptor antagonists (entry inhibitors)

  • HIV integrase strand transfer inhibitors

  • Entry inhibitors (CD4-directed post-attachment inhibitors)

Current DHHS guidelines list the following regimens as preferred in treatment-naive patients[5] :

  • INSTI-based regimens are as follows:
    • Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) - only for patients who are HLA-B*5701–negative
    • DTG plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)
    • Elvitegravir/cobicistat/TDF/FTC (EVG/c/TDF/FTC) - only for patients with pre-ART creatinine clearance (CrCl) of >70 mL/min
    • Raltegravir (RAL) plus TDF/FTC
  • The PI/r-based regimen is darunavir/ritonavir (DRV/r) plus TDF/FTC
  • HIV-2 is intrinsically resistant to NNRTIs and enfuvirtide.

Regimen selection is individualized on the basis of the following[5] :

  • Virologic efficacy

  • Toxicity

  • Pill burden

  • Dosing frequency

  • Drug-drug interaction potential

  • Drug resistance testing results

  • Comorbid conditions

In particular cases, prophylaxis is indicated for specific opportunistic infections, including the following:

  • Pneumocystis jiroveci

  • Toxoplasma

  • Mycobacterium avium complex

  • Fungal and viral infections: Although prophylaxis for these infections is not routinely necessary, some recommend fluconazole in patients with CD4+ T-cell counts under 50/µL to prevent candidal or cryptococcal infections and to protect against endemic fungal infections; oral ganciclovir is indicated for CMV prophylaxis in patients with advanced AIDS

Additional treatment measures include the following:

  • Treatment of opportunistic infections (directed at the specific pathogen)

  • Treatment of HIV lipodystrophy (tesamorelin)

  • Suppressive therapy for herpes simplex virus 2 (HSV-2) infection (acyclovir)

  • Treatment of HIV-associated diarrhea (crofelemer[9] )

The CDC has recommended basic and expanded HIV postexposure prophylaxis (PEP) regimens. An overview of these recommendations is as follows:

  • Basic PEP 2-drug regimen: Tenofovir plus emtricitabine (preferred); alternatives include zidovudine plus lamivudine, zidovudine plus emtricitabine, or tenofovir plus lamivudine
  • Alternative basic PEP regimen: Lamivudine plus stavudine, lamivudine plus didanosine, emtricitabine plus stavudine, or emtricitabine plus didanosine
  • Expanded PEP regimen: Basic PEP regimen plus raltegravir (preferred) or lopinavir-ritonavir

An alternative expanded PEP regimen includes the basic PEP regimen plus one of the following:

  • Atazanavir with or without ritonavir

  • Fosamprenavir with or without ritonavir

  • Indinavir with or without ritonavir

  • Saquinavir with or without ritonavir

  • Nelfinavir

  • Efavirenz

See Treatment and Medication for more detail.

Background

Human immunodeficiency virus (HIV) is a blood-borne, sexually transmissible virus (see the image below.) The virus is typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding.

Electron microscopy of human immunodeficiency viru Electron microscopy of human immunodeficiency virus (HIV)–1 virions. Courtesy of CDC (Dr Edwin P Ewing, Jr).

The most common route of infection varies from country to country and even among cities, reflecting the population in which HIV was introduced initially and local practices. Co-infection with other viruses that share similar routes of transmission, such as hepatitis B, hepatitis C, and human herpes virus 8 (HHV8; also known as Kaposi sarcoma herpes virus [KSHV]), is common.

Two distinct species of HIV (HIV-1 and HIV-2) have been identified, and each is composed of multiple subtypes, or clades. All clades of HIV-1 tend to cause similar disease, but the global distribution of the clades differs. This may have implications on any future vaccine, as the B clade, which is predominant in the developed world (where the large pharmaceutical companies are located), is rarely found in the developing countries that are more severely affected by the disease.

HIV-1 probably originated from one or more cross-species transfers from chimpanzees in central Africa.[10] HIV-2 is closely related to viruses that infect sooty mangabeys in western Africa.[11] Genetically, HIV-1 and HIV-2 are superficially similar, but each contains unique genes and its own distinct replication process.

HIV-2 carries a slightly lower risk of transmission, and HIV-2 infection tends to progress more slowly to acquired immune deficiency syndrome (AIDS). This may be due to a less-aggressive infection rather than a specific property of the virus itself. Persons infected with HIV-2 tend to have a lower viral load than people with HIV-1,[12, 13] and a greater viral load is associated with more rapid progression to AIDS in HIV-1 infections.[14, 15]

HIV-2 is rare in the developed world. Consequently, most of the research and vaccine and drug development has been (perhaps unfairly) focused on HIV-1.

For information on HIV infection in children, see Pediatric HIV.

Initial description and early spread

In the United States, HIV disease was first described in 1981 among 2 groups, one in San Francisco and the other in New York City. Numerous young homosexual men presented with opportunistic infections that, at the time, were typically associated with severe immune deficiency: Pneumocystis pneumonia (PCP) and aggressive Kaposi sarcoma.[16]

HIV itself was not identified for another 2 years.[17] During that time, various other causes were considered, including lifestyle factors, chronic drug abuse, and other infectious agents.[18] The HIV epidemic spread rapidly and silently in the absence of testing.

However, clear clinical implications arose before society became aware of the disease; for example, prior to the recognition of HIV, only one case of Pneumocystis pneumonia not clearly associated with immune suppression was diagnosed in the United States between January 1976 and June 1980. In 1981 alone, 42 similar diagnoses were made, and by December 1994, 127,626 cases of Pneumocystis pneumonia with HIV infection as the only identified cause of immune suppression had been reported to the Centers for Disease Control and Prevention (CDC). Also, Kaposi sarcoma is up to 30,000 times more likely to develop in persons with HIV infection than in immunocompetent persons.

The spread of HIV was retrospectively shown to follow the trucking routes across Africa from logging camps, and the bush-meat trade combined with aggressive logging and improved transportation in the mid-20th century may have allowed what was likely occasional cross-species transmission events to propagate across the country and, eventually, the globe.[19]

Stigma of HIV infection

A considerable amount of stigma has been attached to HIV infection, mostly because of the virus's association with sexual acquisition and the inference of sexual promiscuity. Consequences of this stigma have included discrimination and reluctance to be tested for HIV infection. The stigma of HIV infection is also associated with a fear of acquiring a rapidly fatal infection from relatively casual contact.

Such attitudes are inappropriate because HIV is poorly transmissible without sexual contact or blood contact. In addition, the expected survival is long in patients with HIV infection who are receiving treatment. HIV is not transmitted during casual contact and is readily inactivated by simple detergents. Much of the concern regarding HIV infection is due to the incurability of the infection and the relentless immune decline and eventual premature death in the vast majority of infected people.

AIDS denialism

A small but vocal minority of people, including some scientists, continue to argue that HIV does not exist, or does not cause AIDS, and that the HIV tests are unreliable or that the therapies are toxic. Such misinformation is usually based on a lack of understanding of the scientific literature, deliberate misrepresentation, or logical fallacies based on pseudoscientific arguments.

All of the arguments proposed by these dissenters have been addressed and rebutted in the scientific literature and public discussion and even tested and rejected in the legal system. Nevertheless, they persist, and such views can have extremely harmful effects on people who are exposed to HIV infection unnecessarily or who refuse treatment for their progressing infection.

Clinicians should be aware of these issues, should be able and willing to address misinformation, and should direct their patients to reliable sources of information.

Political denial and inaction have also likely caused considerable damage. Several governments in countries with high HIV infection rates were slow to admit that they had an HIV epidemic, and at least one (South Africa) initially rejected that AIDS was even a problem, then that the disease was caused by HIV infection, and, most recently, that antiretroviral therapy was effective in treating HIV infection and preventing MTCT. Changes have now occurred but have been slow and have cost hundreds of thousands of lives.

A regularly updated reference for addressing AIDS denial and misinformation can be found at AIDSTruth.org.

The quest for understanding of HIV

Since the discovery of HIV and its link to AIDS, great strides have been made in understanding its biology and in developing effective treatments. The difficulty in dealing with HIV on a global scale is largely due to the fact that HIV infection is far more common in resource-poor countries.

In the developed world, antiretroviral therapy has greatly improved prognosis and increased survival rates. Public education programs have raised awareness such that testing and prevention of infection are more common. Both of these approaches are difficult in countries with undereducated or underfunded populations.

A thorough discussion of the history of AIDS and the biologic link between HIV and AIDS can be found in an article entitled " The relationship between the human immunodeficiency virus and the acquired immunodeficiency syndrome " at the National Institute of Allergy and Infectious Diseases Web site. The document was originally written in September 1995, prior to the advent of highly active antiretroviral therapy (HAART), which has significantly improved AIDS-free survival in persons infected with HIV. This version was updated March 2010.

Patient confidentiality

HIV-related health information is typically considered separate from other health information and may require separate consent to share or divulge.

Health care workers who are infected with HIV may be required to divulge their status to their employer or patients and may be restricted in the types of procedures they can perform.

Pathophysiology

HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4+ cells). The loss of CD4+ cells results in the development of opportunistic infections and neoplastic processes.

Virology of HIV

HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA.

HIV contains 3 species-defining retroviral genes: gag, pol, and env. The gag gene encodes group-specific antigen; the inner structural proteins. The pol gene encodes polymerase; it also contains integrase and protease (the viral enzymes) and is produced as a C-terminal extension of the Gag protein). The env gene encodes the viral envelope—the outer structural proteins responsible for cell-type specificity. Glycoprotein 120, the viral-envelope protein, binds to the host CD4+ molecule.

HIV-1 has 6 additional accessory genes: tat, rev, nef, vif, vpu, and vpr. HIV-2 does not have vpu but instead has the unique gene vpx. The only other virus known to contain the vpu gene is simian immunodeficiency virus in chimpanzees (SIVcpz), which is the simian equivalent of HIV.[10] Interestingly, chimpanzees with active HIV-1 infection are resistant to disease.[20]

The accessory proteins of HIV-1 and HIV-2 are involved in viral replication and may play a role in the disease process.[21, 22] The outer part of the genome consists of long terminal repeats (LTRs) that contain sequences necessary for gene transcription and splicing, viral packaging of genomic RNA, and dimerization sequences to ensure that 2 RNA genomes are packaged. (See the image below.)

Genome layout of human immunodeficiency virus (HIV Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

The dimerization, packaging, and gene-transcription processes are intimately linked; disruption in one process often subsequently affects another. The LTRs exist only in the proviral DNA genome; the viral RNA genome contains only part of each LTR, and the complete LTRs are re-created during the reverse-transcription process prior to integration into the host DNA.

The biologic basis for AIDS

The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS.[23, 24, 25]

There is a specific decline in the CD4+ helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.[26, 27] Immune responses to certain antigens begin to decline, and the host fails to adequately respond to opportunistic infections and normally harmless commensal organisms. Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral).

The pattern of opportunistic infections in a geographic region reflects the pathogens that are common in that area. For example, persons with AIDS in the United States tend to present with commensal organisms such as Pneumocystis and Candida species, homosexual men are more likely to develop Kaposi sarcoma because of co-infection with HHV8, and tuberculosis is common in developing countries.

Gut-associated lymphoid tissue (GALT) plays a role in HIV replication.[28] Although the portal of entry for HIV infection is typically through direct blood inoculation or exposure of the virus to genital mucosal surfaces, the GI tract contains a large amount of lymphoid tissue, making this an ideal site for HIV replication.

GALT has been shown to be a site of early viral seeding and establishment of the proviral reservoir. This reservoir contributes to the difficulty of controlling the infection, and efforts to reduce the levels of HIV provirus through sustained antiretroviral therapy (alone or in combination with interleukin-2 activation of resting HIV-infected T cells) have consistently failed.[29]

A feature of HIV replication in GALT is that it is compartmentalized, even among different areas of the gut.[30] Measurements of CD4+ T cells in GALT show relatively less reconstitution with antiretroviral therapy than that observed in peripheral blood.[31, 32] At least one report has suggested that early treatment may result in better GALT CD4+ T-cell recovery,[32] but clinical data generally argue against early initiation of therapy, which has not been shown to improve long-term survival.

In addition, HIV replication can be detected even in patients with supposedly suppressed replication, as judged by plasma viral load measurements. CD8+ killer T-cell responses to HIV occur in GALT and do not decline with antiviral therapy as much as peripheral measurements do.[33] These findings underscore the limitations of peripheral measurements in what is really a central viral replication.

One theory for the discrepancy between GALT and blood measurements is that ongoing viral replication in the lymphoid tissue, and the resulting immune activation, may actually hamper efficient CD4+ T-cell replenishment.[34]

Studies of T-cell–replication kinetics have revealed that untreated HIV infection is characterized by rapid T-cell turnover but a defect in T-cell replication from the thymus.[35, 36, 37] These changes can be reversed with effective long-term antiviral therapy,[38, 39] suggesting that they are due to a direct effect of the virus or are a feature of the immune response against HIV.

It is known that normal cell cycling is necessary to produce a normal cytokine profile[40] and that HIV causes cell-cycle arrest.[41] Whether this is the exact mechanism is unresolved, however. Analysis of cytokine levels in HIV infected, uninfected, and HAART-treated patients with HIV show that cytokines involved in T-cell homeostasis were definitely affected, and therapy partially corrected these defects. In particular there was decreased IL-7, IL-12, IL-15 and FGF-2, and increased TNF-alpha and IP-10.[42, 43]

Several of the HIV proteins directly affect T-cell function, either by disrupting cell cycling or down-regulating the CD4 molecule. The loss of T cells is clearly a primary issue, as the T-cell repertoire narrows in terms of which antigens the immune system will recognize and respond to. Antiviral therapy is able to reverse these changes,[44] but the degree of reversal is decreased if therapy is initiated very late in the infection and is further decreased when therapy is initiated when CD4 T-cell counts are 200/µL and below.

Direct cytotoxic effects of viral replication are likely not the primary cause of CD4 T-cell loss; a significant bystander effect[45] is likely secondary to T-cell apoptosis as part of immune hyperactivation in response to the chronic infection. Infected cells may also be affected by the immune attack.

One interesting issue is that the co-receptor usage of the virus strains tends to change over time. The initial infection nearly always involves a strain that uses the chemokine receptor 5 (CCR5), which is found on macrophages and dendritic cells, as a co-receptor with CD4. People who are homozygous for deletions in the CCR5 gene (ie, CCR5-delta32) tend to be resistant to infection,[46, 47] and those with heterozygosity for the polymorphism tend to show slower progression of disease.[48]

Over time, the receptor usage shifts to chemokine-related receptor (CXCR4) and other related receptors found on CD4+ T cells. These virus strains are more likely to cause cell fusion (syncytia formation). This trend is far from absolute but does correlate in many people with disease progression.[49]

A single case report detailed a possible cure resulting from stem-cell transplantation from a CCR5-delta32 homozygous donor (performed to treat acute myelocytic leukemia). Although this important finding is unlikely to impact routine management of HIV infection, it does suggest that reconstitution of a host immune system with a population of mutant cells is a possible avenue of research to explore.[50]

Regardless of the cause for the disruption, a loss of thymic replacements in the face of an induced state of immune activation and T-cell loss seems to be a key component of the mechanism by which HIV narrows the T-cell repertoire and progresses to AIDS.[51, 52, 53]

Visible effects of HIV infection come in the form of disrupted lymph-node architecture. This disruption is temporal, and, at one point, lymph-node biopsy was considered as a form of staging the disease.[54, 55] The disruption of the follicular dendritic network in the lymph nodes and subsequent failure of normal antigen presentation are likely contributors to the disease process.

HIV replicates in activated T cells (its promotor contains a nuclear factor kappa B [NF-kappa-B]–binding region, the same protein that promotes other proteins in activated T cells and macrophages), and activated T cells migrate to the lymph nodes. As such, much of the viral replication occurs outside of the peripheral blood, even though serum viral load is still a useful surrogate marker of viral replication.

As mentioned above, with regards to GALT, HIV infection may be compartmentalized; specifically, areas of immune-privilege may occur such as in the testes and central nervous system where not only will there be differences in HIV pseudospecies but also different degrees of antiretroviral drug penetration. There is evidence that even with good peripheral control of HIV, the virus may still be detectable in the CSF and semen of some infected patients.[56, 57]

Phases of HIV infection

Clinical HIV infection undergoes 3 distinct phases: acute seroconversion, asymptomatic infection, and AIDS. Each is discussed below. (See the image below.)

Timeline of CD4 T-cell and viral-load changes over Timeline of CD4 T-cell and viral-load changes over time in untreated human immunodeficiency virus (HIV) infection. Courtesy of Wikipedia (based on an original from Pantaleo et al (1993)).

Acute seroconversion

Animal models show that Langerhans cells are the first cellular targets of HIV, which fuse with CD4+ lymphocytes and spread into deeper tissues. In humans, rapid occurrence of plasma viremia with widespread dissemination of the virus is observed 4-11 days after mucosal entrance of the virus.

There is no fixed site of integration, but the virus tends to integrate in areas of active transcription, probably because these areas have more open chromatin and more easily accessible DNA.[58, 59] This greatly complicates eradication of the virus by the host, as latent proviral genomes can persist without being detected by the immune system and cannot be targeted by antivirals. See the image below.

During this phase, the infection is established and a proviral reservoir is created.[60, 61] This reservoir consists of persistently infected cells, typically macrophages, and appears to steadily release virus. Some of the viral release replenishes the reservoir, and some goes on to produce more active infection.

The proviral reservoir, as measured by DNA polymerase chain reaction (PCR), seems to be incredibly stable. Although it does decline with aggressive antiviral therapy, the half-life is such that eradication is not a viable expectation.

The size of the proviral reservoir correlates to the steady-state viral load and is inversely correlated to the anti-HIV CD8+ T-cell responses. Aggressive early treatment of acute infection may lower the proviral load, but generally, treatment in newly infected (but postseroconversion) patients yields no long-term benefit.

At this point, the viral load is typically very high, and the CD4+ T-cell count drops precipitously. With the appearance of anti-HIV antibodies and CD8+ T-cell responses, the viral load drops to a steady state and the CD4+ T-cell count returns to levels within the reference range, although slightly lower than before infection.

Seroconversion may take a few weeks, up to several months. Symptoms during this time may include fever, flulike illness, lymphadenopathy, and rash. These manifestations develop in approximately half of all people infected with HIV.

Asymptomatic HIV infection

At this stage in the infection, persons infected with HIV exhibit few or no signs or symptoms for a few years to a decade or more. Viral replication is clearly ongoing during this time,[62] and the immune response against the virus is effective and vigorous. In some patients, persistent generalized lymphadenopathy is an outward sign of infection. During this time, the viral load, if untreated, tends to persist at a relatively steady state, but the CD4+ T-cell count steadily declines. This rate of decline is related to, but not easily predicted by, the steady-state viral load.

No firm evidence has shown that the initiation of therapy early in the asymptomatic period is effective. However, very late initiation is known to result in a less effective response to therapy and a lower level of immune reconstitution.

AIDS

When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. For surveillance purposes in the United States, a CD4+ T-cell count less than 200/µL is also used as a measure to diagnose AIDS, although some opportunistic infections develop when CD4+ T-cell counts are higher than 200/µL, and some people with CD4 counts under 200/µL may remain relatively healthy.

Many opportunistic infections and conditions are used to mark when HIV infection has progressed to AIDS. The general frequency of these infections and conditions varies from rare to common, but all are uncommon or mild in immunocompetent persons. When one of these is unusually severe or frequent in a person infected with HIV and no other causes for immune suppression can be found, AIDS can be diagnosed.[8]

Immunologic control of HIV

The primary mechanism for immunologic control of HIV appears to be CD8+ cytotoxic T-cells. T-cell responses are correlated with the steady-state viral load and hence, the rate of progression.[63] Cellular immunity is apparently responsible for some multiply-exposed, but uninfected individuals.[64, 65]

Although antibodies against HIV can be detected, it is clear that they are not sufficiently neutralizing to assist with immunologic control of the infection.

The role of NK (Natural Killer) cells may be important in the initial control of HIV. Escape mutations have been detected, implying that immunologic pressure on HIV exists from NK cells.[66]

Opportunistic infections and conditions

Even after starting therapy and with effective suppression of viral load, patients with persistently low CD4 counts remain at high risk for opportunistic infections. In general, all patients remain at a relatively high risk for opportunistic infections and other AIDS-related events for the first 6 months of antiretroviral therapy.[67] An observational study of 20,730 HIV patients in Uganda found that, among patients with more than six months of follow-up after the initiation of antiretroviral therapy, the pre-therapy CD4 count was still predictive of mortality.[68]

Opportunistic infections and conditions include the following ( * added in the 1993 AIDS surveillance case definition):

  • Candidiasis of bronchi, trachea, or lungs

  • Candidiasis, esophageal

  • Cervical cancer, invasive*

  • Coccidioidomycosis, disseminated or extrapulmonary

  • Cryptococcosis, extrapulmonary

  • Cryptosporidiosis, chronic intestinal (duration >1 mo)

  • Cytomegalovirus disease (other than liver, spleen, or nodes)

  • Cytomegalovirus retinitis (with vision loss)

  • Encephalopathy, HIV-related

  • Herpes simplex: chronic ulcer or ulcers (duration >1 mo) or bronchitis, pneumonitis, or esophagitis

  • Histoplasmosis, disseminated or extrapulmonary

  • Isosporiasis, chronic intestinal (duration >1 mo)

  • Kaposi sarcoma

  • Lymphoma, Burkitt (or equivalent term)

  • Lymphoma, immunoblastic (or equivalent term)

  • Lymphoma, primary, of the brain

  • Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary

  • M tuberculosis infection, any site (pulmonary* or extrapulmonary)

  • Mycobacterium infection with other species or unidentified species, disseminated or extrapulmonary

  • Pneumocystis pneumonia

  • Pneumonia, recurrent*

  • Progressive multifocal leukoencephalopathy

  • Salmonella septicemia, recurrent

  • Toxoplasmosis of the brain

  • Wasting syndrome due to HIV infection

Although malaria is not typically considered an opportunistic infection, its incidence was found to be significantly higher among children in Tanzania that were perinatally infected with HIV than those without HIV infection.[69] This was true for physician-diagnosed clinical malaria, probable malaria involving laboratory testing for parasitemia as well as malaria that was confirmed by blood smear.

There also appears to be an increased rate of anal cancer in high-risk groups (in particular, men who have sex with men). This is unsurprising considering the link between anal cancer and human papillomavirus (HPV), and the fact that cervical cancer, also caused by HPV, is considered an AIDS-defining condition.[70]

HIV Encephalopathy is a severe condition usually seen in end-stage disease. Milder cognitive impairments may exist with less advanced disease. For example, one study found significant deficits in cognition, planning, coordination and reaction times in HIV-infected compared to uninfected children, effects that were more pronounced in those with higher viral loads.[71]

Etiology

HIV disease is caused by infection with HIV-1 or HIV-2, both of which cause very similar conditions. They differ in transmission and progression risks.

Epidemiology

United States statistics

According to the Centers for Disease Control and Prevention (CDC), from 2010-2015, the estimated rate of HIV infection diagnoses in all 50 US states decreased from 14.2 per 100,000 population in 2010 to 12.3 per 100,000 population in 2016.[72] In 2016, 39,782 individuals were diagnosed with HIV infection. From 2011 to 2016, the annual number of new HIV infection diagnoses decreased 5.3%.

The CDC reported that, at the end of 2015, the most recent year for which national prevalence statistics are available, there were approximately 990,000 adults and adolescents living with HIV infection in the United States, over 520,000 of whom had infection classified as stage 3 (AIDS).[72]

In 2016, the reported rate of AIDS diagnoses in the United States was 5.6 per 100,000 population.[72] From 1981-2016, 1,232,346 persons were diagnosed with AIDS in the United States, and 692,789 people had died with AIDS by the end of 2015 (although reporting limitations mean that not every "death with AIDS" is directly attributable to AIDS itself).

US rates vary by state. See the latest CDC surveillance report for full details.

The overall figures may give a false impression that the HIV epidemic is relatively homogeneous. In fact, the HIV epidemic is best viewed as numerous separate epidemics among distinct risk groups, although the various epidemics clearly have some level of overlap. In any given area, the infection may be most prevalent among users of intravenous drugs who share needles. In another, the main risk group may be men who have sex with other men. And in yet another, the main risk group may be female sex workers.

These sub-epidemics each follow their own pattern, although there is some degree of interdependence. Early on, nearly all cases of HIV infection detected in the Western Hemisphere were in homosexual men, but the spread of the disease to female partners of bisexual men with HIV infection gave rise to an increased rate among heterosexual persons.

Contributing to the increased cross-prevalence were persons with hemophilia who had been infected with HIV from contaminated factor VIII concentrate and persons who used intravenous drugs, an activity that transcends all sexual preferences. In 2014, 70% of new HIV infections were reported in homosexual men, and infected heterosexual women outnumber infected heterosexual men nearly two to one.[72]

One community-based study targeting areas where men who have sex with men (MSM) meet demonstrated that an average of 44% of study participants appeared unaware of their HIV-positive status. High rates of positivity and unawareness of positive status were associated with younger participants, men of black non-Hispanic race, and lower education levels.

Healthcare visits in the preceding year were associated with a lower rate of unawareness (37% vs 81%) but a higher rate of HIV-positivity (21% vs 12%). Because this study targeted a high-risk group and may involve participation bias, the overall rate of HIV infection (19%) cannot be easily extrapolated to the overall population.[73]

Mortality from HIV disease has not been among the 15 leading causes of death in the US since 1997. The age-adjusted death rate for HIV disease peaked in 1995 at 16.3 per 100,000 population, decreased 69.9% through 1998, then further decreased 30.2% from 1999 through 2007, to 3.7 per 100,000 population. In 2007, a total of 11,295 persons died from HIV disease. However, HIV disease has remained among the 5 leading causes of death for specific age groups for females, and in the black population.[74]

Adolescents and young adults

CDC HIV surveillance statistics from 2015 report that 22.3% (8807 individuals) of new HIV infections in the United States are in adolescents and young adults aged 13 to 24 years. Males accounted for 82.8% of new HIV infections in youth. Of these, 7000 (57.4%) were in African Americans, 2390 (19.6%) in Hispanics, and 2380 (19.5%) in whites. Male-to-male sexual contact accounted for 72.1% (8800 individuals). The percentage of youths tested for HIV infection was 12.9% in high- school students and 34.5% in individuals aged 18-24 years. Testing was lower in males than females. More than half (59.5%) of youths with HIV are unaware of their infection.[75]

International statistics

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS),[76] worldwide in 2015, approximately 36.7 million people (1% of the global adult population aged 15-49 years) were infected with HIV, a decline from 2006 (39.5 million reported at that time). UNAIDS estimates that approximately 2.1 million people were newly infected with HIV and that 1.1 million people died of AIDS in 2015, both statistics showing a decline over time.

The vast majority of infections remain in sub-Saharan Africa, where 5.2% of the population is thought to be infected. Between 2004 and 2006, the prevalence of HIV infection in central and eastern Asia and Eastern Europe increased by 21%. During this period, the number of new HIV infections in persons aged 15 to 64 years rose by 70% in Eastern Europe and central Asia.

The infection rates in many developed countries remain stable, and some developing countries have achieved significant gains in controlling and even reversing the effects of the HIV epidemic. However, this is partially due to deaths in HIV-infected people, together with simultaneous prevention of new infections. India, for example, has used a national prevention campaign focusing on high-risk populations that may have prevented 100,000 new HIV infections over the 5 years it has been implemented, with increasing results seen in areas with higher levels of investment.[77] These figures together show that global HIV infection is in a state of flux.

Men who have sex with men (MSM) are still 28 times more likely than heterosexual individuals to contract HIV infection despite sharp declines of infection among such populations in Western countries. The institution of pre-exposure prophylaxis (PrEP) in Western Europe, North America, and Australia has dramatically decreased transmission rates among gay men in those areas.[78]

The mortality rate in some countries has greatly increased. In South Africa (a country that, despite having a relatively late-onset HIV epidemic, has developed one of the highest prevalence rates), the all-cause HIV-associated mortality rate increased by 79% between 1997 and 2004. In women aged 25-34 years, mortality rates increased by 500% during this period.

Swaziland has the highest overall prevalence of HIV infection (>26% of all adults based on 2007 figures).

The Ministry of Health in Zambia predicts that, without therapy and assuming current levels of prevalence, young adults have a 50% lifetime risk of dying from AIDS.

In developing nations, co-infection with HIV and tuberculosis is very common. The immunosuppressed state induced by HIV infection contributes not only to a higher rate of tuberculosis reactivation but also to an increased disease severity, as with many other opportunistic infections.

Further details of the global epidemic can be found in the Joint United Nations Programme on HIV/AIDS 2009 Epidemic Update.

Racial, sexual, and age-related differences in incidence

In the United States, the rate of HIV infection is highest in blacks (44.3 cases per 100,000 population). The prevalence is also high among Hispanic persons (16.4 per 100,000 population).[72] These increased rates are due to socioeconomic factors rather than genetic predisposition.

In the developed world, HIV infection is much more common in males. In 2015, males accounted for 81% of all diagnoses of HIV infection among adults and adolescents in the United States.[72] Among heterosexuals, females are more likely to acquire HIV infection from an infected male than a male is from an infected female, but a large proportion of infections in males are due to homosexual contact, with or without injection drug use. Males are also more likely to acquire HIV infection from injection drug use alone.

Males were also more likely to acquire HIV infection through contaminated blood products for treatment of hemophilia before universal testing of the blood supply was instituted. The risk of HIV exposure from factor VIII concentrates has been virtually eliminated by viricidal treatment of plasma-derived factor VIII concentrates, as well as the introduction of recombinant factor VIII concentrates and the gradual elimination of albumin from the production process used for these products.

In the developing world, HIV infection is equally common in males and females. The primary route of HIV transmission in the developing world is heterosexual contact.

Young adults tend to be at higher risk of acquiring HIV, typically through high-risk activities such as unprotected sexual intercourse or intravenous drug use. In 2009 in the US, the largest percentage (15% of all diagnoses) and the highest rate (36.9 per 100,000 population) were in persons aged 20–24 years.[72]

Children may become infected by transplacental transmission or by breastfeeding. Rare cases of children infected after sexual abuse by HIV-infected adults have also been reported.

Prognosis

The prognosis in patients with untreated HIV infection is poor, with an overall mortality rate of more than 90%. The average time from infection to death is 8-10 years, although individual variability ranges from less than 1 year to long-term nonprogression. Many variables have been implicated in HIV's rate of progression, including CCR5-delta32 heterozygosity, mental health,[79] concomitant drug or alcohol abuse, superinfection with another HIV strain, nutrition, and age.

There is less evidence that treatment of HIV-2 infection slows progression, and certain antiretroviral medications (specifically the non-nucleoside–analogue reverse-transcriptase inhibitors) are not effective against HIV-2. The HIV-1 viral-load assays are much less reliable at quantifying HIV-2, if they work at all. HIV-2 viral load assays have been developed, but none has been approved by the US Food and Drug Administration except as blood donor–screening tools.

Once infection has progressed to AIDS, the survival period is usually less than 2 years in untreated patients. Persons in whom the infection does not progress long-term may not develop AIDS for 15 years or longer, although many still exhibit laboratory evidence of CD4 T-cell decline or dysfunction.[80, 81, 82, 83]

The appropriate use of combination antiretroviral therapies and prophylaxis for opportunistic infections dramatically improves survival and greatly decreases the risk of secondary opportunistic infections.[84, 85, 86] The risk of AIDS-associated lymphoma is not altered by antiviral therapy and, as such, has grown in prevalence among overall AIDS-defining conditions.

Sackoff et al found that between 1999 and 2004, the HIV-related mortality rate in New York City decreased each year by approximately 50 deaths per 10,000 people with AIDS. The rate of non–HIV-related deaths also showed a decline, more modest but consistent, with about 7.5 fewer deaths per 10,000 people with AIDS per year.[85]

Importantly, many researchers have consistently shown that the primary risk factor for infection affects mortality. For example, the mortality rate among intravenous drug users tends to be higher, whether related to HIV disease or non-HIV disease.

Overall, with the increasing use of antiretroviral therapy and the introduction of better antiviral regimens, survival with HIV infection has increased over time, although it is not yet equivalent to that in uninfected individuals. (See the image below.)

Changes in survival of people infected with HIV. A Changes in survival of people infected with HIV. As therapies have become more aggressive, they have been more effective, although survival with HIV infection is not yet equivalent to that in uninfected people. Modified from Lohse N et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007;146(2):87-95.

In addition to the concern for new opportunistic infections, pre-existing infections can reactivate and cause significant disease in people with AIDS. The most important example on a global scale is that of tuberculosis, as reactivated tuberculosis can cause symptomatic disease with lower levels of reactivation.

Other important pathogens include cytomegalovirus, (which causes retinitis, pneumonitis, and colitis) and Pneumocystis jiroveci (formerly known as Pneumocystis carinii; the causative organism in Pneumocystis pneumonia). In immunocompetent hosts, these organisms are generally nonpathogenic, and asymptomatic infection is common (and in the case of cytomegalovirus infection, life-long).

Antiviral medications are associated with adverse effects and thus contribute to patient morbidity and mortality rates, especially because of the growing population of long-term survivors who are receiving combination antiviral therapy. In particular, protease inhibitors may cause lipid-profile abnormalities.

In a study of 6,036 HIV-infected patients who had achieved suppression of HIV with antiretroviral therapy, researchers found that the incidence of non-Hodgkin lymphoma (NHL) remained high (171 per 100,000 person-years [PY]), far exceeding the rate of approximately 10 to 20 per 100,000 person-years reported in HIV-uninfected populations. The high incidence of NHL was observed even in patients with nadir CD4 cell count > 200 cells/μl (140 per 100,000 PY). After adjustment for older age, white race, male sex, HCV coinfection, and time-varying CD4 cell count, the risk of NHL risk was higher when HIV viremia was above the limit of detection (50 copies/mL) in a dose-dependent manner.[87, 88]

Patient Education

Patients with HIV infection should be counseled about the risks of infecting their sexual partners with HIV. Safer sex practices and treatment of concurrent sexually transmitted diseases, both in the patient and in sexual partners, considerably reduces the risk of transmission. Patients with HIV infection should be encouraged to inform their sexual partners of their status; failure to do so has resulted in successful prosecutions in several countries. Sexual contacts should be tested.

Some HIV-infected people actively seek out other persons with HIV infection for sex under the assumption that they are not putting themselves or anyone else at an increased risk. However, it is clear that co-infections with multiple HIV strains (whether the same or different clades) can and do occur, and that such events may result in a rapid deterioration of a previously stable infection. A growing number of new infections are drug resistant upon first presentation, suggesting that these infections were transmitted from individuals receiving therapy.

Higher viral loads in the source partner are associated with higher transmission rates; thus, because barrier contraception is imperfect (although by far the best method to prevent sexual transmission), good control of viral load is important.

Intravenous drug users should be counseled on the risks of sharing intravenous drug paraphernalia.

For patient education information, see the Infections Center and Sexual Health Center, as well as HIV/AIDS and Rapid Oral HIV Test.

 

Presentation

History

The history should be carefully taken to elicit possible exposures to human immunodeficiency virus (HIV). Risk factors include the following:

  • Unprotected sexual intercourse, especially receptive anal intercourse (8-fold higher risk of transmission)

  • A large number of sexual partners

  • Prior or current sexually transmitted diseases (STDs): Gonorrhea and chlamydia infections increase the HIV transmission risk 3-fold, syphilis raises the transmission risk 7-fold, and herpes genitalis raises the transmission risk up to 25-fold during an outbreak

  • Sharing of intravenous drug paraphernalia

  • Receipt of blood products (before 1985 in the United States)

  • Mucosal contact with infected blood or needle-stick injuries

  • Maternal HIV infection (for newborns, infants, and children): Steps taken to reduce the risk of transmission at birth include cesarean delivery and prenatal antiretroviral therapy in the mother and antiretroviral therapy in the newborn immediately after birth.

The patient may present with signs and symptoms of any of the stages of HIV infection. Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash. The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom.

AIDS manifests as recurrent, severe, and occasionally life-threatening infections and/or opportunistic malignancies. The signs and symptoms are those of the presenting illness, meaning that HIV infection should be suspected as an underlying illness when unusual infections present in apparently healthy individuals.

HIV infection itself does cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause).

Physical Examination

No physical findings are specific to HIV infection. The physical findings are those of the presenting infection or illness. Generalized lymphadenopathy is common. Weight loss may be apparent.

Evidence for risk factors or minor concurrent opportunistic infections (eg, herpetic lesions on the groin, widespread oral candidiasis) may be clues to HIV infection.

 

DDx

Diagnostic Considerations

Human immunodeficiency virus (HIV) infection should be considered in any patient with unusual or recurrent serious infections without another cause, especially in those with risk factors for HIV infection.

Any of the opportunistic infections or cancers associated with acquired immune deficiency syndrome (AIDS) can also occur in the absence of HIV infection, although they usually develop in patients with some other form of immune suppression or defect. The possibility of HIV infection must be considered on a case-by-case basis. Other causes of immune suppression (eg, chemotherapy, immune disorders, severe combined immune deficiency [SCID], severe malnutrition) should be considered. For example, a young adult with leukemia undergoing chemotherapy is at high risk for many opportunistic infections.

Differential Diagnoses

 

Workup

Approach Considerations

Screening for human immunodeficiency virus (HIV) infection is paramount, since infected individuals may remain asymptomatic for years while the infection progresses. Serologic tests are the most important studies in the evaluation for HIV infection.

Secondary testing that may be performed to assist with diagnosis or staging includes the following:

  • Viral culture

  • Lymph node biopsy

  • Proviral DNA polymerase chain reaction (PCR)

  • Genotyping of viral DNA/RNA

In June 2014, the Centers for Disease Control and Prevention (CDC) issued new recommendations for HIV testing in laboratories that are aimed at reducing the time needed to diagnose HIV infection by as much as 3-4 weeks over previous testing approaches. The new testing algorithm is performed as follows[89, 90] :

  • Diagnosis starts with a fourth-generation test that detects HIV in the blood earlier than antibody tests can; it identifies the viral protein HIV-1 p24 antigen, which appears in the blood before antibodies do

  • If this test is positive, an immunoassay that differentiates HIV-1 from HIV-2 antibodies should be performed; results from such assays can be obtained faster than they can from the Western blot test

  • In patients with positive results on the initial antigen test but with negative or indeterminate results on the antibody differentiation assay, HIV-1 nucleic acid testing should be performed to determine whether infection is present

In August 2013, the FDA approved the Alere Determine HIV-1/2 Ag/Ab Combo test (Orgenics, Ltd), the first rapid HIV test for the simultaneous detection of HIV-1 p24 antigen as well as antibodies to both HIV-1 and HIV-2 in human serum, plasma, and venous or fingerstick whole blood specimens. Detection of HIV-1 antigen permits earlier detection of HIV-1 infection than is possible by testing for HIV-1 antibodies alone.[6, 7]

This rapid test can be used in outreach settings to identify HIV-infected individuals who might not be able to be tested in traditional health care settings. The test does not distinguish between antibodies to HIV-1 and HIV-2, and is not intended to be used for screening of blood donors.[6, 7]

Staging of HIV disease is based partially on clinical presentation, but other laboratory tests can help in deciding whether to initiate or modify treatment.

Baseline laboratory studies for other infections (eg, tuberculosis) are important in the initial workup of a patient with newly diagnosed HIV infection. In addition, baseline levels of factors that may be affected by antiretroviral therapy (eg, lipids) should be measured.

Screening for HIV Infection

The U.S. Preventive Services Task Force (USPSTF) strongly recommends that clinicians screen for HIV in all adolescents and adults at increased risk for HIV infection, and all pregnant women.[1]

The American College of Obstetricians and Gynecologists recommends that all females aged 13-64 years be tested for HIV at least once during their lifetime.[91, 92] Retesting annually or more often is recommended for those at high risk because of injection drug use, sex with an injection drug user, sex for money or drugs, sex since their most recent HIV test with men who have sex with men, or sex since their most recent HIV test with more than 1 person.

Guidelines issued in 2015 on HIV testing during pregnancy by the American College of Obstetricians and Gynecologists are as follows:[93, 94]

  • Women should be tested for HIV during routine prenatal testing, on an opt-out basis when possible.
  • Women at high risk for HIV infection, including injection drug users and women with multiple sex partners during their pregnancy, should be retested in their third trimester.
  • Women who have not been tested should be offered rapid screening when in labor; if the rapid test result is positive, antiretroviral therapy should be initiated while awaiting results of a confirmatory test.
  • All pregnant women should be screened for HIV infection as early as possible during each pregnancy using the opt-out approach when allowed.
  • Repeat HIV testing in the third trimester is recommended among women in areas with high HIV incidence or prevalence and among women known to be at risk for acquiring HIV infection.
  • Women who were not tested earlier in pregnancy or whose HIV status is otherwise undocumented should be offered rapid screening upon labor and delivery using the opt-out approach when allowed.
  • If a rapid HIV test result in labor is reactive, antiretroviral prophylaxis should be immediately initiated while awaiting supplemental test results.
  • If the diagnosis of HIV infection is established, the woman should be linked into ongoing care with a specialist in HIV care for comanagement.

The Centers for Disease Control and Prevention (CDC) recommends HIV screening for patients in all health-care settings, after the patient is notified that testing will be performed unless the patient declines (opt-out screening); the CDC recommends that persons at high risk for HIV infection be screened for HIV at least annually.[2]

Citing the benefits of early diagnosis and treatment and the failure of risk-based screening to identify a substantial proportion of HIV-infected patients early in the disease, the American College of Physicians recommends that clinicians adopt routine screening for HIV and encourage all patients to be tested.[3]

Screening assays

A high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) should be used for screening. Most ELISAs can be used to detect HIV-1 types M, N, and O and HIV-2.

A positive ELISA result should be followed with confirmatory testing in the form of one or more Western blot assays or similar specific assay. Specific diagnostic criteria vary by test. Results are typically reported as positive, negative, or indeterminate.

Testing for HIV-2 should be ensured for patients from an HIV-2 endemic area or those who have indeterminate results on HIV-1 Western blot testing. Not all HIV tests include detection of HIV-2 or Group O. In New York City, 62 cases of HIV-2 were detected over an 8-year period, of which 40 were initially misdiagnosed as HIV-1.[95]

Early detection using combination screens may be more effective than simply using serology. The additional detection of p24 antigen or viral RNA may detect a greater number of very recent infections before seroconversion occurs. This would likely result in significant reductions in transmission as well as overall health costs and healthcare burden.[96]

To address the problem of confirmatory supplemental tests giving false-negative results early in the course of HIV infection, the CDC conducted two prospective evaluations of a new HIV diagnostic algorithm. The new diagnostic algorithm replaces the Western blot (WB) with an HIV-1/HIV-2 antibody differentiation assay as the supplemental test and includes an RNA test to resolve reactive immunoassay (IA) with negative supplemental test results.[97]

CD4+ T-cell Count

The CD4 T-cell count is a reliable indicator of the current risk of acquiring opportunistic infections. CD4 counts vary, and serial counts are generally a better measure of any significant changes. The reference range for CD4 counts is 500-2000 cells/μL. After seroconversion, CD4 counts tend to decrease (around 700/μL on average) and continue to decline over time. For surveillance purposes, a CD4 count under 200/μL is considered AIDS-defining in the United States owing to the increased risk of opportunistic infections at this level. The magnitude of discordance between absolute CD4 T-cell numbers and CD4 T-cell percentages is greatest in those with active hepatitis C virus and more advanced liver disease.[98]

In children under five years of age, the CD4 T-cell percentage is considered more important than the absolute count. (Less than 25% is considered worthy of starting therapy, regardless of the total CD4 count). In adults with chronic hepatitis C and low absolute CD4 T-cells, the CD4 percentage may also be more useful, due to probable T-cell sequestration in the liver.[4]

Viral Load

Viral load in peripheral blood is used as a surrogate marker of viral replication rate. This is a surrogate because most of the viral replication occurs in the lymph nodes rather than in the peripheral blood.

The test is a quantitative amplification of the viral RNA using nucleic acid sequence-based amplification (NASBA), reverse-transcription polymerase chain reaction (RT-PCR), or similar technologies. Quantitative viral-load assays should not be used as a diagnostic tool because several false-positive misdiagnoses have been reported in the literature.

The rate of progression to AIDS and death is related to the viral load, although, on an individual level, it is poorly predictive of the absolute rate of CD4 T-cell loss. Patients with viral loads greater than 30,000/μL are 18.5 times more likely to die of AIDS than those with undetectable viral loads.

With therapy, viral loads can often be suppressed to an undetectable level (ie, < 20-75 copies/mL, depending on the assay used); this is considered optimal viral suppression. At the same time, the CD4 count rises and the risk of opportunistic infections and death is reduced. Complete inhibition of viral replication appears impossible and may be unnecessary.

Not uncommonly, successfully treated patients will demonstrate intermittent viremia, with viral loads transiently detectable at low levels (typically, < 400 copies/mL); this appears to occur more commonly with some viral load assays than others. Such “blips” are not thought to represent viral replication or to predict virologic failure.[5] Virologic failure is defined as a confirmed viral load of more than 200 copies/mL; although this is a research definition, it may be useful in clinical practice.[5]

Secondary HIV Testing

Viral culture is expensive and time-consuming and is less sensitive in patients with low viral loads. Viral culture may be performed as part of phenotypic drug-resistance testing.

Lymph node architecture is disrupted during HIV infection. HIV DNA, RNA, and proteins may be detected with molecular techniques, and electron microscopy may reveal virions.

Proviral DNA PCR is usually performed only in newborns because conventional serologic testing is useless in these patients (maternal antibodies may persist for 9 months or longer). Two or more negative results separated by at least one month is considered a negative result.

Genotyping of viral DNA/RNA can guide therapy. Because patterns of mutations that lead to resistance to specific drugs or drug classes are now well-recognized, sequencing of the viral genome allows for the selection of specific antivirals that are more likely to elicit a response.

Baseline Studies

Baseline studies for other infections that are important in the initial workup of a patient with newly diagnosed HIV infection include the following:

  • Purified protein derivative (PPD) skin testing for tuberculosis

  • Cytomegalovirus (CMV) testing

  • Syphilis testing

  • Rapid amplification testing for gonococcal and chlamydial infection

  • Hepatitis A, B, and C serology

  • Anti-Toxoplasma antibody

  • Ophthalmologic examination

A purified protein derivative skin test is placed to evaluate for tuberculosis infection. Chest radiography should be performed in patients with a positive PPD test result.

Serology should be performed to test for CMV infection. The presence of anti-CMV IgG indicates previous exposure to CMV. Ophthalmologic examination is used to evaluate for CMV retinitis in people with very low CD4 T-cell counts.

For syphilis screening, rapid plasma reagent (RPR) testing can be used initially, but more specific testing should be used for follow-up, as RPR can yield false-positive results. Lumbar puncture is used to evaluate neurologic symptoms.

Rapid amplification testing is used to evaluate for gonococcal infection and chlamydia in cases of sexual HIV transmission. Pelvic examination is performed in females (with wet mount for trichomoniasis).

Hepatitis A, B, and C serology is performed to determine the need for vaccination or treatment and to evaluate for chronic infection. Patients infected with hepatitis C may be candidates for treatment. Genotyping and baseline liver function tests are crucial.

Anti-Toxoplasma antibody is measured to determine whether patients have had toxoplasmosis, and thus are at risk for reactivation of infection in the event of immunocompromise. Patients with prior Toxoplasma infection require prophylaxis if their CD4+ T-cell counts drop below 100/µL.

Tests to establish baseline values of factors that may be affected by antiretroviral therapy include the following:

  • Liver function tests

  • Serum chemistries

  • Blood urea nitrogen (BUN)/serum creatinine

  • Fasting lipid panel

  • Vitamin B12 and folate levels

  • Thyroid function studies[99]

Other tests include urinalysis to evaluate for HIV-associated nephropathy and a drug screen to effectively exclude other metabolic and infectious etiologies.[100]

Histologic Findings

Certain histologic findings are characteristic of various features of HIV infection and AIDS. The lymph node architecture is progressively disrupted; this can be reversed with effective antiviral therapy. Findings include hyperplasia, multinucleated syncytia of T cells, and loss of the normal follicular dendritic network. Nucleic acid or immunohistochemical stains for viral antigens shows virus localizing to macrophages, T cells, and dendritic cells. Electron microscopy may reveal virions or intracellular virus within phagosomes in macrophages.

Multinucleated giant cells are a characteristic finding in patients with HIV encephalopathy. Myelin pallor and microgliosis may also be observed.

Staging

The CDC classifies HIV infection into 3 categories, according to the presence of certain infections or diseases.[8] These conditions may be exacerbated by the HIV infection or represent true opportunistic infections.

Category A is asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions.

Category B is HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection. These include, but are not limited to, the following:

  • Bacillary angiomatosis

  • Oropharyngeal candidiasis (thrush)

  • Vulvovaginal candidiasis, persistent or resistant

  • Pelvic inflammatory disease (PID)

  • Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

  • Oral hairy leukoplakia

  • Idiopathic thrombocytopenic purpura

  • Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting more than 1 month

  • Peripheral neuropathy

  • Herpes zoster (shingles), involving 2 or more episodes or 1 or more dermatomes

Category C is HIV infection with AIDS-defining opportunistic infections, as outlined in Pathophysiology.

These 3 categories are further subdivided based on the CD4+ T-cell count. Categories A1, B1, and C1 are characterized by CD4+ T-cell counts greater than 500/µL. Categories A2, B2, and C2 are characterized by CD4+ T-cell counts between 200/µL and 400/µL. HIV infections in patient with CD4+ T-cell counts under 200/µL are designated as A3, B3, or C3.

Importantly, once an HIV infection has been staged into a higher clinical category, it remains in that category permanently. In addition, the infection is classified based on the lowest CD4+ T-cell count in that patient.

For example, if a given HIV-positive patient recovers from a bout of Pneumocystis pneumonia (PCP) and the CD4+ T-cell count improves from 50/µL to 250/µL, that patient’s HIV infection remains classified as C3. Persons with A3, B3, and C1-3 HIV infection are considered to have AIDS. This is important to recognize, as this designation is not based solely on the previous occurrence of opportunistic infections but rather on the current risk of infection based on a reduced CD4+ T-cell count.

 

Treatment

Approach Considerations

The treatment of human immunodeficiency virus (HIV) disease depends on the stage of the disease and any concomitant opportunistic infections.[5] In general, the goal of treatment is to prevent the immune system from deteriorating to the point that opportunistic infections become more likely. Immune reconstitution syndrome is also less likely in patients whose immune systems are weakened to this point.

Highly active antiretroviral therapy (HAART) is the principal method for preventing immune deterioration. In addition, prophylaxis for specific opportunistic infections is indicated in particular cases.

Successful long-term HAART results in a gradual recovery of CD4 T-cell numbers and an improvement of immune responses and T-cell repertoire (previously lost antigen responses may be restored). The peripheral T-cell counts initially surge after therapy is initiated, but this represents redistribution of activated T cells from the viral replication centers in the lymph nodes rather than a true increase in total-body CD4 T-cell counts.[101, 102]

In addition to virologic response and reduced risk of opportunistic infection, there is evidence to suggest that non-AIDS-defining illnesses, in particular psychiatric and renal disease, may also be reduced when on HAART. Although multifactorial in nature (transmission mode and patient educational level are independent risk factors for these events) there may also be a direct role of HIV in these events, or an indirect role mediated through the subsequent immune dysfunction. Some non-AIDS-defining illnesses, such as liver and cardiovascular disease, are not improved by HAART.[103]

Treatment guidelines for HIV infection are age-specific. Guidelines for pediatric populations are compiled by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children; guidelines for adults and adolescents are compiled by the Panel on Clinical Practices for Treatment of HIV Infection. Complete treatment guidelines may be viewed at the National Institutes of Health Web site.

For discussion of antiretroviral drugs and regimens, see Antiretroviral Therapy for HIV Infection.

Primary care interventions

The Infectious Diseases Society of America (IDSA) issued updated guidelines in November 2013 for the management of HIV infection.[104, 105] Because of advances in management, HIV-infected patients are now having fewer complications and surviving longer; as a result, they are increasingly experiencing common health problems seen in the general population, and these problems must be addressed. Accordingly, the updated IDSA guidelines emphasize the role of primary care interventions, as follows:

  • HIV-infected individuals should undergo screening for diabetes, osteoporosis, and colon cancer as appropriate and should be vaccinated against pneumococcal infection, influenza, varicella, and hepatitis A and B

  • Lipid monitoring and management of lipids and other cardiovascular risk factors should be performed

  • Patients with well-controlled infection should undergo blood monitoring for viral levels every 6-12 months

  • Women with HIV should undergo annual trichomoniasis screening, and all infected patients who may be at risk should undergo annual screening for gonorrhea and chlamydia

HAART Studies and DHHS Guidelines

The introduction of HAART has significantly improved mortality rates. One study of nearly 7000 men with HIV infection found that annual mortality rates decreased from 7% in 1996 to 1.3% in 2004, although the findings highlighted the fact that non–AIDS-related illnesses were accounting for a greater proportion of deaths.[86]

These findings were repeated in another, more recent study of over 83,000 people with AIDS in the United States from 1990-2006,[106] which showed that cancers as a cause of mortality decreased overall but increased as a percentage of deaths, with non-Hodgkin lymphoma being the most common AIDS-related cancer and lung cancer being the most common non–AIDS-related cancer.

A National Cancer Institute study attributed increased non-AIDS-defining cancer mortality to the 4-fold expansion in the HIV-infected population in the United States, which was largely driven by greater numbers of people aged 40 years and older.[107]

Treatment failures are most closely related to the timing of therapy initiation (and, therefore, of timeliness of diagnosis). CD4 counts under 200/μL and evidence for AIDS (in the form of cytomegalovirus retinitis) are strong predictors of mortality (risk ratios of 2.7 and 1.6, respectively).[108]

Research data led to US guidelines recommending that antiretroviral therapy be initiated at a CD4 count threshold of 350/μL, although 2013 guidelines from the World Health Organization (WHO) now recommend a threshold of 500/μL.[109, 110] They also state that in some cases, antiretroviral treatment should begin immediately, regardless of the CD4 count, including in HIV-positive serodiscordant couples, patients with hepatitis-B coinfection, pregnant or breastfeeding women, and children under age 5 years.[109, 110]

Updated 2013 guidelines from the European AIDS Clinical Society (EACS) advise that antiretroviral drugs be considered and actively discussed even with asymptomatic patients with HIV whose CD4 count is still higher than 500/μL.[111, 112] In addition, they address diagnosis and management of comorbid conditions, including the following:

  • Hypertension

  • Type 2 diabetes

  • Bone disease - Osteopenia, osteoporosis, osteomalacia, and osteonecrosis (fracture reduction is a newly addressed topic in the guidelines)

  • Dyslipidemia

  • Vitamin D deficiency

  • Kidney disease - Antiretroviral drug–associated nephrotoxicity, proximal renal tubulopathy

  • Liver disease - Increased liver enzymes, cirrhosis, hepatorenal syndrome

  • Lipodystrophy

  • Hyperlactemia and lactic acidosis

  • Sexual dysfunction (a new topic in the guidelines)

  • Depression

Studies on the initiation of antiretroviral therapy

An analysis of a series of 18 prospective cohort studies in the United Kingdom found that deferring combination antiretroviral therapy until patients reached a CD4 cell count of 251-350 cells/μL was associated with higher rates of AIDS and death than starting therapy at 351-450 cells/μL. The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. The researchers suggested than the minimum threshold for initiating treatment should be 350 CD4+ T cells/μL rather than 200/μL.[113]

This finding was echoed in a Haitian study (a resource-limited setting), where early initiation of antiretroviral therapy significantly decreased the rates of death and incident tuberculosis. Initiating antiretroviral therapy treatment during early phases of disease (CD4+ T-cell count between 200/μL and 350/μL) was found to increase survival in Haitians compared with waiting until CD4+ T cells fell below 200/μL.[114]

The HIV-CAUSAL Collaboration analyzed data from the United States Veterans Health Administration and HIV clinics in Europe to compare the results of therapy initiation at CD4 cell counts from 0.200-0.500 × 109 cells/L. The study concluded that initiating HAART therapy at the 0.350 × 109 cells/L threshold decreased AIDS-free survival compared with initiation at 0.500 × 109 cells/L, but did not substantially increase mortality. A significant rise in mortality was seen at initiation thresholds below 0.300 × 109 cells/L. This result differs from other studies. Because CD4 cell count at initiation is not randomized in such observational cohort studies, confounding factors may exist.[115]

The first randomized controlled trial to investigate the question of when to initiate therapy was the NIH Comprehensive International Program of Research on AIDS (CIPRA) HT 001 clinical study. This work showed that starting antiretroviral therapy at CD4+ T-cell counts between 200 and 350 cells/µL improves survival compared with deferring treatment until the CD4+ T-cell count drops to less than 200 cells/µL (the standard of care at the time).

Interim analysis of CIPRA HT 001 showed that of 816 HIV-infected adults with early HIV disease, 6 of those who began antiretroviral therapy within 2 weeks of enrollment (early treatment) died, while 23 participants in the standard-of-care group died.[116] Among participants who began the study without tuberculosis infection, 18 individuals in the early treatment group developed tuberculosis, while 36 people in the standard-of-care group developed tuberculosis.

These interim results were statistically significant and led to ending the trial early to offer antiretroviral therapy to all participants in the standard-of-care group with a CD4+ T-cell count of less than 350 cells/µL.

One study has suggested that extremely early initiation of antiretroviral therapy during this acute seroconversion period (within 2 weeks of converting) may result in better long-term CD4 counts and steady-state viral load. Although the numbers were small, acutely-treated individuals had a mean of 0.48 Log10 copies/ml lower viral load, and higher CD4 counts (average 112 cells/µL) than an untreated cohort. The effects were less pronounced and lasted for a shorter time for patients with an “early” initiation of therapy (within 2 weeks to 6 months of seroconversion).[117]

There have been attempts made to characterize the timeframe of seroconversion, especially in patients without a clear source of exposure which can be dated accurately. Although imperfect, algorithms based on the number of Western Blot bands and the actual ELISA signal compared to the positive cutoff may have some utility here.[118]

Therapy initiation recommendations in the United States

In July 2014, the International Antiviral Society-USA (IAS-USA) released antiretroviral treatment recommendations for adults, including the following:[119, 120]

  • Initiate ART in all HIV-infected adults who are willing/ready to start therapy. CD4 count is no longer considered a criterion of when to start therapy.
  • Consider NRTI-sparing approaches rather than boosted protease inhibitor monotherapy.
  • For refractory cases, during the failing treatment regimen and before switching therapy, use rapid confirmation, perform resistance testing, and reevaluate.

Antiretroviral agents

Classes of antiretroviral agents include the following:

  • Nucleoside reverse transcriptase inhibitors (NRTIs)

  • Protease inhibitors (PIs)

  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

  • Fusion inhibitors

  • CCR5 co-receptor antagonists (entry inhibitors)

  • HIV integrase strand transfer inhibitors

Current drug regimen recommendations

The April 2015 DHHS guideline lists the following regimens as preferred in treatment-naive patients:

  • INSTI-based regimens are as follows:
    • Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) - only for patients who are HLA-B*5701–negative
    • DTG plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)
    • Elvitegravir/cobicistat/TDF/FTC (EVG/c/TDF/FTC) - only for patients with pre-ART CrCl of >70 mL/min
    • Raltegravir (RAL) plus TDF/FTC
  • The PI/r-based regimen is darunavir/ritonavir (DRV/r) plus TDF/FTC
  • HIV-2 is intrinsically resistant to NNRTIs and enfuvirtide.

Women who become pregnant while taking antiretroviral agents should contact their physician and register with the Antiretroviral Pregnancy Registry

Regimen selection

Antiretrovirals should be prescribed by an infectious disease specialist. Antiretroviral regimen selection is individualized, on the basis of the following[5] :

  • Virologic efficacy

  • Toxicity

  • Pill burden

  • Dosing frequency

  • Drug-drug interaction potential

  • Drug resistance testing results

  • Comorbid conditions

Drug resistance testing typically involves genotyping or phenotyping of resistance in the patient's viral strains. The January 2011 DHHS guidelines recommend genotypic testing to guide the choice of initial therapy in antiretroviral-naïve patients, as well as in patients in whom first or second regimens produce a suboptimal virologic response or virologic failure. Phenotypic testing is generally added to genotypic testing when complex drug resistance mutation patterns, especially to protease inhibitors, are confirmed or suspected.[5]

Recent research on antiretroviral agents

A review of 2725 HIV isolates for protease inhibitor susceptibility helped delineate the specific contributions of various resistance mutations to each currently available protease inhibitor. The study revealed that certain mutations could result in increased susceptibility to a particular drug, and that some effects on resistance had been underestimated. The study concluded that cross-resistance between the various protease inhibitors now and in the future may be missed without systematic analysis of the effects of specific mutations.[121]

A study by Lennox et al in treatment-naive patients from 67 centers on 5 continents demonstrated benefits of raltegravir (another INSTI) over efavirenz (an NNRTI) as part of combination antiretroviral therapy.[122] Participants had viral RNA (vRNA) concentrations greater than 5000 copies/mL and demonstrated no baseline drug resistance to efavirenz, tenofovir, or emtricitabine. They were randomly assigned to receive raltegravir 400 mg bid (n=281) or efavirenz 600 mg daily (n=282).

The primary endpoint was a vRNA concentration of less than 50 copies/mL at week 48. In the raltegravir group, 86.1% achieved the primary endpoint, compared with 81.9% in the efavirenz group (difference 4.2%, 95% CI, -1.9 to 10.3). The time to viral suppression was shorter in the raltegravir group than in the efavirenz group. Significantly fewer adverse drug reactions were reported in the raltegravir group (44.1%) than in the efavirenz group (77%).[122]

Similarly, in a randomized, phase III, noninferiority trial of raltegravir-based treatment versus efavirenz-based therapy, in 563 treatment-naïve HIV-1–infected patients, the addition of raltegravir to tenofovir/emtricitabine, compared with the addition of efavirenz to tenofovir/emtricitabine, resulted in significantly greater vRNA suppression rates and increases in baseline CD4 counts at week 240. In addition, significantly fewer patients in the raltegravir group experienced neuropsychiatric and drug-related adverse events.[123]

A new INSTI, dolutegravir (Tivicay), was approved by the FDA in August 2013 for treatment of HIV-1 infection in combination with other antiretroviral agents in adults and children aged 12 years or older who weigh at least 40 kg. Approval was based on several studies showing evidence of virologic suppression in both treatment-naive and treatment-experienced patients on a daily regimen of the drug.[124, 125, 126, 127] Approval of dolutegravir for the indication in children aged 12 years or older was based on data in integrase-naïve patients.

Knowledge of resistance patterns in resource-limited areas is vital in the selection of first-line antiretroviral treatment. In a subset of the Development of Antiretroviral Treatment in Africa (DART) trial, the virological response to zidovudine-lamivudine plus abacavir (an NRTI) at 32 weeks was inferior to the response to zidovudine-lamivudine plus nevirapine (an NNRTI). HIV RNA levels were lower in the nevirapine group than in the abacavir group.

The authors concluded that first-line zidovudine-lamivudine plus abacavir therapy will eventually lead to extensive nucleoside analogue resistance and that continued research is needed to optimize first- and second-line therapies in resource-limited settings.[128]

Approval of the ART combination product elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) was based on analyses of 48-week data from 2 randomized, double-blind, active-controlled trials in treatment-naïve, HIV-1 infected individuals (n=1408). Results showed a single tablet regimen of Stribild met its primary objective of noninferiority compared to Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg) and to a regimen containing ritonavir-boosted atazanavir plus Truvada (emtricitabine/tenofovir).[129, 130]

In a study of 484 HIV-infected pregnant women, 3 short-term antiretroviral strategies, initiated simultaneously with the administration of single-dose nevirapine (sdNVP), resulted in a low rate (1.2%) of new NVP-resistance mutations. In the study, HIV-infected pregnant women were randomized to receive sdNVP and either zidovudine/lamivudine (3TC), tenofovir/emtricitabine (FTC), or lopinavir/ritonavir for either 7 or 21 days. According to theresults, 21-day antiretroviral regimens are better at preventing the emergence of minor NVP resistance variants compared to 7-day regimens. Of the 412 women who had primary endpoint results available, 4 of 215 in the 7-day arms had new NVP resistance (1.9%), whereas only 1 of 197 (0.5%) in the 21-day arms exhibited the same resistance.[131]

Prophylaxis for Opportunistic Infections

Prophylaxis for Pneumocystisjiroveci (a normally harmless commensal organism) is most important, as this causes a common, preventable, serious infection. In patients with CD4 counts of less than 200/μL, prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim) has been shown to prevent Pneumocystis pneumonia (PCP).

In patients whose CD4+ T-cell counts rise above 200/μL with effective therapy, PCP prophylaxis may be discontinued. When TMP-SMX cannot be used, alternatives include dapsone (after screening for glucose-6-phosphate dehydrogenase [G6PD] deficiency) and atovaquone or monthly nebulized pentamidine treatments.

TMP-SMX also prevents toxoplasmosis and should be administered when the CD4+ T-cell count drops to below 100/µL if the patient is not already receiving it to prevent PCP.

CD4+ counts below 50/µL place the patient at risk for Mycobacterium avium complex infection, and weekly azithromycin or clarithromycin is recommended as prophylaxis.

Prophylaxis for fungal or viral infections is not routinely necessary, but some have recommended fluconazole in patients with CD4+ T-cell counts under 50/µL to prevent candidal or cryptococcal infections and to protect against endemic fungal infections in geographic locales of hyperendemicity for histoplasmosis or coccidioidomycosis. However, the emergence of resistant Candida strains is a realistic concern.

Oral ganciclovir is indicated for prophylaxis of cytomegalovirus infection in patients with advanced AIDS and is about 50% effective in reducing invasive disease.[132] As with fluconazole, there are concerns about resistance, and prophylaxis should be reserved for those with CD4+ T-cell counts under 50/µL and evidence of previous cytomegalovirus infection.

Treatment of Opportunistic Infections

Treatment of opportunistic infections is paramount and should be directed at the specific pathogen. Although effective antiretroviral therapy reduces the risk of acquiring an opportunistic infection and reverses the effects of many opportunistic infections (eg, Kaposi sarcoma, cytomegalovirus retinitis), aggressive treatment of life-threatening or otherwise serious infections may necessitate a temporary stay of antiretroviral therapy to avoid drug interactions or cumulative toxicity.

With specific regard to TB, the relationship with antiretroviral therapy is complex. A large multi-national study found that the relative risk of acquiring TB after starting HAART was approximately half that of those in whom HAART was not started. However, there was evidence for immune reconstitution inflammatory syndrome (IRIS) in some patients co-infected with HIV and TB in the first few months of therapy. In addition, those older than 50, or with pretreatment CD4 T-cell counts less than 50/µL, were less likely to see the same reduction in TB incidence.[133]

Treatment of HIV-Associated Lipodystrophy

HIV lipodystrophy is a syndrome of abnormal central fat accumulation and/or localized loss of fat tissue that occurs in patients taking antiretroviral drugs. Tesamorelin (Egrifta), a growth hormone–releasing factor, was approved by the US Food and Drug Administration in 2010 to reduce excess visceral abdominal fat in HIV-infected patients with lipodystrophy.

FDA approval of tesamorelin was based on 2 studies in which visceral adipose tissue was significantly decreased from baseline at 26 weeks and sustained at 52 weeks.[134, 135, 136] These multicenter, randomized, double-blind, placebo-controlled phase 3 studies consisting of a 26-week main phase and a 26-week extension phase in 816 HIV-infected patients with excess abdominal fat associated with lipodystrophy. In phase III, randomized, double-blind studies that assessed the effect of tesamorelin on HIV-associated abdominal fat accumulation, a reduction in adiposity correlated with overall improved metabolic profiles of lipids and glucose.[137]

Suppressive Therapy for Herpes Simplex Virus 2 Infection

Most individuals infected with HIV-1 are also infected with herpes simplex virus type 2 (HSV-2). Suppressive therapy of HSV-2 with acyclovir reduces plasma HIV-1 concentrations. Lingappa et al found that acyclovir reduced risk for HIV-1 disease progression by 16% compared with placebo.[138] Disease progression was defined as first occurrence of CD4+ T-cell counts dropping below 200/μL.

In this study, patients (n=3381) who were dually infected with HSV-2 and HIV-1, had CD4+ cell counts of at least 250/μL, and were not taking antiretroviral therapy were randomized to receive either acyclovir 400 mg PO orally twice daily or placebo. In patients with CD4+ counts of 350/μL or more, acyclovir delayed risk of CD4+ counts falling below 350/μL by 19%. The use of acyclovir to suppress HSV-2 before initiating antiretroviral therapy merits further study to determine its effects on HIV-1 disease progression.

A second study of 440 people in Uganda showed that, in those with HIV and HSV-2 as well as HIV viral loads above 50,000, there was a significant delay in the progression to AIDS-defining illnesses or CD4 T-cell decline in the acyclovir group compared to placebo. Interestingly, no significant benefit was found for those with viral loads below 50,000.[139]

Treatment of HIV-Associated Diarrhea

In December 2012, the FDA approved crofelemer for the relief of diarrhea in patients with HIV/AIDS who are undergoing antiretroviral therapy.[9] However, before patients are treated with this drug, they should be properly tested to confirm that the diarrhea is not caused by an infection or a gastrointestinal (GI) disease.

Deterrence and Prevention of HIV Infection

On an individual level, the most effective methods for prevention of HIV infection include (1) avoidance of sexual contact outside a monogamous relationship, (2) the use of safer sex practices for all other sexual encounters, and (3) abstinence from nonmedical parenteral drug use.

In addition, measures can also be taken to prevent or deter HIV transmission risk from infected persons to noninfected individuals through behavioral, biomedical, and structural interventions aimed at reducing their infectiousness and their risk of exposing others to HIV. Such measures are detailed in the CDC's Recommendations for HIV Prevention With Adults and Adolescents With HIV in the United States, 2014.[140]

In March 2019, the CDC reported that approximately 80% of new US HIV infections are transmitted by 40% of persons with HIV infection. In 2016, persons unaware of their HIV infection (15% of the infected population) transmitted 38% of new HIV infections. Persons aware of their HIV infection but not receiving care (23% of the infected population) transmitted 43% of new HIV infections. Persons with HIV infection receiving care but not virally suppressed (11% of the infected population) transmitted 20% of new HIV infections. HIV-infected persons undergoing treatment with viral suppression (51% of the infected population) transmitted 0% of new infections.[141]

These findings suggest that increased HIV status awareness, HIV treatment initiation and sustained treatment compliance, effective viral suppression with ART, and prevention methods such as condom use and pre-exposure prophylaxis (PrEP) can greatly reduce the rate of new HIV infections.

Sexual transmission

Prevention measures include the following:

  • Abstinence when possible

  • Reduction in number of sexual partners

  • Using barrier contraception

  • Treatment of concurrent sexually transmitted diseases (STDs)

  • Testing of self and partner for HIV infection and other STDs

Concomitant infection with other STDs (eg, gonorrhea, herpes, syphilis) is the most well-known risk factor that predisposes to transmission of HIV. These STDs may cause mucosal ulcerations or tears or a higher concentration of inflammatory cells in the mucosa, which are targets for HIV infection. Comprehensive testing for these should be obtained when a sexual transmission is suspected or the source of infection is unknown, both in the patient and in sexual partners.

Certain sexual acts are more likely to lead to HIV infection than others. For example, fellatio carries the lowest risk of transmission (with very few case reports in the literature), while receptive anal intercourse carries the highest risk (a likelihood of approximately 1.5% per act with an infected individual).

An apparent effect of hormonal contraception on HIV transmission to and from women has been reported, with a slight but statistically significant increase in transmission involving women on hormonal contraception. In a study of 3790 serodiscordant couples from Africa, the hazard ratios for transmission were 1.98 to, and 1.97 from women on hormonal contraception. Although barrier contraception should be employed in instances of serodiscordance anyway, this finding further strengthens that recommendation in those couples where the female partner is using hormonal contraception.[142]

Vertical transmission

Prevention measures include the following:

  • Maternal testing

  • Effective control of maternal infection

  • Prenatal antiviral therapy and treatment of mother and infant during labor, delivery, and the neonatal period

  • Cesarean delivery

  • Avoidance of breastfeeding (unless local conditions make this unsafe or unfeasible)

A retrospective cohort study reviewed the records of 3,273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009. Patients were treated with triple antiviral therapy during pregnancy until 6 months postpartum for prevention of vertical transmission. Regardless of CD4 count, ART provided a protective effect against mortality, fetal demise, and premature birth.[143]

The prevention of mother-to-child transmission of HIV-2 is less certain than for HIV-1, from which most of the recommendations have been derived. Transmission of HIV-2 is less frequent (perhaps 10-fold less efficient), but HIV-2 is intrinsically resistant to the non-nucleoside RTI nevirapine, removing one option for pharmacologic prophylaxis at the time of delivery.

In a large French cohort study, the mother-to-child transmission rate of HIV-2 infection was 0.6%.[144] Transmission was related to poor control of HIV-2 infection in the mother or due to breastfeeding.

In the absence of definitive clinical trial data, the only definite conclusion is that effective control of maternal infection is paramount, and other nonspecific measures (identification of infected mothers, caesarean section, avoidance of breastfeeding) are probably effective at preventing transmission.

Empiric prophylaxis with zidovudine, as in HIV-1 infection, is probably warranted and effective but does not appear to be evidence-based.

Blood-borne transmission

Prevention measures include the following:

  • Blood-product and donor screening

  • Avoidance of reusing needles for intravenous drug abuse (needle-exchange programs are widespread in the developed world, but the evidence that they have had a significant effect is debatable)

Postexposure prophylaxis

The CDC has recommended basic and expanded HIV postexposure prophylaxis (PEP) regimens. For details, see the Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. Also see the Medscape Reference articles Antiretroviral Therapy for HIV Infection and Body Fluid Exposures.

An overview of the CDC recommendations for PEP are as follows:

  • Basic PEP 2-drug regimen: zidovudine plus lamivudine, zidovudine plus emtricitabine, tenofovir plus lamivudine, or tenofovir plus emtricitabine

  • Alternative basic PEP regimen: lamivudine plus stavudine, lamivudine plus didanosine, emtricitabine plus stavudine, or emtricitabine plus didanosine

  • Expanded PEP regimen: basic PEP regimen plus lopinavir-ritonavir

An alternative expanded PEP regimen includes the basic PEP regimen plus one of the following:

  • Atazanavir with or without ritonavir

  • Fosamprenavir with or without ritonavir

  • Indinavir with or without ritonavir

  • Saquinavir with or without ritonavir

  • Nelfinavir

  • Efavirenz

Use of nevirapine for PEP is generally not recommended because of a risk of early onset rash and severe hepatotoxicity.

Vaccination efforts

The initial hope of an effective vaccine against HIV has not been fulfilled. Aside from the virus being able to rapidly mutate antigenic portions of key surface proteins, HIV infection progresses despite the host’s humoral and cellular immune responses; therefore, any vaccination effect needs to surpass the normal host response to HIV.

A study from Thailand suggests a possible benefit of vaccines in heterosexuals at risk for HIV-1 transmission.[145] In the randomized, multicenter, double-blind, placebo-controlled trial by Rerks-Ngarm et al, 16,402 healthy participants aged 18-30 years received either 4 priming injections of recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus 2 booster shots of recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) or placebo.

In the per-protocol analysis, which excluded subjects who seroconverted during the vaccination series, the vaccine efficacy was 26.2%. In the modified-intention-to-treat analysis, which excluded subjects who had baseline HIV-1 infection, the vaccine efficacy was 31.2%. However, the 95% confidence intervals in these analyses were extremely wide (-13.3 to 51.9 and 1.1 to 52.1, respectively), which precludes concluding that the vaccine had proven efficacy.[145]

Among study subjects who developed HIV-1 infection, viremia and CD4+ T cell counts were unchanged by vaccination. This suggests that, if infection did occur, there was no apparent immunologic benefit from having received the vaccine.

With respect to risk behavior, a post-hoc analysis of efficacy found that the combination of the HIV vaccines, ALVAC-HIV (vCP1521) and AIDSVAX B/E, was more effective in those who maintained lower-risk sexual behavior compared to those that reported high or increasing-risk behavior.[146]

Preexposure prophylaxis

An innovative and controversial strategy for preventing HIV transmission is regular use of antiretroviral medications by uninfected individuals. An updated clinical practice guideline released in May 2014 by the CDC, extends recommendations for preexposure prophylaxis (PrEP) of HIV in high-risk patients.[147, 148] According to these guidelines, PrEP should be considered for the following non-HIV-infected individuals:

  • Anyone who is in an ongoing sexual relationship with an HIV-infected partner

  • A gay or bisexual man who has had sex without a condom or has been diagnosed with a sexually transmitted infection within the past 6 months and is not in a mutually monogamous relationship with a partner who recently tested HIV-negative

  • A heterosexual man or woman who does not always use condoms when having sex with partners known to be at risk for HIV and is not in a mutually monogamous relationship with a partner who recently tested HIV-negative

  • Anyone who, in the preceding 6 months, has injected illicit drugs and shared equipment or been in a treatment program for injection drug use

Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg (Truvada) has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults. Daily emtricitabine/tenofovir is one prevention option that is part of the general guidelines for HIV prevention. For more information, see Preexposure HIV Prophylaxis.

PrEP treatment guidelines include the following recommendations:

  • Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed; evidence level IA

  • The only medication regimen approved by the FDA and recommended for PrEP with all the populations specified in the CDC guideline is daily TDF 300 mg coformulated with FTC 200 mg (Truvada); evidence level IA

  • TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied; evidence level IC

  • Use of other ART medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended; evidence level IIIA

  • Oral PrEP for coitally-timed or other noncontinuous daily use is not recommended; evidence level IIIA

Interim CDC guidelines were issued in 2011 based on the multinational study called the Pre-exposure Prophylaxis Initiative (iPrEx) trial that found that once-daily emtricitabine plus tenofovir disoproxil fumarate (FTC-TDF) provided an additional 44% protection against HIV infection in a study population of 2499 high-risk, HIV-negative men or transgender women who have sex with men.[149]

Over a median 1.2 years of follow up, 36 patients in the FTC-TDF group and 64 in the placebo group became infected with HIV. All study subjects also received comprehensive prevention services that included monthly HIV testing, condom provision, counseling, and management of other STDs.[149]

Additional studies have been completed or are ongoing in serodiscordant heterosexual couples and intravenous drug users.[150, 151]

There remain policy considerations surrounding costs, opportunity costs, and ethical issues that must be addressed before broad implementation in the United States.[152] Potential drawbacks include the possibility that pre-exposure prophylaxis may encourage some recipients to practice less-safe sex; it does not address transmission of other STDs; and it could encourage the development of drug resistance.

Compliance is essential. In studies, the level of protection varied widely depending on how consistently participants used pre-exposure prophylaxis. Among those whose data (based on self-reports, bottles dispensed, and pill counts) indicate use on 90% or more days, HIV risk was reduced by 73%. Among those whose adherence by the same measure was less than 90%, HIV risk was reduced by only 21%.[153, 154]

Topical antivirals could potentially help with preventing transmission, but studies to date have failed to produce positive results. For example, a double-blinded, randomized, controlled trial of a vaginal microbicide gel with in vitro activity against HIV failed to show protective effects. The study involved 9385 women from South Africa, Tanzania, Uganda, and Zambia who used a synthetic naphthalene sulphonate polymer. Infection rates per 100 person-years were similar between groups (4.7 for 2% gel, 4.6 for 0.5% gel, and 3.9 for placebo).

IAS-USA guidelines

In July 2014, the International Antiviral Society-USA (IAS-USA) released new recommendations for HIV prevention in adolescents and adults in clinical care settings[155, 119] in conjunction with updated recommendations on antiretroviral treatment (ART) of adult HIV infection.[119, 120]

The IAS-USA panel suggested that combined biomedical/behavioral approaches to HIV prevention in clinical settings have the potential to not only prevent the disease but also cause nearly all HIV-infected individuals to become noninfectious.[155, 119] Among its key HIV-prevention recommendations for teens and adults are the following[155, 119] :

  • Perform HIV testing at least once for all adults and adolescents; repeat testing often for those at increased risk.

  • Be vigilant for potential HIV infection, and promptly perform diagnostic testing in those with suspected acute HIV infection.

  • For HIV-confirmed patients, provide multimodal interventions to include prompt initiation of ART, support for treatment adherence, individualized risk assessment and counseling, assistance with partner notification, and periodic screening for common sexually transmitted infections.

  • For high-risk, HIV-uninfected patients, administer preexposure prophylaxis with daily emtricitabine/tenofovir disoproxil fumarate and provide multimodal interventions (eg, individualized counseling on risk reduction).

  • Provide intravenous/injection drug users with multimodal harm reduction services such as access to needle/syringe exchange programs, supervised injection, medically assisted therapies, and detoxification programs.

  • Administer prompt postexposure prophylaxis in individuals with mucosal/parenteral HIV exposure from a known infected source.

Consultations

Consultation with an infectious disease or HIV specialist should be strongly considered for all new cases of HIV infection. Studies have clearly shown that the successful management of patients with HIV is related to the expertise and HIV caseload of the treating physician. In particular, pediatric cases of HIV infection are handled differently; cutoffs for CD4 counts at which prophylaxis would be recommended and antiviral drug availability (on- or off-study for experimental drugs or regimens) differ on the basis of age.

Input from an infectious disease consultant may be helpful in the management of other unrelated illnesses in patients infected with HIV.

Long-Term Monitoring

Guidelines from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents recommend performing the following tests every 3 months in patients on antiretroviral therapy[5] :

  • Basic chemistry profile

  • Liver function studies

  • Complete blood count with differential

The basic chemistry studies should include serum sodium, potassium, bicarbonate, chloride, blood urea nitrogen (BUN), and creatinine, and glucose (preferably fasting), plus an estimate of creatinine clearance. Fasting glucose is repeated every 3-6 months if abnormal at the last measurement, or every 6 months if normal at the last measurement.

A fasting lipid profile is measured every 6 months if abnormal at the last measurement, or every 12 months if normal at the last measurement.

In a clinically stable patient on an regimen whose viral load is suppressed and whose CD4+ T-cell count is well above the threshold for opportunistic infection risk, 2011 DHHS guidelines recommend that the CD4+ T-cell count may be monitored every 6-12 months (instead of every 3-6 months), unless there are changes in the patient’s clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents.[5]

 

Guidelines

CDC Guidelines on HIV Screening in Men Who Have Sex with Men

The following are guidelines on HIV screening among men who have sex with men (MSM)[156]

  • The CDC concludes that the evidence, programmatic experience, and expert opinions are insufficient to warrant changing the current recommendation of annual screening for men who have sex with men (MSM) to more frequent screening (every 3 or 6 months).
  • Providers in clinical settings should offer HIV screening at least annually to all sexually active MSM.
  • Clinicians can also consider the potential benefits of more frequent HIV screening (eg, every 3 or 6 months) for some asymptomatic sexually active MSM based on their individual risk factors, local HIV epidemiology, and local policies.
  • Among MSM who are prescribed preexposure prophylaxis, HIV testing every 3 months and immediate testing whenever signs and symptoms of acute HIV infection are reported is indicated.
  • MSM who experience a specific high-risk sexual exposure or have symptoms of recent HIV infection should seek immediate HIV testing, and clinicians should be alert for the symptoms of acute HIV infection and provide appropriate diagnostic testing.

European AIDS Clinical Society Guidelines on Antiretroviral Therapy and Chronic HIV Infection

Antiretroviral therapy (ART) is recommended in all adults with chronic HIV infection, irrespective of CD4 counts.

Human papillomavirus (HPV) vaccination is now recommended for all HIV-positive persons up to 26 years of age and up to 40 years of age for men who have sex with men (MSM).

All HIV-positive women of reproductive age should have a pregnancy test.

Screen for sexually transmitted infections (STIs) not only for those at risk, but also during pregnancy.

Pre-exposure prophylaxis (PrEP) should be used in adults at high risk of acquiring HIV infection when condoms are not used consistently.

Before PrEP is initiated, HBV serology status should be documented.

Intermittent tuberculosis (TB) regimens (2 or 3 times per week) are contraindicated in HIV-positive persons.

PrEP is recommended in HIV-negative MSM and transgender individuals when condoms are not used consistently with casual partners or with HIV-positive partners who are not on treatment. A recent STI, use of post-exposure prophylaxis, or chemsex may be markers of increased risk for HIV acquisition.

PrEP may be considered in HIV-negative heterosexual women and men who are inconsistent in their use of condoms and have multiple sexual partners, some of whom are likely to have HIV infection and not being on treatment.

Documented negative fourth-generation HIV test is recommended prior to starting PrEP. During PrEP, this test should be repeated every 3 months, and PrEP should be stopped immediately in case of early clinical signs of HIV seroconversion or a positive HIV diagnostic test and the person referred for evaluation to an HIV unit.

 

Medication

Medication Summary

Effective antiretroviral therapy is the most important intervention in terms of improving longevity and preventing opportunistic infections in patients with human immunodeficiency virus (HIV) infection. Therapy should involve combinations of drugs recommended by current guidelines. Recommendations are specific for various patient groups (eg, treatment naïve, treatment experienced, coinfection with hepatitis C).[5] Antiretroviral drug classes and agents within each class are listed in Table 1, below (see individual medication tables for more detail).

Many of the antiretroviral drugs that have been approved for HIV-infected adults and adolescents are gaining FDA approval for use in younger children. For more information, see Pediatric HIV Infection.

Of the antiretroviral drugs that have been approved, several are no longer being manufactured either because of the development of improved formulations (ie, amprenavir replaced by fosamprenavir) or because of limited use (ie, delavirdine and zalcitabine [ddC]).

Several combination products that contain tenofovir alafenamide (TAF) are now approved in the United States. TAF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than that of tenofovir DF, as well as an improved renal and bone safety profile.

Table 1. Antiretroviral Drug Classes and Agents (Open Table in a new window)

Nucleoside reverse transcriptase inhibitors (NRTIs)

Abacavir (Ziagen, ABC)

Didanosine (Videx, Videx EC, ddI)

Emtricitabine (Emtriva, FTC)

Lamivudine (Epivir, 3TC)

Stavudine (Zerit, Zerit XR, d4T)

Tenofovir DF (Viread, TDF)

Tenofovir AF (TAF)

Zalcitabine (Hivid, ddC)*

Zidovudine (Retrovir, ZDV, AZT)

Protease inhibitors (PIs)

Amprenavir (Agenerase, AVP)*

Atazanavir (Reyataz , ATV)

Darunavir (Prezista, DRV)

Fosamprenavir (Lexiva, f-APV)

Indinavir (Crixivan, IDV)

Lopinavir and ritonavir (Kaletra, LPV/r)

Nelfinavir (Viracept, NFV)

Ritonavir (Norvir, RTV)

Saquinavir (Invirase [hard gel] capsule, SQV)

Tipranavir (Aptivus, TPV)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine (Rescriptor, DLV)

Efavirenz (Sustiva, EFV)

Etravirine (Intelence, ETR)

Nevirapine (Viramune, NVP)

Rilpivirine (Edurant)

Doravirine (Pifeltro, DOR)

Fusion inhibitors

Enfuvirtide (Fuzeon, T-20)

Cellular chemokine receptor (CCR5) antagonists

Maraviroc (Selzentry, MVC)

Integrase inhibitors

Raltegravir (Isentress, RAL)

Dolutegravir (Tivicay, DTG)

Elvitegravir (Vitekta, EVG)

Entry inhibitors (post-attachment inhibitors) Ibalizumab

*No longer available on market

Combination therapy has been shown to dramatically reduce the likelihood of drug resistance (many drug-resistant mutations are mutually exclusive) and to suppress viral replication to the point that progression to AIDS is significantly slowed. Antiviral-resistance mutations often affect more than one drug simultaneously because of similar development pipelines and the ultimate molecular structure of the drug, and combination choices should account for this possibility.

Ritonavir, a PI that may be used in its own right, boosts blood levels of other PIs. This permits a reduced dosage of the coadministered drug. Various products have been formulated to include PIs combined with ritonavir.

Combination products

Numerous antiretroviral combination products are available on the market to assist patients with compliance and decrease the daily number of tablets and capsules required (see Table 2, below).

Table 2. Antiretroviral Combination Products (Open Table in a new window)

Drug Content per Tablet/Capsule*

Brand Name

Adult Dose (≥40 kg)

Darunavir 800 mg

Cobicistat 150 mg

Emtricitabine 200 mg

Tenofovir AF 10 mg

Symtuza# 1 tab PO qd with food

Bictegravir 50 mg

Emtricitabine 200 mg

Tenofovir AF 25 mg

Biktarvy# 1 tab PO qd

Efavirenz 400 mg

Lamivudine 300 mg

Tenofovir DF 300 mg

Symfi Lo# 1 tab PO qHS on an empty stomach

Efavirenz 600 mg

Lamivudine 300 mg

Tenofovir DF 300 mg

Symfi# 1 tab PO qHS on an empty stomach

Dolutegravir 50 mg

Rilpivirine 25 mg

Juluca#

1 tab PO qd with a meal

Note: This is a complete once-daily regimen in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance

Dolutegravir 50 mg

Lamivudine 300 mg

Dovato#

1 tab PO qd with or without food

Note: This a complete once-daily regimen in treatment-naïve adults with no known substitutions associated with resistance to dolutegravir or lamivudine

Elvitegravir 150 mg

Cobicistat 150 mg

Emtricitabine 200 mg

Tenofovir AF 10 mg

Genvoya# 1 tab PO qd

Elvitegravir 150 mg

Cobicistat 150 mg

Emtricitabine 200 mg

Tenofovir DF 300 mg

Stribild#

1 tab PO qd

Abacavir 600 mg

Lamivudine 300 mg

Epzicom

1 tab PO qd

Abacavir 600 mg

Dolutegravir 50 mg

Lamivudine 300 mg

Triumeq

1 tab PO qd

Abacavir 300 mg

Lamivudine 150 mg

Zidovudine 300 mg

Trizivir

1 tab PO bid

Efavirenz 600 mg

Emtricitabine 200 mg

Tenofovir DF 300 mg

Atripla#

1 tab PO qd on empty stomach

Note: May be used alone as a complete regimen or in combination with other ARTs

Emtricitabine 200 mg

Rilpivirine 25 mg

Tenofovir DF 300 mg

Complera#

1 tab PO qd with a meal

Emtricitabine 200 mg

Rilpivirine 25 mg

Tenofovir AF 25 mg

Odefsey#

1 tab PO qd with a meal

Emtricitabine 200 mg

Tenofovir DF 300 mg

Truvada

1 tab PO qd

CrCl 30-49 mL/min: 1 tab PO q48h

CrCl < 30 mL/min: Do not administer

Emtricitabine 200 mg

Tenofovir AF 300 mg

Descovy

1 tab PO qd

CrCl < 30 mL/min: Do not administer

Lamivudine 150 mg

Zidovudine 300 mg

Combivir

1 tab PO bid

Lamivudine 300 mg

Tenofovir DF 300 mg

Cimduo 1 tab PO qd

Doravirine 100 mg

Lamivudine 300 mg

Tenofovir DF 300 mg

Delstrigo# 1 tab PO qd with or without food

*Not indicated for patients requiring dosage adjustments (eg, weight < 40 kg, renal impairment, hepatic impairment, dose-limiting adverse effects) unless otherwise stated.

#Complete once-daily regimen

A subgroup analysis of black patients with HIV enrolled in the 48-week, open-label SPIRIT (Switching PI to Rilpivirine In-combination with Truvada) trial showed that switching from an antiretroviral regimen consisting of a boosted PI and ritonavir (RTV) plus 2 nucleoside/nucleotide reverse-transcriptase inhibitors (PI+RTV+2NRTIs) to a simplified once-daily, single-tablet regimen of rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) is safe and effective in this population.[157, 158]

Patients were randomized to undergo an immediate switch to RPV/FTC/TDF at baseline or to maintain their PI+RTV+2NRTIs regimen for 24 weeks and then switch to RPV/FTC/TDF for 24 weeks (delayed switch).

At 24 weeks, a subgroup analysis of black patients in the study showed that viral suppression rates (HIV-1 RNA < 50 copies/mL) were 95% in the RPV/FTC/TDF group and 91% in the group receiving PI+RTV+2NRTIs; ie, no significant difference existed. At 48 weeks, 89% of black patients in the immediate-switch group maintained viral suppression, compared with 95% of those in the delayed-switch group, which again was not considered a significant difference.[157, 158]

At 48 weeks, when all patients in the study were taken into account, there was no significant difference in viral suppression between the immediate-switch (89%) and delayed-switch (92%) groups; the rates of adverse events were similar in both groups as well.[157, 158] However, investigators noted significant improvement in lipid levels in patients who received the single-tablet RPV/FTC/TDF regimen.[158]

The FDA has approved a once-daily, fixed-dose triple-combination pill (Triumeq) containing the antivirals dolutegravir, abacavir, and lamivudine for the treatment of patients aged 18 years or older with HIV infection. The FDA based its approval primarily on the results of 2 studies, in one of which, a 96-week study in treatment-naive adults, virologic suppression occurred in 80% of patients receiving dolutegravir and abacavir/lamivudine (administered separately), compared with 72% of patients taking a single-pill regimen of efavirenz, emtricitabine, and tenofovir (Atripla).[159]

The FDA approved the NNRTI doravirine in August 2018. Also with this new drug, a complete regimen combination containing doravirine/lamivudine (3TC)/tenofovir DF (TDF) was also approved. Approval was based on the DRIVE-FORWARD clinical trial (n=766). Patients who were antiretroviral-naïve were randomly assigned to once-daily treatment with doravirine or darunavir 800 mg plus ritonavir 100 mg (DRV+r), each in combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC. Treatment with doravirine led to sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferiority compared with DRV+r, each in combination with FTC/TDF or ABC/3TC. At week 48, 84% of the doravirine group and 80% of the DRV+r group had plasma HIV-1 RNA levels of less than 50 copies/mL.[160]

The doravirine/3TC/TDF combination was approved based on data from the DRIVE-AHEAD trial (n=728). Patients who were antiretroviral-naïve were randomly assigned to once-daily treatment with doravirine/3TC/TDF or efavirenz (EFV)/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg). The doravirine/3TC/TDF combination provided sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferiority compared with EFV/FTC/TDF. At week 48, 84% of the doravirine/3TC/TDF group had plasma HIV-1 RNA levels of less than 50 copies/mL, as did 81% of the EFV/FTC/TDF group.[161]

Antiretroviral agent, nucleoside reverse-transcriptase inhibitor

Class Summary

NRTIs agents inhibit viral replication by inhibiting viral RNA–dependent DNA polymerase.

Abacavir (Ziagen)

This NRTI interferes with HIV viral RNA–dependent DNA polymerase and inhibits viral replication. Guidelines from the Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection recommends screening for HLA-B*5701 before starting patients on a regimen that contains abacavir, to reduce the risk of hypersensitivity reaction.

Didanosine (Videx, Videx EC)

Didanosine interferes with HIV viral RNA–dependent DNA polymerase and inhibits viral replication.

Emtricitabine (Emtriva)

This agent is a synthetic nucleoside cytosine analog classified as an NRTI. It competes with deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination.

Lamivudine (Epivir)

Lamivudine is a thymidine analog that inhibits viral replication.

Stavudine (Zerit, Zerit XR)

Stavudine competes with deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination.

Tenofovir disoproxil fumarate (Viread)

This agent inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. It is administered as the prodrug bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir, which is converted, through various enzymatic processes, to tenofovir, a nucleotide analog of adenosine 5'-monophosphate. Bioavailability is enhanced by a high-fat meal. Prolonged intracellular distribution allows for once-daily dosing.

This drug has shown substantial efficacy and safety in PReP trials with IV drug users and heterosexually active adults. CDC guidelines recommend tenofovir alone as an alternative regimen to emtricitabine/tenofovir for these populations, but not for MSM, among whom its efficacy has not been studied.

Zidovudine (Retrovir)

Zidovudine is a thymidine analog that inhibits viral replication.

Antiretroviral Agent, Protease Inhibitor

Class Summary

PIs inhibit protein precursors necessary for HIV infection of uninfected cells.

Atazanavir (Reyataz)

An azapeptide HIV-1 PI, atazanavir prevents virion maturation by selectively inhibiting Gag and Gag-Pol polyproteins in HIV-1–infected cells.

Darunavir (Prezista)

This HIV-1 PI selectively inhibits HIV-encoded Gag-Pol polyprotein cleavage in infected cells, thereby preventing mature virus particle formation. It is indicated for HIV disease that has not responded to treatment with other antiretroviral agents. Coadminister with low-dose ritonavir (ritonavir-boosted therapy decreases elimination and increases darunavir serum concentration).

Darunavir is typically coadministered with other anti-HIV agents (eg, NRTIs). Food increases maximum plasma concentration (Cmax) and area under the curve (AUC). This agent is indicated for HIV infection in antiretroviral treatment–experienced adults (eg, those with HIV-1 strains resistant to more than one PI).

Fosamprenavir (Lexiva)

Fosamprenavir is a prodrug that is converted to amprenavir by cellular phosphatases in vivo.

Lopinavir and ritonavir (Kaletra)

Lopinavir inhibits HIV protease and renders the enzyme incapable of processing polyprotein precursor, leading to production of noninfectious immature HIV particles. Ritonavir inhibits CYP3A metabolism of lopinavir, increasing plasma levels of lopinavir.

Nelfinavir (Viracept)

Nelfinavir inhibits HIV-1 protease, resulting in the production of an immature and noninfectious virus.

Indinavir (Crixivan)

Indinavir prevents formation of protein precursors necessary for HIV infection of uninfected cells and viral replication.

Ritonavir (Norvir)

This HIV PI is used as a part of double or triple therapy with nucleosides and other protease inhibitors.

Saquinavir (Invirase)

Saquinavir inhibits HIV protease and renders the enzyme incapable of processing polyprotein precursor, leading to production of noninfectious immature HIV particles.

Tipranavir (Aptivus)

A nonpeptidic PI that inhibits HIV replication. Indicated for combination antiretroviral treatment in adults with HIV-1 infection who have evidence of viral replication and who are highly experienced with treatment or who have HIV-1 strains that are resistant to multiple PIs.

Tipranavir must be coadministered with ritonavir (200 mg) to attain therapeutic levels (ie, tipranavir/ritonavir). Administration alone, without ritonavir-boosted levels, is not effective. Genotypic or phenotypic testing and/or treatment history should guide use.

Antiretroviral agent, non-nucleoside reverse-transcriptase inhibitor

Class Summary

NNRTIs inhibit viral replication.

Delavirdine (Rescriptor)

An NNRTI of HIV-1, delavirdine directly binds to reverse transcriptase and inhibits RNA- and DNA-dependent DNA polymerase.

Efavirenz (Sustiva)

Efavirenz is an NNRTI with activity against HIV-1. This agent binds to reverse transcriptase and blocks RNA-dependent and DNA-dependent DNA polymerase activities, including HIV-1 replication. Efavirenz does not require intracellular phosphorylation for antiviral activity.

Etravirine (Intelence)

Etravirine is an NNRTI of HIV-1 that binds directly to reverse transcriptase, causing catalytic site disruption. This action blocks RNA- and DNA-dependent DNA polymerase activities. Etravirine does not inhibit human DNA polymerases alpha, beta, or gamma.

This agent is indicated for use in combination with other antiretroviral agents for treatment-experienced HIV-infected adults who have viral replication and HIV-1 strains resistant to NNRTIs and other antiretroviral agents. If virologic failure was experienced with other NNRTIs, do not use etravirine in combination with NRTIs only.

Nevirapine (Viramune)

Nevirapine is an NNRTI that limits virus replication by a mechanism different from the nucleosidase inhibitors such as zidovudine and lamivudine.

Rilpivirine (Edurant)

Rilpivirine is a NNRTI that inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase. It does not inhibit the human cellular DNA polymerases alpha, beta, and gamma.

Doravirine (Pifeltro)

Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve adults.

Antiretroviral Agent, Integrase Inhibitor

Class Summary

This agent prevents insertion of a DNA copy of the viral genome into host cell DNA. It is indicated for HIV-1 infection combination therapy in treatment-experienced adults with evidence of viral replication and drug-resistant HIV-1 strains.

Raltegravir (Isentress)

Raltegravir was the first available agent in the class of integrase strand transfer inhibitors.

Dolutegravir (Tivicay)

Dolutegravir is an integrase strand transfer inhibitor (INSTI) that inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication. It is approved for use in children 12 years or older who weigh at least 40 kg.

Elvitegravir (Vitekta)

Integrase inhibitor that is used in combination with an HIV protease inhibitor (ie, atazanavir, lopinavir, darunavir, fosamprenavir, or tipranavir) and coadministered with ritonavir plus other antiretroviral drug(s) as indicated for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults. It was originally approved as part of the combination product elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild).

Antiretroviral Agent, Fusion Inhibitor

Class Summary

These agents disrupt the ability of HIV to fuse with and infect healthy T cells.

Enfuvirtide (Fuzeon)

This is the first agent in the new anti-HIV class called fusion inhibitors. Indicated for use in combination with other antiretroviral agents for HIV-1 infection in treatment-experienced patients who demonstrate evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Enfuvirtide binds to HIV gp41 surface protein, thereby, disrupting the virus's ability to fuse with and infect healthy T cells. In clinical trials, subjects were twice as likely to achieve undetectable HIV-1 plasma levels (eg, < 40 copies/mL) when enfuvirtide was added to antiretroviral optimized regimens than without enfuvirtide added to therapy.

Antiretroviral agent, CCR5 antagonist

Class Summary

These agents block viral entry into white blood cells via the CCR5 co-receptor.

Maraviroc (Selzentry)

Maraviroc blocks viral entry via the CCR5 co-receptor into WBCs, reduces viral load, and increases T-cell counts in infection with CCR5-tropic HIV-1 (ie, R5 virus). Accelerated approval by the US Food and Drug Administration (FDA) was based on 24-wk data. This agent is indicated for combination treatment with optimized background therapy in treatment-experienced adults infected with only R5 virus who have evidence of viral replication and have HIV-1 strains resistant to multiple antiretroviral agents.

HIV, Entry Inhibitors

Class Summary

Approval of ibalizumab was based on the MB-301 phase 3 trial. MB-301 was a single-arm, 24-week study of ibalizumab plus optimized background regimen (OBR) in treatment-experienced patients infected with multidrug-resistant HIV-1 virus.

The following study results were observed at 24 weeks:[162]

Among study participants, 43% achieved viral suppression < 50 copies/mL, and half achieved < 200 copies/mL.

While 60% of those with a baseline CD4 count of > 50 cells/µL achieved undetectable viral load, this fell to < 20% in those with lower CD4 counts.

Among participants, 55% had at least a 1 log decrease and 48% had at least a 2 log decrease in HIV RNA; the average reduction from baseline was 1.6 log.

The overall average CD4 cell gain was 48 cells/µL, but this differed according to baseline level; people who started with at least 50 cells/µL saw a mean gain of about 75 cells/µL, while those with lower baseline levels gained an average of 9 cells/µL.

Ibalizumab (Ibalizumab-uiyk, Trogarzo)

CD4-directed post-attachment inhibitor that prevents viral entry and fusion within the CD4 cell. Ibalizumab does not inhibit HIV gp120 attachment to CD4; however, its postbinding conformational effects block the gp120-CD4 complex from interacting with CCR5 or CXCR4 and thus prevents viral entry and fusion while preserving normal immunological function. It is indicated for HIV-1 infection in heavily treated adults with multidrug-resistance. It is used in combination with the patient’s current ART regimen.

Complete Regimen Combinations

Class Summary

Complete fixed-dose regimens assist with medication adherence. Two-, three-, and four-drug combination products are available to decrease pill burden and administration frequency.

Dolutegravir/rilpivirine (Juluca)

First 2-drug, fixed-dose combination complete regimen approved for HIV infection. It is indicated for adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) and on a stable ART regimen for ≥ 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine.

Dolutegravir/lamivudine (Dovato)

First 2-drug, fixed-dose, complete regimen for treatment-naïve adults with HIV-1 infection with no known substitutions associated with resistance to dolutegravir or lamivudine. Combines integrase strand transfer inhibitor (INSTI) plus nucleoside reverse transcriptase inhibitor (NRTI). 

Elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya)

Antiretroviral combination product that provides a complete, once-daily regimen for treatment-naïve adults and adolescents aged ≥ 12 y, or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure. Each tablet contains an integrase inhibitor (elvitegravir 150 mg) and 2 NRTIs (emtricitabine 200 mg and tenofovir AF 10 mg). It also contains cobicistat, a CYP3A4 inhibitor used as a booster for elvitegravir, a CYP3A4 substrate.

Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza)

Complete regimen indicated for treatment of HIV-1 infection in adults who have no prior antiretroviral (ART) treatment history or who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

Emtricitabine/rilpivirine/tenofovir AF (Odefsey)

Antiretroviral combination product that provides a complete, once-daily regimen for treatment-naïve adults and adolescents aged ≥ 12 y, or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure. Each tablet contains 1 NNRTI (rilpivirine 25 mg) and 2 NRTIs (emtricitabine 200 mg and tenofovir AF 25 mg).

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild)

Antiretroviral combination product that provides a complete, once-daily regimen for treatment-naïve adults. Contains an integrase inhibitor and 2 NRTIs plus cobicistat, a CYP3A4 inhibitor used as a booster for elvitegravir, a CYP3A4 substrate. Cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine/rilpivirine/tenofovir DF (Complera)

Complete regimen combination consisting of 2 NRTIs and 1 NNRTI. It is indicated for treatment of HIV-1 infection in patients aged ≥ 12 years with no antiretroviral treatment history and with HIV-1 RNA ≤ 100,000 copies/mL at the start of therapy, and in certain virologically-suppressed (HIV-1 RNA < 50 copies/mL) patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen.

Bictegravir/emtricitabine/tenofovir AF (Biktarvy)

Three-drug combination of bictegravir (BIC), an HIV-1 integrase strand transfer inhibitor (INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Indicated as a complete regimen for treatment of HIV-1 infection in adults and pediatric patients weighing ≥25 kg who are ART-naïve or replacement of current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA

Efavirenz/lamivudine/tenofovir DF (Symfi, Symfi Lo)

Three-drug combination of a non-nucleoside reverse transcriptase inhibitor, and two nucleo(t)side reverse transcriptase inhibitors and is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children who weigh at least 35 kg (Symfi Lo) and 40 kg (Symfi).

Doravirine/lamivudine/tenofovir DF (Delstrigo)

Indicated as a complete, once daily, regimen for treatment of HIV-1 infection in adults without prior antiretroviral therapy (ART) treatment history.

Antiretroviral Combinations

Class Summary

Combination products are valuable to patient care and help ensure compliance.

Abacavir, lamivudine, zidovudine (Trizivir)

Abacavir is a nucleoside reverse transcriptase inhibitor, which interferes with HIV viral RNA dependent DNA polymerase and inhibits viral replication. Lamivudine and zidovudine are thymidine analogs that inhibit viral replication.

Abacavir/lamivudine (Epzicom)

This is a NRTI combination product. It is indicated in combination with other ART agents (eg, NNRTIs, PIs) for the treatment of HIV-1 infection in adults and pediatric patients aged 12 years or older. It is also indicated in combination with safer sex practices for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples. CDC guidelines include additional populations (eg, IV drug users, heterosexual individuals at high risk).

Abacavir/dolutegravir/lamivudine (Triumeq)

Contains 2 NRTIs (abacavir 600 mg and lamivudine 300 mg) and an integrase strand inhibitor (dolutegravir 50 mg). Dosage modification may be required when coadministered with strong CYP3A4 inducers by adding a single-entity evening dose of dolutegravir.

Emtricitabine/tenofovir DF/efavirenz (Atripla)

NRTI and NNRTI combination product.

Lamivudine/zidovudine (Combivir)

NRTI combination product.

Emtricitabine/tenofovir DF (Truvada)

NRTI combination product. Indicated in combination with other ART agents (eg, NNRTIs, PIs) for the treatment of HIV-1 infection in adults. It is also approved for pediatric patients who weigh at least 17 kg and can swallow the tablet whole. It is also indicated in combination with safer sex practices for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples. CDC guidelines include additional populations (eg, IV drug users, heterosexual individuals at high risk).

Emtricitabine/tenofovir AF (Descovy)

NRTI combination product. Indicated in combination with other ART agents (eg, NNRTIs, PIs) for the treatment of HIV-1 infection in adults and pediatric patients aged 12 y or older. Unlike Truvada, it is not indicated for PrEP.

Lamivudine/tenofovir DF (Cimduo)

Combination contains 2 NRTIs (lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg) and is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children who weigh at least 35 kg.

CYP3A4 Inhibitors

Class Summary

Boosting agents (eg, ritonavir, cobicistat) may be part of various ART drug regimens to inhibit metabolism of ART CYP3A substrates, resulting in increased systemic exposure and efficacy.

Cobicistat (Tybost)

CYP3A inhibitor. As a single agent, it is indicated to increase systemic exposure of atazanavir or darunavir (once-daily dosing regimen) in combination with other antiretroviral agents. It was originally approved as part of the combination product elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild).

Antibiotic, Sulfonamide Derivative

Class Summary

Therapy should cover all likely pathogens in this clinical setting.

Sulfamethoxazole and Trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS, Sulfatrim)

This combination inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid. This results in inhibition of bacterial growth.

Growth hormone releasing factor

Class Summary

This agent decreases visceral adipose tissue.

Tesamorelin (Egrifta)

Tesamorelin is a growth hormone–releasing factor (GRF) analog indicated for reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This agent stimulates growth hormone production and increases serum levels of insulin-like growth factor–1 (IGF-1). It elicits anabolic and lipolytic actions.

 

Questions & Answers

Overview

What is HIV and how is it transmitted?

What are the signs and symptoms of HIV infection?

What are risk factors for HIV exposure?

What are the recommendations for HIV screening?

What is the role of CD4 T-cell count in the risk assessment of opportunistic infection in HIV infection?

What is the role of viral load in peripheral blood in the management of HIV infection?

Which HIV test is FDA approved?

What tests are performed following the initial diagnosis of HIV infection?

What are the three categories of HIV?

What are the DHHS guidelines for initiation of antiretroviral therapy (ART) for HIV infection?

What are the classes for antiretroviral agents used in the treatment of HIV infection?

Which regimens are preferred by the DHHS guidelines for treatment-naive patients with HIV infection?

What is the basis for regimen selection for treatment of HIV infection?

When is prophylaxis against opportunistic infections indicated in the management of HIV infection?

Which treatments may be needed in the management of HIV infection?

What are the CDC recommended HIV postexposure prophylaxis (PEP) regimens?

What is the expanded PEP regimen for HIV infection?

What is HIV and how is it transmitted?

What is the most common route of HIV transmission?

How does the global distribution of HIV species vary?

What is the history of the HIV epidemic in the US?

What are the stigmas associated with HIV infection?

What common misinformation about HIV exists?

How has antiretroviral therapy (ART) affected HIV survival rates?

How is HIV-related health information linked to other health information?

What is the pathophysiology of HIV infection?

How is HIV characterized?

What are the three species-defining retroviral genes of HIV?

What are the HIV-1 accessory genes?

What are the accessory proteins of HIV?

What is the pathogenesis of AIDS?

What is the role of CD4+ helper T cells in the pathogenesis of HIV infection?

What is the global pattern for opportunistic infections in HIV infection?

What is the role of gut-associated lymphoid tissue (GALT) in the pathogenesis of HIV infection?

What is a feature of HIV replication in GALT?

How is the discrepancy in viral load between GALT and blood measurements explained?

What have the studies of T-cell–replication kinetics revealed about HIV infection?

What is the role of cell-cycling in the pathogenesis of HIV infection?

How do the HIV proteins affect T-cell function?

What is the role of direct cytotoxic effects of viral replication in the pathogenesis of HIV infection?

Which individuals tend to be resistant to HIV infection?

What is the role of the chemokine-related receptor (CXCR4) in the pathogenesis of HIV infection?

What is the role of stem-cell transplantation in the management of HIV infection?

What is the relationship between T-cell loss and how HIV progresses to AIDS?

What is the role of lymph nodes in the pathogenesis of HIV infection?

How does HIV replicate?

How is HIV compartmentalized?

What are the three distinct phases of HIV pathogenesis?

What are the first cellular targets of HIV?

Where does HIV tend to integrate in the body?

What happens during acute seroconversion of HIV infection?

How long will it take for symptoms of HIV infection to appear?

What are the HIV symptoms during the acute seroconversion stage of infection?

When is AIDS diagnosed?

What is the primary mechanism for immunologic control of HIV infection?

When are patients at a higher risk for opportunistic infections and other AIDS-related events?

Which opportunistic infections and conditions are seen in patients with AIDS?

What is HIV encephalopathy?

What causes HIV infection?

What is the prevalence of HIV infection in the US?

What is the incidence of AIDS in the US?

Who is at higher risk of infection with HIV?

What group is most likely to be unaware they are HIV positive?

Among groups at high risk for HIV, what is the effect of health care visits?

What is the mortality rate of HIV infection?

How does the prevalence of HIV vary by age and race?

What is the global prevalence of HIV infection?

Which races and ethnicities in the US have the highest prevalence of HIV infection?

How does the prevalence of HIV vary by sex?

Who is at a higher risk for acquiring HIV infection?

What is the prognosis of untreated HIV infection?

What is the efficacy of antiretroviral medications for treatment of HIV-2?

How long is the survival period for untreated AIDS?

What can increase survival for AIDS patients?

What is the mortality rate of AIDS in New York City?

What is the effect of pre-existing infections on people with AIDS?

Which organisms become pathogenic in patients with AIDS?

What are adverse effects of antiviral medications for AIDS?

What is the risk for non-Hodgkin lymphoma in patients with HIV infection?

What information about HIV should patients receive?

What are the risks of unprotected sex when both partners are HIV positive?

What information about HIV should IV drug users receive?

Presentation

What are the risk factors for exposure to HIV?

What are the signs and symptoms of HIV infection?

What are the signs and symptoms of AIDS?

What are the sequelae of HIV infection?

Which physical findings suggest HIV infections?

Which minor opportunistic infections suggest HIV infection?

DDX

What causes of immune suppression should be included in the differential diagnoses of HIV infection?

What are the differential diagnoses for HIV Infection and AIDS?

Workup

Why is screening for HIV infection needed?

What secondary testing is helpful in the diagnosis of HIV infection?

What are the CDC recommendations for HIV testing?

What is the Alere Determine HIV-1/2 Ag/Ab Combo test?

How is the HIV rapid test used?

What is the staging of HIV infection?

What baseline tests are performed in newly diagnosed patients with HIV infection?

What are the USPSTF recommendations for HIV screening?

What are the ACOG recommendations for HIV testing?

What are the ACOG guidelines on HIV testing during pregnancy?

What are the CDC recommendations for HIV screening in high risk groups?

What are the benefits of early diagnosis of HIV infection?

What test should be used for HIV screening?

How are HIV test results reported?

When is HIV-2 testing indicated?

Which testing is most effective for early detection of HIV infection?

What is the CDC diagnostic algorithm for HIV diagnosis?

What is the role of CD4 T-cell count in the management of HIV infection?

What is the role of CD4 T-cell percentage in the management of HIV in children under five years of age?

What is the role of RT-PCR in the management of HIV infection?

What affects the rate of progression of HIV infection to AIDS?

How are HIV viral loads suppressed?

What is HIV virologic failure?

When is viral cultures for HIV indicted?

What is disrupted during HIV infection?

Which HIV test is performed only in newborns?

What can guide therapy for HIV infection?

What studies are performed in newly diagnosed patients with HIV infection?

Which tests are performed to evaluate tuberculosis infection in patients with newly diagnosed HIV infection?

Which tests is used to evaluate CMV infection in patients with newly diagnosed HIV infection?

Which tests are used to screen for syphilis in patients with newly diagnosed HIV infection?

Which STDs are evaluated in patients with newly diagnosed HIV infection?

Why is hepatitis serology performed in patients with newly diagnosed HIV infection?

What is toxoplasma antibody testing performed in newly diagnosed HIV infections?

What are the baseline values that may be affected by antiretroviral therapy (ART) for HIV infection?

What are histologic findings characteristic of HIV infection and AIDS?

What is the CDC classification of HIV infection?

What happens once an HIV infection has been staged into a higher clinical category?

Treatment

How is treatment for HIV infection determined?

What is the principal treatment for HIV infection?

What are the results of successful HAART therapy for HIV infection?

Which secondary diseases may be reduced for HIV patients on HAART?

Who has released treatment guidelines for HIV infection?

What are the IDSA treatment guidelines for HIV infection?

How has the introduction of HAART affected mortality rates?

What increase in non-AIDS-defining cancer is attributed to HIV infection?

What are strong predictors of mortality for AIDS?

When should antiretroviral therapy (ART) be initiated for HIV infection?

What are the European AIDS Clinical Society (EACS) recommendations for management of HIV infection?

What are the adverse effects of delay in antiretroviral therapy (ART) for HIV infection?

At what CD4+T cell count should antiretroviral therapy (ART) for HIV be initiated?

What is the result of early initiation of antiretroviral therapy (ART) during the acute seroconversion period in HIV infection?

What are the International Antiviral Society-USA (IAS-USA) antiretroviral treatment recommendations for adults with HIV infection?

What are the classes for antiretroviral agents for HIV infection?

What are the DHHS guidelines for treatment-naive patients with HIV infection?

How should HIV be treated during pregnancy?

What is the basis for antiretroviral regimen selection for HIV infection?

What the DHHS recommend for genotypic testing in HIV infection?

What mutations could result in increased susceptibility to a particular drug in HIV infection?

What is the impact of combination antiretroviral therapy (ART) on HIV/AIDS?

What is the role of dolutegravir (Tivicay) in the treatment of HIV infection?

What is an important factor in selecting first-line antiretroviral therapy (ART) for HIV infection?

What is the role of zidovudine-lamivudine plus abacavir for the treatment of HIV infection?

What is the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) for the treatment of HIV infection?

What the benefits of 21-day antiretroviral regimens during pregnancy?

Why is prophylaxis for Pneumocystis jiroveci important for HIV management?

When is PCP prophylaxis discontinued in the management of HIV infection?

What is the role of TMP-SMX in the management of HIV infection?

When are HIV patients at risk for Mycobacterium avium complex infection?

When is prophylaxis for fungal or viral infections indicated in the management of HIV infection?

What is the role of oral ganciclovir in the management of AIDS?

How should opportunistic infections be treated in HIV infection?

What is the relationship between TB and HIV infection?

What is HIV lipodystrophy?

What is the role of acyclovir in the treatment of HIV infection?

What is the role of crofelemer in the treatment of HIV infection?

How is HIV infection prevented?

What are sexual transmission prevention measures for HIV infection?

What is the role of STDs in the transmission of HIV?

Which sexual acts are more likely to lead to HIV infection than others?

How do oral contraceptives affect the risk for HIV transmission?

What are vertical transmission prevention measures for HIV infection?

How effective is triple antiviral therapy for HIV during pregnancy?

How is vertical transmission of HIV-2 prevented?

What is the mother-to-child transmission rate of HIV-2 in France?

What measures can be taken to prevent vertical HIV transmission?

What is the role of zidovudine in the prevention of vertical HIV transmission?

How is blood-borne transmission of HIV prevented?

What has the CDC recommended for HIV postexposure prophylaxis (PEP)?

What regimens does the CDC recommend for PEP?

What does an expanded PEP regimen include?

What is the role of nevirapine in the prevention of HIV infection?

What HIV vaccinations are available?

What is the role of antiretroviral medications for the prevention of HIV transmission?

What is the efficacy of preexposure prophylaxis (PrEP) in the prevention of HIV infection?

What are the CDC guidelines for PrEP in HIV infection?

What is the efficacy of PrEP in preventing HIV infection?

What are the limitations in the US to broad implementation of PrEP for prevention of HIV infection?

What was the reduction in risk with compliant pre-exposure prophylaxis against HIV infection?

What is the role in topical antivirals in the prevention of HIV infection?

What does the International Antiviral Society-USA (IAS-USA) recommend for HIV prevention in adolescents and adults?

Which specialists should be consulted for all new cases of HIV infection?

Which tests does the DHHS recommend be performed every 3 months in patients with HIV infection?

What is the role of basic chemistry studies in the management of HIV infection?

How often should fasting lipid profiles be measured in the management of HIV infection?

How often should T-cell counts be monitored in the management of HIV infection?

Guidelines

What are the CDC guidelines on HIV screening in men who have sex with men (MSM)?

What are the European AIDS Clinical Society guidelines on antiretroviral (ART) therapy and chronic HIV infection?

Medications

What is the role of antiretroviral therapy (ART) for HIV infection?

What are the benefits of combination therapy for the treatment of HIV infection?

Which antiretroviral combination products are used to treat HIV infection?

What have been shown to be safe and effective for treatment of black patients with HIV infection?

What is the role of Triumeq in the treatment of HIV infection?

What is the role of the NNRTI doravirine in the treatment of HIV infection?

Which medications in the drug class Antiretroviral agent, nucleoside reverse-transcriptase inhibitor are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral Agent, Protease Inhibitor are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral agent, non-nucleoside reverse-transcriptase inhibitor are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral Agent, Integrase Inhibitor are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral Agent, Fusion Inhibitor are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral agent, CCR5 antagonist are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class HIV, Entry Inhibitors are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Complete Regimen Combinations are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antiretroviral Combinations are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class CYP3A4 Inhibitors are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Antibiotic, Sulfonamide Derivative are used in the treatment of HIV Infection and AIDS?

Which medications in the drug class Growth hormone releasing factor are used in the treatment of HIV Infection and AIDS?