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HIV Disease Treatment & Management

  • Author: Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Apr 07, 2016
 

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.[100, 101]

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.[102]

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.[103, 104] 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
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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.[85]

These findings were repeated in another, more recent study of over 83,000 people with AIDS in the United States from 1990-2006,[105] 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.[106]

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).[107]

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.[108, 109] 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.[108, 109]

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.[110, 111] 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.[112]

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.[113]

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.[114]

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.[115] 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).[116]

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.[117]

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:[118, 119]

  • 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.[120]

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.[121] 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%).[121]

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.[122]

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.[123, 124, 125, 126] 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.[127]

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).[128, 129]

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.[130]

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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.[131] 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.

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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.[132]

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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.[133, 134, 135] 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.[136]

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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.[137] 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.[138]

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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.

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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.[139]

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.[140]

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.[141]

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%.[142] 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.[143] 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.[143]

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.[144]

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.[145, 146] 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.[147]

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.[147]

Additional studies have been completed or are ongoing in serodiscordant heterosexual couples and intravenous drug users.[148, 149]

There remain policy considerations surrounding costs, opportunity costs, and ethical issues that must be addressed before broad implementation in the United States.[150] 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%.[151, 152]

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[153, 118] in conjunction with updated recommendations on antiretroviral treatment (ART) of adult HIV infection.[118, 119]

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.[153, 118] Among its key HIV-prevention recommendations for teens and adults are the following[153, 118] :

  • 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.
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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.

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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]

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Contributor Information and Disclosures
Author

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics

Disclosure: Received research grant from: Cubist Pharmaceuticals, Durata Therapeutics, and Biota Pharmaceutical<br/>Received income in an amount equal to or greater than $250 from: HealthyCT insurance<br/>Medico legal consulting for: Various.

Coauthor(s)

Shelley A Gilroy, MD Associate Professor of Medicine, Infectious Disease and HIV Medicine, Albany Medical College

Shelley A Gilroy, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Gilead<br/>Received income in an amount equal to or greater than $250 from: Gilead.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Aaron Glatt, MD Professor of Clinical Medicine, New York Medical College; President and CEO, Former Chief Medical Officer, Departments of Medicine and Infectious Diseases, St Joseph Hospital (formerly New Island Hospital)

Aaron Glatt, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Infectious Diseases Society of America, International AIDS Society, and Society forHealthcare Epidemiology of America

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Electron microscopy of human immunodeficiency virus (HIV)–1 virions. Courtesy of CDC/Dr. Edwin P. Ewing, Jr.
Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.
Timeline of CD4 T-cell and viral-load changes over time in untreated human immunodeficiency virus (HIV) infection. From Wikipedia, based on an original from Pantaleo et al (1993).
Incidence of HIV infection by risk group. From the CDC Web site (copyright free) derived from the revised 2006 estimated figures.
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 an original published by Lohse et al (2007), "Survival of persons with and without HIV infection in Denmark, 1995-2005."
Table 1. Antiretroviral Drug Classes and Agents
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)



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)



*No longer available on market
Table 2. Antiretroviral Combination Products
Drug Content per Tablet/Capsule* Brand Name Adult Dose (≥40 kg)
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
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
*Not indicated for patients requiring dosage adjustments (eg, weight < 40 kg, renal impairment, hepatic impairment, dose-limiting adverse effects) unless otherwise stated.
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