HIV Disease Treatment & Management

The treatment of human immunodeficiency virus (HIV) disease depends on the stage of the disease and any concomitant opportunistic infections.^[76] 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.^{[79, 80]}

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.

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.^[71]

These findings were repeated in another, more recent study of over 83,000 people with AIDS in the United States from 1990-2006,^[81] 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.^[82]

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).^[83]

World Health Organization (WHO) guidelines for resource-limited settings, issued in 2003, called for initiating antiretroviral therapy in patients with early stage HIV infection (WHO stages I-II) before the CD4 count drops below 200/μL.^[84] However, more recent research has led to United States guidelines recommending a CD4 count threshold of 350/μL.

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.^[85]

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.^[86]

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.^[87]

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.^[88] 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).^[89]

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.^[90]

Therapy initiation recommendations in the United States

In January 2011, the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents issued updated guidelines on initiation of antiretroviral therapy, as follows^[76] :

• Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness (see Staging) or with a CD4 count below 350 cells/µL
• Antiretroviral therapy should be initiated regardless of CD4 count in pregnant patients, patients with HIV-associated nephropathy, and those with hepatitis B virus coinfection when treatment of hepatitis B virus infection is indicated
• The panel was divided on the initiation of antiretroviral therapy in patients with CD4 counts between 350 and 500 cells/µL: 55% of panel members considered this a strong recommendation, while 45% considered it a moderate recommendation
• The panel was also divided on initiation of antiretroviral therapy in patients with CD4 counts above 500 cells/µL: half of the panel members favored initiation in this setting, while the other half considered treatment initiation as optional

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 January 2011 DHHS guidelines lists the following regimens as preferred in treatment-naive patients^[76] :

• Efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC)
• Ritonavir-boosted atazanavir + tenofovir/emtricitabine (ATV/r + TDF/FTC)
• Ritonavir-boosted darunavir + tenofovir/emtricitabine (DRV/r + TDF/FTC)
• Raltegravir + tenofovir/emtricitabine

The guidelines consider lopinavir/ritonavir–based regimens as alternative rather than preferred, except in pregnant women, in whom twice-daily lopinavir/ritonavir plus zidovudine/lamivudine remains preferred.

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^[76] :

• 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.^[76]

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.^[91]

A study by Lennox et al in treatment-naive patients from 67 centers on 5 continents demonstrated benefits of raltegravir (the only integrase inhibitor) over efavirenz (an NNRTI) as part of combination antiretroviral therapy.^[92] 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 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%).^[92]

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.^[93]

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.^[94] 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 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.

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.^{[95, 96, 97]} 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.

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, but its effect on HIV-1 progression is unknown. Lingappa et al found that acyclovir reduced risk for HIV-1 disease progression by 16% compared with placebo.^[98] 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 and had CD4⁺ cell counts of at least 250/μL and 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.

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.

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.^[99]

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.^[100]

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%.^[101] 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.^[102] 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.^[102]

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.

Chemoprophylaxis

An innovative and controversial strategy for preventing HIV transmission is regular use of antiretroviral medications by uninfected individuals. Although no data are currently available on the benefits of this strategy in heterosexuals or injection-drug users, clinical trial results indicate that preexposure prophylaxis can be safe and effective for men who have sexual intercourse with men.

A multinational study called the Pre-exposure Prophylaxis Initiative (iPrEx) trial 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.^[103]

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.^[103]

The Centers for Disease Control and Prevention (CDC) will determine how to most effectively use FTC-TDF in combination with other prevention strategies to reduce new HIV infections. The CDC, National Institutes of Health, and other institutions are also conducting trials to determine the safety and effectiveness of pre-exposure prophylaxis in these populations.^{[104, 105]}

There remain policy considerations surrounding costs, opportunity costs, and ethical issues that must be addressed before broad implementation in the United States.^[106] 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%.^{[107, 108]}

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).

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.

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^[76] :

• 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.^[76]