Antiretroviral Treatment of Human Immunodeficiency Virus Infection

Available Drugs

Each of the more than 30 antiretroviral drugs that are approved by the U.S. Food and Drug Administration (FDA; Table 357-1 ) is designed to block a specific step ( Fig. 357-1 ) of the HIV life cycle (see also E-Figs. 354-2 and 354-3 ). Drugs must be used in combinations that block different steps so as to reduce the emergence of drug resistance, and once-daily two- or three-drug combination regimens are the standard of care.

Four kinds of HIV drugs target the first step in the HIV life cycle, which is viral entry by: (1) binding gp120 and inhibiting its attachment to the CD4 receptor (CD4 attachment inhibitors); (2) inhibiting conformational changes after gp120 attachment (CD4 post-attachment inhibitors); (3) inhibiting CCR5 chemokine receptor binding (CCR5 antagonists); or (4) inhibiting membrane fusion (fusion inhibitors). The nucleoside analogue reverse transcriptase inhibitors (NRTIs) target the viral-specific enzyme HIV reverse transcriptase . A second class of HIV reverse transcriptase inhibitors are the non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), which bind to a different part of the same enzyme. The capsid inhibitors (CIs) disrupt the formation of the HIV capsid that protects HIV’s genetic material and enzymes. The integrase strand transfer inhibitors (INSTIs) inhibit the viral-specific enzyme HIV integrase by specifically targeting the transfer of viral DNA to the host cell genome. The HIV protease inhibitors (PIs) bind to the active site of the HIV protease enzyme and prevent precursor protein cleavage, and thereby, viral maturation, and infectivity.

When to Start Antiretroviral Therapy

The goals of antiretroviral therapy are to suppress viral replication, prevent the emergence of drug-resistant viral strains, enhance immunologic responses, decrease clinical events, and prolong healthy life. Antiretroviral therapy should be started as soon as possible after HIV infection is diagnosed ( Chapter 355 ), because it reduces symptoms and signs and improves patients’ outcomes compared with delayed treatment. In addition, antiretroviral therapy suppresses viremia and thereby reduces the risk for transmission to others by more than 90%.

Multiple FDA-approved fixed-dose combinations include more than 10 one-pill, once-daily complete regimens. These simple regimens are popular with clinicians and patients because they are easy to use, promote adherence, and can achieve virologic suppression rates of more than 90% ( Table 357-2 ). Potency, convenience, and tolerability are essential qualities of current antiretroviral drug regimens and account for their durable clinical benefits.

What to Start

Because of the risk for acquiring drug-resistant HIV, estimated to be about 17% in the United States, antiretroviral therapy should be started while awaiting the results of the HIV genotype. Guidelines recommend starting a bictegravir-, or dolutegravir-containing regimen and then adjusting when the genotypic results are available.

Currently recommended initial regimens in the United States ( Table 357-3 ) are combinations of one or two nucleoside analogues together with a third drug (integrase inhibitor). Globally, the preferred antiretroviral regimen is co-formulated tenofovir disoproxil fumarate/lamivudine/dolutegravir. However, some two-drug antiretroviral regimens (e.g., the combination of dolutegravir with lamivudine), given either as initial or maintenance therapy, are equivalent to three-drug regimens. ^, The first long-acting antiretroviral regimen is the two-drug combination of injectable cabotegravir and rilpivirine, given every other month. Monotherapy, by comparison, does not appear to be adequate for chronic HIV suppression.

What to Monitor

In a stable patient who is taking antiretroviral therapy, HIV RNA should be monitored every 3 to 6 months. In general, an adherence level of 80 to 85% can achieve effective viral suppression. HIV RNA levels suppressed below the level of detection of the assay are unlikely to result in the emergence of drug-resistant viral strains. Even with initial virologic suppression rates of more than 90%, however, some patients will experience virologic failure, with a once-suppressed viral load level becoming repeatedly detectable above the limit of the HIV RNA assay (20, 40, or 50 copies/mL).

When antiretroviral therapy is started, the glomerular filtration rate should be measured at baseline, after antiretroviral therapy is started, and whenever it is changed. Even in people who are living with HIV and who are otherwise stable, it should be monitored at least twice a year. Urinalysis should be checked at baseline, when ART is initiated or changed, and at least annually in patients who are stable. Patients should be referred to a nephrologist if the glomerular filtration rate declines by more than 25% and to less than 60 mL/minute, or if proteinuria exceeds 300 mg/day or is associated with hematuria (see Fig. 359-1 ).

When to Change Antiretroviral Therapy