Treatment Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: An Update

On April 8, 2015, HSS released updated HIV treatment guidelines.¹ The original 1998 guidelines for the use of antiretroviral agents for treating adults and adolescents infected with HIV emphasized the benefit of potent combination antiretroviral therapies (ARTs) that included protease inhibitors (PIs).^2,3 Since then there have been more than 25 HSS guidelines focusing primarily on when to initiate ART and which ART to prescribe. The question of when to start ART had been controversial, but the most recently issued guidelines have addressed this question. For the first time, HSS recommends ART for all individuals infected with HIV regardless of CD4+ T-cell count.¹ The timely initiation of effective ART with an associated reduction in HIV viremia benefits patients infected with HIV and substantially decreases transmission of HIV to uninfected sexual partners.³

Three large, international randomized placebo-controlled studies conducted between 2002 and 2015 provide evidence that the benefits of ART outweigh the potential deleterious effects of long-term ART. The Strategies for Management of Antiretroviral Therapy (SMART) was the first published study in this trifecta.^4,5 Given concern about the adverse effects (AEs) of ART, particularly PIs, this study was designed to investigate whether long-term ART was associated with more toxicities than was deferred therapy, determined by CD4+ cell counts. The study was halted prematurely, because the risk of death or grade-4 toxicity was statistically greater among those receiving episodic ART than among those on continuous therapy. The SMART trial demonstrated that ART therapy was beneficial, but it did not determine when to initiate ART, particularly in asymptomatic persons.⁵

It was thought that the risk of transmission of HIV through sexual contact or shared drug paraphernalia was significantly lower for patients on ART who achieve viral suppression compared with those with uncontrolled viremia. The HIV Prevention Trials Network study enrolled HIV-serodiscordant couples to examine transmission of HIV. The trial compared HIV-positive patients who initiated ART when their CD4+ cell count was between 350 to 550 cells/mm3 with patients who began therapy when their CD4+ cell count was < 250 cells/mm3 or when an AIDS-defining illness was diagnosed. The difference in the rate of transmission to a HIV-negative partner was dramatic. The rate was 96% less among those in the early-therapy group vs those in the deferred-therapy group. In addition, there was a 40% reduction in the progression of HIV-related disease in the participants randomized to the early-therapy group.⁶

In March 2011, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which conducted SMART, initiated the Strategic Timing of AntiRetroviral Treatment (START) study to define the optimal time to begin ART among asymptomatic patients with a CD4+ count of > 350 cells/mm3. Patients with a CD4+ cell count of > 500 cells/mm3 were randomized to either initiate ART, or defer ART until the CD4+ cell count fell to < 350 cells/mm3 or until an AIDS-defining illness occurred^.7 On May 15, 2015, the study was terminated early. Based on an interim analysis, the data safety and monitoring board announced that the risk for a serious AIDS-related event, serious non-AIDS-related event, or death from any cause was 57% less in the early treatment group. When compared with patients who delayed ART, for those on ART, serious AIDS-related events were reduced 72%, and serious non-AIDS events were reduced 39%.⁸ A similar study conducted in the Ivory Coast from March 2008 to January 2015 also favored early rather than deferred ART^.9

Experience in clinical practice, these landmark clinical trials, and several cohort studies served as the basis of the changes in the new HSS guidelines that endorse ART for all HIV-infected persons. The World Health Organization (WHO) has recently published similar guidelines.¹⁰ It is yet to be determined whether the guidelines have been implemented successfully. Nonetheless, for both the clinician and the patient where access to ongoing care and ART are available, the new guidelines greatly simplify the treatment choices.

What's New in the Guidelines?

The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents presents significant changes in several of the tables that are most clinically useful, including Tables 6, 7, and 8.¹ Table 6 presents recommended, alternative, and other antiretroviral regimen options. The guidelines also added new tables describing antiretroviral regimen considerations for initial therapy and the mechanisms of antiretroviral-associated drug interactions.

Initial Combination Regimens for the Antiretroviral-Naïve Patient

Five regimens are now recommended for ART-naïve patients: 4 are integrase strand transfer inhibitor-based regimens, and 1 is a ritonavir-boosted PI-based regimen (Table 1). A nonnucleoside reverse transcriptase inhibitor-based regimen is no longer recommended. The guidelines include regimens that are now considered less favorable for a variety of reasons, including reduced virologic activity and greater risk of toxicities, higher pill burden, and more potential drug interactions. Several regimens that have been widely used are now included in this latter option, in particular efavirenz plus abacavir/lamivudine (3TC), lopinavir/ritonavir plus abacavir (ABC)/3TC, and tenofovir fumarate (TDF)/emtricitabine (FTC).

The most significant change in the guideline is the reclassification of efavirenz from a recommended to an alternative therapy. The principal reasons for this change are central nervous system (CNS) AEs, which can include depression and a reported 2-fold increase in the risk of suicide or suicidal ideation.¹¹

In November 2015, the FDA approved Genvoya, a once-daily, fixed-dose combination tablet containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (TAF).¹² With this approval, there are now 5 once-daily HIV treatment options. This new drug is similar to elvitegravir/cobicistat/TDF/FTC, but it substitutes TAF for TDF. The benefits of this substitution include less bone loss and decreased renal toxicity.^13-15 Genvoya may be prescribed in patients with a 30 mL/min creatinine clearance. The TAF-containing once-daily formulation achieves higher intracellular levels and lower blood levels of TAF. Therefore, the cholesterol-lowering benefits are less than those of the TDF-containing alternative.

In the 2015 guidelines, Table 7 provides concise guidance on the selection of an ART regimen based on patient and regimen characteristics, including food-based AEs; the presence of other medical and/or psychiatric conditions; and the presence of co-infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis.¹ In addition, Table 8 outlines the advantages and disadvantages of the different classes of ART.¹ For example, dolutegravir may have a higher barrier to resistance than that of elvitegravir or raltegravir.¹⁶ It is now possible for those living with HIV to have ongoing viral suppression, which will not only improve their lives, but also decrease the risk of HIV transmission to sexual partners. Starting from the time of diagnosis, achieving viral suppression is dependent on a link to care with initiation of ART and retention in care. The 5 once-daily options should improve adherence. The infrastructure to ensure lifelong retention in care, medication availability, and adherence still poses many challenges.