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Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg School of Medicine
Babafemi Taiwo, MBBS, has disclosed that he has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and funds for research support from Janssen.
New agents and strategies continue to improve the options for successful antiretroviral therapy (ART) across the spectrum from treatment-naive persons to heavily treatment–experienced individuals with multiclass drug resistance. Prominent among emerging approaches is the 2-drug construct.
Initial ART With Dolutegravir/Lamivudine
In the GEMINI studies, the 2-drug regimen of dolutegravir (DTG) plus lamivudine (3TC) was noninferior to DTG plus emtricitabine (FTC)/tenofovir disoproxil fumarate through Week 144. One patient receiving DTG plus 3TC developed M184V at Week 132 and R263R/K at Week 144 without meeting the study definition of virologic failure. DTG/3TC is now among the recommended first-line regimens for most people with HIV, except if baseline HIV-1 RNA is >500,000 copies/mL, if hepatitis B virus coinfection is present, or if ART is initiated before the results of reverse transcriptase resistance or hepatitis B virus testing are available. A switch to DTG/3TC also showed noninferiority to continued 3-drug or 4-drug tenofovir alafenamide (TAF)–containing therapy for maintenance of viral suppression in the TANGO and SALSA studies.
Parenteral ART With Long-Acting Cabotegravir Plus Rilpivirine
The first complete parenteral ART regimen also features only 2 drugs, long-acting (LA) cabotegravir (CAB) plus rilpivirine (RPV). Efficacy and safety of this LA combination for maintenance of virologic suppression was established in FLAIR, ATLAS, and ATLAS-2M. In a post hoc analysis of pooled Week 48 data from these studies, 1.25% (13/1039) had virologic failure. Risk factors identified to be associated with failure of this LA regimen are BMI >30 kg/m2, presence of RPV resistance associated substitutions at baseline, low RPV trough concentration at Week 8, and HIV genotype A6/A1. Of note, 96.7% of participants in FLAIR, ATLAS, and ATLAS-2M had 0 or 1 of these risk factors, and only 0.4% of this subgroup had virologic failure. The presence of ≥2 risk factors increased the risk of failure. When patients experience failure of LA CAB plus RPV, resistance commonly occurs to integrase strand transfer inhibitor and/or nonnucleos(t)ide reverse transcriptase inhibitors. A 2-drug regimen may even be an option for carefully selected patients experiencing virologic failure. Current Department of Health and Human Services guidelines for this population state that “a new regimen can include 2 fully active drugs if at least 1 with a high resistance barrier is included (eg, DTG or boosted darunavir) … If no fully active drug with a high resistance barrier is available, then every effort should be made to include 3 fully active drugs.”
Investigational 2-Drug Regimens
The newest data from studies of investigational drugs and regimens further highlight the relevance of 2-drug ART regimens. In the P011 study, islatravir, the first-in-class nucleotide reverse transcriptase translocation inhibitor, is being investigated for maintenance therapy in combination with doravirine (DOR) following 24 weeks of initial ART with islatravir, DOR, and lamivudine. At Week 96, HIV-1 RNA <50 copies/mL was achieved in 81.1% (73/90) of participants receiving maintenance islatravir plus DOR.
Lenacapavir, another first-in-class agent, is a capsid inhibitor with potential for use in 2-drug regimens. Unique in its availability for SC every-6-month dosing, lenacapavir administered orally for 2 weeks followed by SC injection every 6 months in combination with daily oral FTC/TAF was highly effective (92% to 94%) in suppressing HIV-1 RNA to <50 copies/mL at Week 28 among treatment-naive patients in the CALIBRATE trial. However, 1 participant had emergent capsid and reverse transcriptase inhibitor resistance at Week 10. In this ongoing trial, participants with HIV-1 RNA <50 copies/mL at Weeks 16 and 22 will be transitioned at Week 28 to a 2-drug maintenance regimen of SC lenacapavir injection every 6 months plus daily oral TAF or daily oral bictegravir for follow-up through Week 80.
Despite the promise of selected dual-therapy regimens, 2-drug therapy is not for all patients. Only proven combinations should be considered in any patient, and it is best used when both agents are active. There is no 2-drug therapy for patients with hepatitis B coinfection, and none is recommended during pregnancy. However, since DTG is now recommended in all stages of pregnancy, including preconception, early pregnancy, and late pregnancy as the risk of neural tube defects in the Tsepamo study was not significantly different between women exposed to DTG and those exposed to non-DTG ART at conception, perhaps dual therapy with DTG-based regimens will be possible during pregnancy in the future.
Investigational Options for Salvage Therapy and HIV Prevention
Outside of the 2-drug construct, lenacapavir is being investigated in salvage therapy for heavily treatment–experienced patients. In the randomized cohort of the CAPELLA study, HIV-1 RNA <50 copies/mL was achieved in 81% (29/36) of heavily treatment–experienced participants treated with lenacapavir plus an optimized background regimen. Based on these findings, lenacapavir has the potential to join ibalizumab and fostemsavir as a new drug option for patients with a complex treatment history and otherwise limited options.
HIV remains a lifelong disease despite the progress made in its treatment, emphasizing the importance of interventions to prevent new infections. However, research in this direction continues to yield mixed results. We currently await an FDA decision on the use of LA injectable CAB every 2 months for HIV pre-exposure prophylaxis (decision expected in early 2022), and islatravir has shown potential as a monthly oral agent for pre-exposure prophylaxis, with intracellular trough concentrations of the active triphosphate staying above the pharmacokinetic threshold for HIV prevention for at least 8 weeks following the last dose. On the other hand, HVTN 705, the randomized, placebo-controlled phase IIb efficacy trial of mosaic recombinant Ad26 vaccine plus Clade C gp140 boost, was prematurely stopped on August 31, 2021, due to insufficient protection against HIV infection. Despite setbacks, and judging from the results of informal polling of participants at the 2021 CCO HIV Symposium, there is a reservoir of enthusiasm that we will ultimately end the HIV/AIDS epidemic.
Which evolving strategy for HIV treatment or prevention are you most excited about offering to your patients? Answer the polling question and join the discussion by posting a comment. For more discussion of HIV treatment, comorbidities, prevention, and COVID-19–related issues, download the slides and watch the videos from our recent HIV Annual Update symposium.