Multidrug-Resistant HIV With Limited Treatment Options: No Longer an Unmet Need?

Where Have We Come From?
In a European cohort, the prevalence of highly treatment–experienced people with HIV in follow-up from 2010-2016 was 10.4%, but with a range of 1.1% to 15.7% depending on region. The percentage of highly treatment–experienced patients with viral suppression increased substantially over time with most individuals considered to have limited treatment options achieving virologic suppression.

In a US cohort, the prevalence of highly treatment–experienced people with HIV with limited treatment options—defined as having ≤2 available classes—remained quite constant for years at 4.0% to 7.5%. However, in 2007, prevalence suddenly dropped to 1.8% and has remained <1.0% thereafter.

The reason? For the first time in HIV/AIDS history, 3 new drugs were launched around 2007 with activity against drug-resistant HIV: ritonavir-boosted darunavir, raltegravir, and etravirine. And these drugs were in 3 separate classes: boosted protease inhibitor, integrase strand transfer inhibitor (a novel class at the time), and second-generation nonnucleos(t)ide reverse transcriptase inhibitor, respectively. Individuals with multidrug-resistant HIV and virologic failure were no longer forced to receive sequential functional monotherapy with new antiretroviral agents added to an inactive background regimen, with the corresponding risk of resistance development against each new agent. This shift from the addition of 1 new agent to failing treatments to providing patients with 2 or 3 new and active drugs changed the landscape of treatment for highly treatment–experienced patients.

In addition, new salvage regimens including all 3 drugs (ritonavir-boosted darunavir, raltegravir, and etravirine) were studied in the ANRS 139 TRIO trial. The reported high rates of virologic suppression (90% with HIV-1 RNA <50 copies/mL at the Week 24 primary endpoint) matched the efficacy of initial antiretroviral regimens for the first time.

Where Are We Going?
Despite the fact that more potent drugs have dramatically reduced the prevalence of highly treatment–experienced people with HIV and limited treatment options, small percentages of our patients have remained at high risk for disease progression and death because of limited remaining treatment options.

For drugs targeted at this population, the FDA and European Medicines Agency recommended a streamlined trial design for drug development that included 4 design elements:

1. Smaller sample size (subjects were rare)
2. Primary assessment of HIV-1 RNA decay 7-14 days after initiation of treatment
3. Addition of individualized optimized background regimen designed on the basis of resistance testing, immediately after the HIV-1 RNA decay assessment
4. Durability and safety analyses are conducted at 24 weeks, rather than 48 weeks

Three new drugs with special interest in this scenario have completed salvage studies with this design and have either recently launched or are expected to launch soon in both the United States and in Europe: ibalizumab, fostemsavir, and lenacapavir.

Ibalizumab and fostemsavir are entry inhibitors with no in vitro cross-resistance with other entry inhibitors such as maraviroc or enfuvirtide.

Ibalizumab is a humanized monoclonal IgG4 antibody that binds to a second extracellular domain of the CD4 receptor on host cells and is administered intravenously every 2 weeks. The TMB-301 study evaluating ibalizumab included 31 patients with documented resistance to at least 1 drug in at least 3 classes. Among those receiving ibalizumab with an optimized background regimen, 43% achieved HIV-1 RNA <50 copies/mL and 50% achieved HIV-1 RNA <200 copies/mL at Week 25.

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to the viral envelope glycoprotein 120, close to the CD4-binding site. It is administered orally twice daily. The BRIGHTE study included 371 participants; among these, 272 had only 1-2 active drug classes remaining and 99 had virtually no active options. Among those with 1-2 active classes, 60% achieved HIV-1 RNA <40 copies/mL at 96 weeks on fostemsavir, and among those with no active options, 37% achieved HIV-1 RNA <40 copies/mL at 96 weeks.

Lenacapavir is a first-in-class capsid inhibitor with multiple sites of action in the HIV cycle. Lenacapavir is administered subcutaneously every 6 months following a short oral lead-in. The CAPELLA study included 72 participants with ≤2 fully active agents from 4 main antiretroviral classes. Among those who received lenacapavir, 79% had HIV-1 RNA <50 copies/mL at 26 weeks.

All 3 of these drugs have demonstrated significantly greater decreases in the HIV-1 RNA level in the initial randomized period than placebo, high rates of subsequent efficacy, and safety. However, all 3 have low barriers against resistance, and HIV resistance did emerge in some subjects with virologic failure in their pivotal studies, highlighting the paramount importance of the optimal design of suppressive regimens in this scenario.

A New Revolution
A new revolution is, therefore, now taking place. For the second time in HIV history, an accumulation of new drugs with new mechanisms of action and no cross-resistance with any previous antiretroviral drug will allow most highly treatment–experienced patients with limited treatment options and multidrug-resistant HIV to regain virologic suppression, providing a new optimistic outlook for our patients.

Your Thoughts?
When should we prescribe these new drugs and how should we combine them? How must we review the prior antiretroviral history and accumulated resistance selected? Stay tuned to the online educational program titled, “Key Decisions in HIV Care” to learn more about the design of salvage regimens that can be lifesaving in patients with multidrug-resistant HIV and limited treatment options.

Do you have any patients with limited treatment options? How are you managing them? Post a comment below and join the discussion.