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Infectious Diseases Division
Fight Infections Foundation
University Hospital Germans Trias
Badalona, Barcelona, Spain
Josep M. Llibre, MD, PhD: consultant/advisor/speaker: Gilead Sciences, Janssen, ViiV Healthcare.
Guidelines and Approvals for Newer Antiretroviral Agents
Ibalizumab and fostemsavir have been approved by both the European Medicines Agency and the FDA; lenacapavir has been approved only by the European Union (EU) for use in adults with multidrug-resistant (MDR) HIV. However, these newer agents have indications that are restrictive: for the treatment of HIV-1 infection in heavily treatment-experienced adults with MDR HIV-1 infection failing their current antiretroviral regimen [ibalizumab and fostemsavir (US indication)] or only for those individuals for whom it is otherwise impossible to construct a suppressive antiretroviral regimen [lenacapavir and fostemsavir (EU indication)]. These restrictive indications are based on the inclusion criteria of the pivotal phase III studies TMB-301, BRIGHTE, and CAPELLA for ibalizumab, fostemsavir, and lenacapavir, respectively.
According to the European AIDS Clinical Society guidelines, when a 2- to 3-drug active regimen cannot be constructed, fostemsavir or ibalizumab can be added to create such a regimen. The Department of Health and Human Services guidelines state that patients with ongoing detectable viremia who lack sufficient treatment options to construct a fully suppressive regimen may be candidates for fostemsavir or ibalizumab. The use of these conditional verbs “can” and “may”―expressing just possibility―could have important clinical consequences.
One would expect that administering these newer drugs (with novel mechanisms of action) to people with MDR HIV, who have limited treatment options, in the exact same way as they were prescribed in the registration trials would only provide the exact same results as those observed in those trials. Efficacy rates observed in the randomized trials for initial antiretroviral therapy (ART) or switch studies can reasonably be expected to match efficacy rates in real life, but that could fall short in the late-salvage ART scenario.
Virologic Suppression and ART Resistance
Beyond medication adherence, all studies on advanced-salvage ART have identified 3 main factors that are significantly associated with lower rates of virologic suppression.
In people with varying degrees of previous HIV drug resistance, the selection of new resistance accumulates with each virologic failure. If some drugs had partial activity at the time the regimen was prescribed, this residual activity can be further reduced or completely lost if the new regimen fails. The same is true for the CD4+ T-cell count: It can worsen with each virologic failure. As a result, the longer we wait to prescribe these new drugs, the less likely it is to achieve complete virologic suppression and a robust CD4 cell response. Waiting until the point where it is otherwise impossible to construct a suppressive ART regimen may cause many patients to receive these life-saving drugs when it is too late.
Mortality, especially any HIV-related or avoidable fatality, is not common in a first or switch ART trial. However, this was not the case in the BRIGHTE trial, where mortality was not unusual. Although the TMB-301 (ibalizumab) and CAPELLA (lenacapavir) trials had a limited number of participants (31 and 72 [36 in the randomized cohort], respectively), 371 patients were treated with fostemsavir in the BRIGHTE trial (including 272 in the randomized cohort and 99 in the nonrandomized cohort), allowing for a thorough analysis. In the BRIGHTE trial, people in the randomized cohort received at least 1 fully active, approved antiretroviral drug in at least 1 but no more than 2 antiretroviral classes, whereas those in the nonrandomized cohort received virtually no remaining active antiretroviral options.
The 2 arms of the BRIGHTE study unequivocally demonstrated what ensues when these drugs with novel mechanisms of action are administered too late―as a last resort―in people with MDR HIV with limited treatment options. Although the median baseline CD4+ T-cell count was only 99 and 41 cells/mm3 in patients in the randomized and nonrandomized cohorts, respectively, the most significant life-threatening factor was having 1-2 vs 0 active medications remaining. Similar to the observations in the BRIGHTE trial, in the TMB-301 (ibalizumab) study, 10% of the participants (13% of those who completed all scheduled visits) died by Week 25, and all had a baseline CD4+ T-cell count <50 cells/µL
In the recently reported BRIGHTE 240-week analysis, 6% of participants in the randomized cohort and 20% in the nonrandomized cohort died. Most deaths were AIDS related, caused by infections linked to immune suppression resulting from HIV or non–AIDS-related cancers that have an increased prevalence in people with HIV. Of importance, most deaths took place in the first 48 weeks. To me, at least some of these deaths might have been avoided if the salvage treatment was started earlier.
Therefore, I would strongly urge a modification in the wording of the current guidelines and the current approach pertaining to the recommendation for the use of these life-saving drugs in people with MDR HIV with limited treatment options, for whom a suppressive regimen cannot be constructed. A change from “they can be used” to “they should be strongly considered” is very crucial, as these drugs affect not only the rates of virologic suppression, but also the clinical endpoints, such as mortality.
In your clinical practice, what strategy do you follow for the treatment of patients with MDR HIV with limited treatment options? Join the discussion by posting a comment.