What’s in the pipeline for multidrug-resistant HIV infections?

Issue: August 2021

ByShannon Ketchem, PharmD

ByKati Shihadeh, PharmD, BCIDP

Therapeutic options for adults with heavily treatment-experienced (HTE) HIV-1 infection and virologic failure are limited.

Barriers to successful therapies include side effects, drug resistance, past intolerance, pill burden and administration difficulties. Two new agents, islatravir and lenacapavir, are in the pipeline and currently being studied for multidrug-resistant (MDR) HIV-1 in HTE patients.

Clinical trials

Islatravir (ISL) is a novel nucleoside reverse transcriptase translocation inhibitor that has shown potency against MDR HIV strains. It is in an ongoing phase 2b, double-blind, active-comparator-controlled, dose-ranging, study evaluating ISL in treatment-naive adults with HIV-1 infection without history of antiretroviral (ARV) resistance. Participants were randomly assigned to receive 0.25 mg, 0.75 mg or 2.25 mg ISL in combination with doravirine (DOR) and lamivudine (3TC) or to receive DOR/3TC/tenofovir disoproxil fumarate (TDF) as a comparator group. At week 48, 0.75 mg ISL/DOR resulted in the greatest percentage of participants with HIV-1 RNA of less than 50 copies/mL compared with DOR/3TC/TDF (90% vs. 83.9%), suggesting it works at least as well as DOR/3TC/TDF. Out of 30 participants who received ISL 0.75 mg, 86.7% experienced an adverse event, with three drug-related events and two serious adverse events. The most common adverse events were diarrhea and nausea (13.3% each). None of the 30 participants experienced an adverse event that led to discontinuation of therapy. Adverse events were comparable with the active comparator.

Although ISL demonstrated a higher inhibitory quotient against drug-resistant HIV compared with approved nucleoside reverse transcriptase inhibitors in a previous pharmacokinetics study, it is still under investigation in phase 3 trials. These ongoing studies include evaluating ISL/DOR among HIV-1 treatment-naive patients compared with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) (ClinicalTrials.gov identifier: NCT04233879), switching to ISL/DOR from a current ART regimen in virologically suppressed HIV-1 patients (NCT04223778), switching from BIC/FTC/TAF to ISL/DOR in virologically suppressed HIV-1 patients (NCT04223791), comparing ISL/DOR with placebo in HIV-1-infected HTE patients (NCT04233216), using ISL/DOR as a once-monthly dose for HIV prophylaxis (NCT04003103) and using IDL/DOR as an implant for HIV prophylaxis.

Lenacapavir (LEN) is in an ongoing phase 2/3 double-blind, placebo-controlled study, CAPELLA, to evaluate its safety and efficacy as an add-on to a failing optimized background regimen (OBR) in HTE patients with MDR HIV-1 infection. The study includes adult patients on two or more fully active agents, with resistance to at least two agents from three of four main ARV classes and HIV-1 RNA of 400 copies/mL or higher.

A total of 36 participants were randomly assigned to receive either LEN or placebo for 14 days as part of the functional monotherapy period, and a separate cohort of 36 participants received open-label LEN. During the functional monotherapy period, those prescribed LEN received the oral lead-in dose. On day 15, those assigned LEN were transitioned to open-label subcutaneous (SC) injections every 6 months in addition to OBR. Those assigned placebo were switched to open-label LEN with the oral lead-in dose followed by SC injections every 6 months.

The primary endpoint was the proportion of participants who achieved at least a 0.5 log₁₀ copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period (day 14). Secondary outcomes included the proportion of participants with plasma HIV-RNA less than 50 copies/mL, as well as those less than 200 copies/mL at week 26 and then at week 52.

Preliminary data showed that a significantly higher proportion of participants who received LEN (n = 24) achieved the primary endpoint compared with placebo (n = 12), 88% vs 17% (p < 0.0001). Those who received LEN had a significantly greater mean decrease in viral load compared with placebo, –1.93 log₁₀ copies/ml vs. –0.29 log₁₀ copies/ml (P < .0001). According to the available data, 73% (19/26) of the participants who received SC LEN at week 26 had achieved HIV-1 RNA of less than 50 copies/mL.

Two participants developed treatment-emergent resistance. Both achieved resuppression with a change in their OBR. The most common adverse events reported with LEN included injection site reactions, such as swelling and erythema, headache, nausea, cough and diarrhea. There was one death reported due to pneumonia that was judged to be unrelated to the study drug.

Supported by results from the CAPELLA study, Gilead submitted a new drug application to the FDA for the approval of LEN in combination with other ARV agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg with MDR HIV-1 infection who are currently on a failing AVR regimen due to resistance, intolerance or safety considerations.

Conclusion

Participants who initiated on ISL/DOR in combination with 3TC and those who switched to ISL/DOR experienced high efficacy at week 48 as measured by proportion of participants with HIV-1 RNA less than 50 copies/mL, which was similar to those on DOR/3TC/TDF, and the regimen was well tolerated. More data are needed to evaluate the use in HTE patients with MDR HIV-1 infection.

LEN has shown potent antiviral activity when added to a failing regimen, led to high rates of virologic suppression when combined with an OBR and was well tolerated with no adverse events leading to discontinuation in HTE patients with MDR HIV-1 infection. The current CAPELLA study is still ongoing, and longer term data are limited.

References:
A phase 3, randomized, active-controlled, double-blind clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV- 1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). ClinicalTrials.gov identifier: NCT04223791. Updated April 29, 2021. Accessed August 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04223791.
A phase 3 randomized, active-controlled, double-blind clinical study to evaluate the antiretroviral activity, safety, and tolerability of doravirine/islatravir once-daily in HIV-1 infected treatment-naïve participants. ClinicalTrials.gov identifier: NCT04233879. Updated July 29, 2021. Accessed August 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04233879.
A phase 3 randomized, active-controlled, open-label clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV-1 virologically suppressed on antiretroviral therapy. ClinicalTrials.gov identifier: NCT04223778. Updated March 9, 2021. Accessed August 2, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04223778.
A phase 3, randomized, clinical study in HIV-1-infected heavily treatment-experienced participants evaluating the antiretroviral activity of blinded islatravir (ISL), doravirine (DOR), and doravirine/islatravir (DOR/ISL), each compared to placebo, and the antiretroviral activity, safety, and tolerability of open-label DOR/ISL. ClinicalTrials.gov identifier: NCT04233216. Updated July 29, 2021. Accessed August 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04233216.
Gilead submits new drug application to US Food and Drug Administration for lenacapavir, an investigational, long-acting capsid inhibitor for the treatment of HIV-1 in people with limited therapy options. News release. Gilead Sciences. June 28, 2021. Accessed July 15, 2021.
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Molina JM, et al. Lancet. 2021;doi:10.1016/S2352-3018(21)00021-7.
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Safety and pharmacokinetics of oral islatravir (MK-8591) once monthly in participants at low risk of human immunodeficiency virus 1 (HIV-1) infection (MK-8591-016). ClinicalTrials.gov identifier: NCT04003103. Updates December 10, 2020. Accessed August 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04003103.
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Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (CAPELLA). ClinicalTrials.gov identifier: NCT04150068. Updated February 8, 2021. Accessed August 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04150068.

For more information:
Shannon Ketchem, PharmD, is a clinical pharmacist at Denver Health Medical Center.
Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.

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Disclosures: Ketchum and Shihadeh report no relevant financial disclosures.

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What’s in the pipeline for multidrug-resistant HIV infections?

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