How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

Abstract

Purpose of reviewTo review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs). Recent findingsThe greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.

Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial

“…HIV drug resistance selected from the use of PrEP could affect success of future treatment or could be transmitted to a partner and contribute to rising community resistance prevalence. 28 In the HPTN-084 trial of long-acting injectable cabotegravir (CAB-LA) as PrEP, 44% of infections in the CAB-LA arm developed mutations in the integrase gene, likely due to delayed detection of infection with ongoing lowlevel replication that enabled selection of resistance. [29][30][31] By contrast, only 2 of 13 individuals (15%) who continued ring use for at least 3 months after HIV infection had NNRTI resistance mutations and neither had decreases in viral susceptibility to DPV.…”

Promises and potential pitfalls of long-acting injectable pre-exposure prophylaxis

“…The development of integrase inhibitor resistance is concerning because it will render the individual unable to use Dolutegravir and other integrase inhibitors during treatment. 33 Drug-resistant variants have been found in people who have been initiated onto CAB LA with an undiagnosed HIV infection and in the rare instances (< 0.3% in HPTN 083; 0.06% in HPTN 084) breakthrough infections have occurred while the individuals had high (protective) systemic concentrations of Cabotegravir. 34 , 35 This may be due to false-negative HIV screening during acute HIV infection prior to seroconversion.…”

N-Substituted Bicyclic Carbamoyl Pyridones: Integrase Strand Transfer Inhibitors that Potently Inhibit Drug-Resistant HIV-1 Integrase Mutants

“…INSTIs are important components of cART formulations. − The first-generation INSTIs raltegravir (RAL, 1 ) and elvitegravir (EVG, 2 ) have been superseded by the second-generation INSTIs dolutegravir (DTG, 3 ), bictegravir (BIC, 4 ), and cabotegravir (CAB, 5 ) (Figure ). ,,, Treatment with the first-generation INSTIs has led to the emergence of INSTI-resistant mutant forms of IN and, although second-generation INSTIs are less susceptible to the development of resistance than first-generation INSTIs, resistance is a significant problem. ,− Causes of virological failure (VF) for INSTIs are currently an active area of investigation . Because of the emergence of resistance to the second-generation INSTIs and the potential for an increased frequency of VF associated with long-acting antiretroviral therapy (LA-ART), it is critical to develop new INSTIs that retain good antiviral efficacy against the known resistant IN mutants.…”

“…In single-round infection assays that employ viral constructs with wild-type (WT) IN or mutant INs having resistance mutations, reductions in susceptibility to DTG relative to WT are >5-fold for G118R, 2-fold for R263K, and 2-fold for G140S/Q148H. , Recently, the FDA has approved an injectable formulation of CAB in combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine for use in LA-ART. However, if there are adherence issues, these therapies carry an increased risk of breakthrough infection and selection for resistance, due to CAB’s long pharmacokinetic half-life (suboptimal plasma level concentrations can last for several months). ,, The potential for virological failure during CAB therapy arises in part from the fact that this drug has a significant reduction in susceptibility to the IN mutants G118R, R263K, N155H and G140S/Q148H. Close monitoring is recommended to minimize the emergence of drug-resistant mutant forms of IN …”

“…However, if there are adherence issues, these therapies carry an increased risk of breakthrough infection and selection for resistance, due to CAB’s long pharmacokinetic half-life (suboptimal plasma level concentrations can last for several months). 23 , 29 , 30 The potential for virological failure during CAB therapy arises in part from the fact that this drug has a significant reduction in susceptibility to the IN mutants G118R, R263K, N155H and G140S/Q148H. Close monitoring is recommended to minimize the emergence of drug-resistant mutant forms of IN.…”