Managing HIV Treatment Failure: Time to REVAMP?

Abstract

Current antiretroviral regimens suppress viral load levels, increase CD4 cell counts, and reduce HIVrelated morbidity and mortality as well as HIV transmission. More than 27 million people with HIV are currently receiving antiretroviral therapy worldwide, and 90% of them are virally suppressed (1). Despite the efficacy of first-line antiretroviral regimens, virologic failure occurs and must be assessed andmanaged appropriately. Virologic failure on a first-line antiretroviral regimen is assessed by confirming the viral load elevation, assessing adherence and tolerability, and, in resource-rich countries, conducting genotypic drug resistance testing on the basis of short-term virologic benefits demonstrated in studies from more than 20 years ago (2, 3). This assessment seeks to identify the cause of virologic failure and informs antiretroviral regimen management—often either 1) reinforcing adherence or managing toxicity and continuing the current regimen or 2) identifying drug resistance and choosing an optimal second-line antiretroviral regimen based on the results. Genotypic resistance testing can be technically and financially challenging for resource-poor countries, although it is increasingly considered (4). Should resistance testing now be recommended for management of virologic failure on first-line regimens in lowandmiddle-income countries? To address this question, Siedner and colleagues (5) did the REVAMP (Resistance Testing Versus Adherence Support for Management of Patients with Virologic Failure on First-Line Antiretroviral Therapy in sub-Saharan Africa) trial. They enrolled 840 adults in South Africa and Uganda with HIV viral load levels of 1000 copies/mL or higher and randomly assigned them to genotypic resistance testing or standard of care management—adherence counseling and repeated viral load testing, as recommended by the World Health Organization (WHO). The proportion with viral load levels below 200 copies/mL at month 9, the primary end point, did not differ between groups (63% in the genotype group and 61% in the standard of care group). The authors attribute these relatively low suppression rates to the public-sector setting of the trial. Of note, among those with an HIV RNA viral load of 1000 copies/mL or higher at 9months, 76% in the SOCgroup had antiretroviral resistance versus 59% in the genotype group, a statistically significant difference. The study has significant strengths, including its realworld setting in public health ambulatory clinics, successful completion despite disruption by the COVID-19 pandemic, and very good retention with few participant crossovers. There were few exclusions, and about half of the participants were women, including a small number who were pregnant. Several limitations are noteworthy: A full understanding of the results is limited by the lack of granular data on viral load levels, timing of changes to second-line therapy, and frequency of specific mutations in the genotype group at baseline and in both groups among those with persistent viremia at month 9. The unblinded design could have led to differences in management between groups, although blinding would not have been practical. Most notably, participants were receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens at study entry, which is no longer the standard of care. Guidelines fromWHO now recommend initiation of an integrase inhibitor–based regimen—dolutegravir with 2 nucleoside reverse transcriptase inhibitors (6)—and many patients have transitioned to this regimen from older NNRTI-based and protease inhibitor (PI)–based regimens throughout theworld (7). Furthermore, currentWHOguidelines formanaging virologic failure of first-line regimens recommend empirically switching from NNRTIs to dolutegravir rather than to a PI-based regimen, as was the standard strategy in this trial. These secular trends in management hinder generalizability of the results to the current era. Suboptimal adherence is a common cause of virologic failure (8), but management strategies may vary by the specific antiretroviral regimen and its barrier to drug resistance. Some drugs (such as emtricitabine, lamivudine, NNRTIs, and the integrase inhibitors elvitegravir and raltegravir) have a low barrier to resistance, and suboptimal adherence readily leads to ongoing viral replication, selection of drug-resistant viral strains, and failure that necessitates changing the regimen. The REVAMP study showed that, with the initial NNRTI-based regimens used, simply confirming a viral load level of 1000 copies/mL or higher in the standard of care group was enough for the clinician to infer drug resistance and change the regimen: No benefit for drug resistance testing in the intervention group could be shown. With other drugs that have a high barrier to resistance even in the setting of suboptimal adherence (such as PIs and the integrase inhibitors bictegravir and dolutegravir), resistance testing better informs the decision about whether resistance exists and the regimen needs to be changed. Current guidelines around the world now recommend dolutegravir-based (and in some settings, bictegravir-based) regimens for first-line antiretroviral therapy on the basis of their potency, convenience, tolerability, and barrier to resistance (6, 9). Optimal second-line regimens are informed by drug resistance testing in resource-rich countries and should include 2 new active drugs (1 with a high barrier to resistance) (9). In lowand middle-income countries, WHO provides an algorithm for choosing the second-line regimen based on drug resistance considerations (6). The recent NADIA (Nucleosides And Darunavir/ Dolutegravir In Africa) study enrolled participants with confirmed virologic failure receiving an NNRTI-based regimen at 7 sites in sub-Saharan Africa; without using real-time results of drug resistance testing, the researchers found that of participants randomly assigned to empirically change to regimens with dolutegravir or the PI darunavir, 85% reestablished virologic control (10). Selection of third-line regimens is more complicated, and current