High Prevalence of Drug Resistance Mutations Among Patients Failing First-Line Antiretroviral Therapy and Predictors of Virological Response 24 Weeks After Switch to Second-Line Therapy in São Paulo State, Brazil

Abstract

Universal antiretroviral treatment with sustained viral suppression benefits patients and reduces HIV transmission. Effectiveness of therapy may be limited by antiretroviral drug resistance. Information on the resistance profile at treatment failure and its impact on antiretroviral drugs may subsidize subsequent treatment strategies. Partial pol sequences from 319 patients failing first-line therapy were analyzed for resistance associated mutations (RAMs) and HIV subtype. Demographic data, CD4 T cell count, viral load, and antiretroviral regimens and mutational profile at first-line failure were also investigated for associations to the response to second-line regimens. RAMs at the reverse transcriptase gene were frequent. Most sequences (88%) showed at least one mutation. A higher number of reverse transcriptase RAMs were associated to lower CD4 T cell counts and the use of tenofovir/lamivudine in first line. Among 205 with follow-up data, 76.6% were virally suppressed (below 200 copies/ml) after 24 weeks of second-line therapy. Most cases initiated second line with a regimen genotypic susceptibility score ≥2, but it did not predict viral suppression, that was independently associated with higher CD4 T cell counts and with the presence of nucleos(t)ide analog reverse transcriptase inhibitor (NRTI) RAMs. This study documented extensive resistance at first-line failure in this area in Brazil, highlights the risks of low CD4 T cell counts to second-line therapy, and supports the notion that recycled NRTIs may contribute to viral suppression even when genotypic resistance is present.

Virologic suppression in response to antiretroviral therapy despite extensive resistance within HIV-1 reverse transcriptase after the first virologic failure

“…The K103 N/S mutation was documented in most genotypic sequences, due to the frequent use of EFV as the primary NNRTI in the first-line therapy for more than a decade in Brazil. These findings are similar to the national data [ 10 – 12 ] and data from low- and middle-income countries [ 14 , 15 , 26 , 27 ]. The susceptibility of etravirine, a second-generation NNRTI, was not influenced by experiencing a long period of time in virologic failure while using EFV or NVP, or by the number of NNRTI-associated mutations.…”

“…In addition, it decreases the replication capacity of HIV-1 [ 23 , 24 ]. Its presence has been associated with virologic success [ 10 ], but we did not observe this success in the present study.…”

“…We found no association between the number of NRTI(t)-associated mutations and the ARVs used at the time of genotyping, including ARV regimens with or without TDF. There are studies showing a greater number of resistance-associated mutations among AZT [ 30 ] and TDF users [ 10 , 31 ]. However, those studies had populations with different characteristics, especially with regard to subtype prevalence.…”

“…A recent study from the city of São Paulo 10 on patients who failed first-line therapy between 2013 and 2015 found a higher prevalence of the M184 V/I mutation (74.3%) and K103 codon (56.7%), similar to that found in other Brazilian states [ 11 ]. Among the 205 subjects who started the second-line therapy with NRTI(t)s combined with protease inhibitor/ritonavir (PI/r), 76.6% experienced virologic suppression (< 200 copies/ml), despite the extensive resistance of the virus to NRTI(t)s [ 10 ].…”

Prevalence of Antiretroviral Drug Resistance Mutations in HIV Seropositive Patients from an Outpatient Clinic of a Large University Hospital from São Paulo, Brazil

“…9 The presence of DRM is an important concern both when initiating an ARV therapy and to plan modification of therapy in patients with virologic failure observed during ARV regimen. 10 Inadequate adherence and virologic failure are frequently associated with the occurrence of these mutations, [11][12][13] but the presence of some mutations, as to the nucleoside reverse transcriptase inhibitor (NRTI) class at first-line failure, may actually be used as a proxy of success in second-line therapy, 13,14 either as a marker of adherence of due to some, yet uncharacterized, loss of viral fitness. The major concern is the fact that resistance to HIV drugs can compromise not only therapy but also current and future prophylactic ARV prevention strategies.…”