HIV-1 re-suppression on a first-line regimen despite the presence of phenotypic drug resistance

Abstract

We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV-1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.

HIV-1 Treatment Failure, Drug Resistance, and Clinical Outcomes in Perinatally Infected Children and Adolescents Failing First-Line Antiretroviral Therapy in Western Kenya

“…Resuppression despite resistance was described in adults, although reasons are ill-defined. 35 Notably, all 4 had low VLs (740-2160 copies/mL). Speculations, potentially Fourth, 3 of 4 CALWH with 40 , VL , 1000 copies/mL had resistance, 2 dual-class.…”

“…Resuppression despite resistance was described in adults, although reasons are ill-defined. 35 Notably, all 4 had low VLs (740–2160 copies/mL). Speculations, potentially related to such paradoxical observations demanding further investigation, include unclear mutation development timing, temporary viremia, low quasispecies proportion with DRMs, subtype, remarkable adherence, and unreported medications.…”

Prevalence and patterns of HIV drug resistance in patients with suspected virological failure in North-Western Tanzania

“… 12 If the cause of ART failure is extensive HIV drug resistance, durable re-suppression to a viral load level below 1000 copies/mL is unlikely to be achieved with enhanced adherence counselling. 13 However, patients are switched to pre-defined second-line regimens after first-line ART failure in countries implementing the public health treatment approach, including Tanzania, rather than being based on ARV resistance patterns. 7 Consequently, patients are put on ART regimens that may be suboptimal because of cross-resistance between first- and second-line ARVs.…”

Impact of Human Immunodeficiency Virus Drug Resistance Mutations Detected in Women Prior to Antiretroviral Therapy With Efavirenz + Tenofovir Disoproxil Fumarate + Lamivudine (or Emtricitabine)

“…It is notable that most study participants with PDR comprised of major NNRTI mutations, including K103N (estimated to confer a 15- to 40-fold reduction in EFV susceptibility for subtype C [ 19 ]), had suppression of HIV replication during treatment with TXE. This finding is consistent with studies of Kenyans and South Africans in whom PDR to NNRTI alone did not affect virologic outcome to EFV-based ART [ 5 , 7 ].…”