High level of HIV-1 drug resistance mutations in patients with unsuppressed viral loads in rural northern South Africa

Abstract

BackgroundCombination antiretroviral therapy (cART) has significantly reduced HIV morbidity and mortality in both developed and developing countries. However, the sustainability of cART may be compromised by the emergence of viral drug resistance mutations (DRM) and the cellular persistence of proviruses carrying these DRM. This is potentially a more serious problem in resource limited settings.MethodsDRM were evaluated in individuals with unsuppressed viral loads after first or multiple lines of cART at two sites in rural Limpopo, South Africa. Seventy-two patients with viral loads of >1000 copies/ml were recruited between March 2014 and December 2015. Complete protease (PR) and partial Reverse Transcriptase (RT) sequences were amplified from both plasma RNA and paired proviral DNA from 35 of these subjects. Amplicons were directly sequenced to determine subtype and DRM using the Stanford HIV Drug Resistance Interpretation algorithm.ResultsAmong the 72 samples, 69 could be PCR amplified from RNA and 35 from both RNA and DNA. Sixty-five (94.2%) viruses were subtype C, while one was subtype B (1.4%), one recombinant K/C, one recombinant C/B and one unclassified. Fifty-eight (84%) sequences carried at least one DRM, while 11 (15.9%) displayed no DRM. DRM prevalence according to drug class was: NRTI 60.8% NNRTI 65.2%, and PI 5.8%. The most common DRMs were; M184V (51.7%), K103N (50%), V106M (20.6%), D67N (13.3%), K65R (12%). The frequency of the DRM tracked well with the frequency of use of medications to which the mutations were predicted to confer resistance. Interestingly, a significant number of subjects showed predicted resistance to the newer NNRTIs, etravirine (33%) and rilpivirine (42%), both of which are not yet available in this setting. The proportion of DRM in RNA and DNA were mostly similar with the exception of the thymidine analogue mutations (TAMs) D67N, K70R, K219QE; and K103N which were slightly more prevalent in DNA than RNA. Subjects who had received cART for at least 5 years were more likely to harbour >2 DRM (p < 0.05) compared to those treated for a shorter period. DRM were more prevalent in this rural setting compared to a neighbouring urban setting.ConclusionWe found a very high prevalence of NRTI and NNRTI DRM in patients from rural Limpopo settings with different durations of treatment. The prevalence was significantly higher than those reported in urban settings in South Africa. The dominance of NNRTI based mutations late in treatment supports the use of PI based regimens for second line treatment in this setting. The slight dominance of TAMs in DNA from infected PBMCs compared to plasma virus requires further studies that should include cART subjects with suppressed virus. Such studies will improve our understanding of the pattern of drug resistance and dynamics of viral persistence in these rural settings.

Prevalence and characteristics of HIV drug resistance among antiretroviral treatment (ART) experienced adolescents and young adults living with HIV in Ndola, Zambia

“…As a result, even before the restricted availability of etravirine in Zambia, more than one out of three (36%) patients with HIVDR may potentially be resistant to the only salvage NNRTI available in the public health sector in Zambia. The high prevalence of the Y181C and Y188C mutations has been demonstrated in earlier studies from the region including Zambia [9,26,11]. In our study, resistance to these drugs may be due in part to cross resistance with nevirapine and efavirenz which are widely used in PMTCT or first line ART.…”

“…High levels of HIVDR mutations are not unique to AYA or Zambia. Several studies among adults from Zambia, South Africa, Togo and Tanzania, have shown a range of HIVDR from 84-98% [26,27]. The only study among children and adolescents conducted in Tanzania, found 90% had drug resistance with 79% having multiclass resistance.…”

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice

“…The prevalence of RPV-resistant isolates ranges from 4 to 10% in individuals who are treatment naive (26)(27)(28)(29)(30)(31)(32)(33) to 42 to 72% in individuals with viremia during non-RPVcontaining ART (34)(35)(36)(37)(38)(39)(40)(41). Three clinical studies evaluated the efficacy of RPV-containing regimens compared to EFV-containing regimens in treatment-naive individuals (the ECHO, THRIVE, and STaR trials), all of which identified multiple RPV-associated resistance mutations that arose in subjects on RPV-containing ART (42,43).…”

Factors Associated with Adverse Therapeutic Outcomes in People Living with HIV (PLHIV) Monitored in Roi Baudouin Health Care Center, Dakar, Senegal

“…Thus, special attention in addition to strengthening therapeutic education must be paid to patients who replicate between 50 and 1000 copies to minimize the occurrence of mutations. This is even more true since a lot of scientific evidence has shown in so-called controlled patients with persistent viral replication, a higher risk of occurrence of therapeutic failure [16] [17] [18] [19]. Virological failure in our series was 19%.…”