Trends in Pretreatment HIV-1 Drug Resistance in Antiretroviral Therapy-naive Adults in South Africa, 2000–2016: A Pooled Sequence Analysis

Chimukangara, Benjamin; Lessells, Richard; Rhee, Soo-Yon; Giandhari, Jennifer; Kharsany, Ayesha B. M.; Naidoo, Kogieleum; Lewis, Lara; Cawood, Cherie; Khanyile, David; Ayalew, Kassahun; Diallo, Karidia; Samuel, Reshmi; Hunt, Gillian; Vandormael, Alain; Stray‐Pedersen, Babill; Gordon, Michelle; Makadzange, Tariro; Kiepiela, Photini; Ramjee, Gita; Ledwaba, Johanna; Kalimashe, Monalisa; Morris, Lynn; Parikh, Urvi M.; Mellors, John W.; Shafer, Robert W.; Katzenstein, David; Moodley, Prashini; Rk, Gupta; Pillay, Deenan; Karim, Salim Safurdeen. Abdool; Oliveira, Túlio de

doi:10.1016/j.eclinm.2019.03.006

Cited by 66 publications

(62 citation statements)

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“…NAMSAL reported a much lower prevalence of NNRTI resistance (6%) than we did (14%), which is consistent with other data in the region. 41 In NAMSAL, investigators reported no impact of baseline NNRTI resistance on outcomes, although 6/16 failures on EFV had pre-existing NNRTI resistance. In that study, none of the three failures in the DTG arm at 48 weeks had baseline resistance to NNRTIs, the 6% of those that did appeared to suppress during the study.…”

Section: Discussionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Siedner¹,

Moorhouse²,

Simmons³

et al. 2020

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Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

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Section: Discussionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Siedner¹,

Moorhouse²,

Simmons³

et al. 2020

Preprint

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“…Pretreatment drug resistance (PDR) is defined by the WHO as resistance that is detected among people either newly initiating or reinitiating first-line ART [3]. In previous studies, non-nucleoside reverse transcriptase inhibitor (NNRTI) related PDR exceeded 10% in many African settings, supporting the move to include the integrase inhibitor dolutegravir (DTG) in first-line regimens [4,5]. Malawi has set up an effective HIV treatment program.…”

Section: Introductionmentioning

confidence: 99%

Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi

et al. 2020

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Background: Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi. Methods: We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019. Results: PDR testing was successful in 197 of 200 samples. The overall NNRTI-PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI-PDR was 11.2% (22/197). The most common mutation was K103N (5.6%, 11/197), followed by Y181C (3.6%, 7/197). In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI-PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up. Conclusion: The prevalence of NNRTI-PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa.

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“…Consistent use of ART improves immunological response and leads to viral suppression in PLHIV with a subsequent decline in the frequencies of opportunistic infections, including OC [ 29 – 31 ]. The small increase in the prevalence of OC observed between 2012 and 2014 could be due to the increasing number of the “late presenters” [ 32 , 33 ]. That is, patients presenting to care with advanced HIV disease or those already on ART re-presenting to care with advanced HIV disease due to treatment failure [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of HIV-associated esophageal candidiasis in sub-Saharan Africa: a systematic review and meta-analysis

et al. 2020

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Background Esophageal candidiasis (OC) is a common AIDS-defining opportunistic infection. Antiretroviral therapy (ART) reduces the occurrence of OC and other opportunistic infections among persons living with HIV (PLHIV). We sought to determine and compare the prevalence of OC in the ART and pre-ART era among PLHIV in sub-Saharan Africa (SSA). Methods We searched PubMed, Embase, Web of Science, and the African Journals Online databases to select studies in English and French reporting the prevalence of HIV-associated OC in SSA from January 1980 to June 2020. Reviews, single-case reports, and case series reporting < 10 patients were excluded. A random-effect cumulative meta-analysis was performed using STATA 16.0, and trend analysis performed using GraphPad Prism 8.0. Results Thirteen eligible studies from 9 SSA countries including a total of 113,272 patients were qualitatively synthesized, and 9 studies were included in the meta-analysis. Overall pooled prevalence of HIV-associated OC was 12% (95% confidence interval (CI): 8 to 15%, I2 = 98.61%, p <. 001). The prevalence was higher in the pre-ART era compared to the ART era, but not to statistical significance (34.1% vs. 8.7%, p = 0.095). In those diagnosed by endoscopy, the prevalence was higher compared to patients diagnosed by non-endoscopic approaches, but not to statistical significance (35.1% vs. 8.4%, p = .071). The prevalence of OC significantly decreased over the study period (24 to 16%, p < .025). Conclusion The prevalence of OC among PLHIV in the ART era in SSA is decreasing. However, OC remains a common problem. Active endoscopic surveillance of symptomatic patients and further empirical studies into the microbiology, optimal antifungal treatment, and impact of OC on quality of life of PLHIV in SSA are recommended.

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Trends in Pretreatment HIV-1 Drug Resistance in Antiretroviral Therapy-naive Adults in South Africa, 2000–2016: A Pooled Sequence Analysis

Cited by 66 publications

References 64 publications

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi

Prevalence of HIV-associated esophageal candidiasis in sub-Saharan Africa: a systematic review and meta-analysis

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