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HIV type 1 drug resistance patterns among patients failing first and second line antiretroviral therapy in Nairobi, Kenya.

ABSTRACT: BACKGROUND: The ever-expanding rollout of antiretroviral therapy in poor resource settings without routine virological monitoring has been accompanied with development of drug resistance that has resulted in limited treatment success. METHODS: A cross-sectional study with one time viral load was conducted during the period between 2012 and 2013 to determine treatment failure and drug resistance mutations among adults receiving first-line (44) (3TC_d4T/AZT_NVP/EFV) and second-line (20) (3TC/AZT/LPV/r) in Nairobi, Kenya. HIV-1 pol-RT genotyping for drug resistance was performed using an in-house protocol. RESULTS: A total of 64 patients were recruited (mean age 36.9 yrs.) during the period between 2012 and 2013 of the 44 adult patients failing first-line 24 (40.9%) had drug resistance mutations. Eight (8) patients had NRTI resistance mutations with NAMS M184V (54.2%) and K65R (8.4%) mutations being the highest followed by TAMs T215Y and K70R (12.5%). In addition, among patients failing second-line (20), six patients (30%) had NNRTI resistance; two patients on K103N and G190A mutations while V106A, Y184V, A98G, Y181C mutations per patient were also detected. However, for NRTI two patients had TAM T215Y. M184V mutation occurred in one patient. CONCLUSIONS: The study findings showed that HIV-1 drug resistance was significantly high in the study population. The detected accumulated resistance strains show that emergence of HIV drug resistance will continue to be a big challenge and should be given more attention as the scale up of treatment in the country continues.

SUBMITTER: Koigi P

PROVIDER: S-EPMC4295353 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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HIV type 1 drug resistance patterns among patients failing first and second line antiretroviral therapy in Nairobi, Kenya.

Koigi Peter P Ngayo Musa Otieno MO Khamadi Samoel S Ngugi Caroline C Nyamache Anthony Kebira AK

BMC research notes 20141209

<h4>Background</h4>The ever-expanding rollout of antiretroviral therapy in poor resource settings without routine virological monitoring has been accompanied with development of drug resistance that has resulted in limited treatment success.<h4>Methods</h4>A cross-sectional study with one time viral load was conducted during the period between 2012 and 2013 to determine treatment failure and drug resistance mutations among adults receiving first-line (44) (3TC_d4T/AZT_NVP/EFV) and second-line (2 ...[more]

PMID: 25487529

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Project description:WHO recommends starting therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs), i.e. nevirapine or efavirenz, with lamivudine or emtricitabine, plus zidovudine or tenofovir. Few studies have compared resistance patterns induced by efavirenz and nevirapine in patients infected with the CRF01_AE Southeast Asian HIV-subtype. We compared patterns of NNRTI- and NRTI-associated mutations in Thai adults failing first-line nevirapine- and efavirenz-based combinations, using bayesian statistics to optimize use of data.In a treatment cohort of HIV-infected adults on NNRTI-based regimens, 119 experienced virologic failure (>500 copies/mL), with resistance mutations detected by consensus sequencing. Mutations were analyzed in relation to demographic, clinical, and laboratory variables at time of genotyping. The Geno2Pheno system was used to evaluate second-line drug options. Eighty-nine subjects were on nevirapine and 30 on efavirenz. The NRTI backbone consisted of lamivudine or emtricitabine plus either zidovudine (37), stavudine (65), or tenofovir (19). The K103N mutation was detected in 83% of patients on efavirenz vs. 28% on nevirapine, whereas Y181C was detected in 56% on nevirapine vs. 20% efavirenz. M184V was more common with nevirapine (87%) than efavirenz (63%). Nevirapine favored TAM-2 resistance pathways whereas efavirenz selected both TAM-2 and TAM-1 pathways. Emergence of TAM-2 mutations increased with the duration of virologic replication (OR 1.25-1.87 per month increment). In zidovudine-containing regimens, the overall risk of resistance across all drugs was lower with nevirapine than with efavirenz, whereas in tenofovir-containing regimen the opposite was true.TAM-2 was the major NRTI resistance pathway for CRF01_AE, particularly with nevirapine; it appeared late after virological failure. In patients who failed, there appeared to be more second-line drug options when zidovudine was combined with nevirapine or tenofovir with efavirenz than with alternative combinations.

Project description:INTRODUCTION:Tenofovir-based first-line antiretroviral therapy (ART) is recommended globally. To evaluate the impact of its incorporation into the World Health Organization (WHO) guidelines, we examined treatment failure and drug resistance among a cohort of patients on tenofovir-based first-line ART at the Academic Model Providing Access to Healthcare, a large HIV treatment programme in western Kenya. METHODS:We determined viral load (VL), drug resistance and their correlates in patients on ?six months of tenofovir-based first-line ART. Based on enrolled patients' characteristics, we described these measures in those with (prior ART group) and without (tenofovir-only group) prior non-tenofovir-based first-line ART using Wilcoxon rank sum and Fisher's exact tests. RESULTS:Among 333 participants (55% female; median age 41 years; median CD4 336 cells/µL), detectable (>40 copies/mL) VL was found in 18%, and VL>1000 copies/mL (WHO threshold) in 10%. Virologic failure at both thresholds was significantly higher in 217 participants in the tenofovir-only group compared with 116 in the prior ART group using both cut-offs (24% vs. 7% with VL>40 copies/mL; 15% vs. 1% with VL>1000 copies/mL). Failure in the tenofovir-only group was associated with lower CD4 values and advanced WHO stage. In 35 available genotypes from 51 participants in the tenofovir-only group with VL>40 copies/mL (69% subtype A), any resistance was found in 89% and dual-class resistance in 83%. Tenofovir signature mutation K65R occurred in 71% (17/24) of the patients infected with subtype A. Patients with K65R had significantly lower CD4 values, higher WHO stage and more resistance mutations. CONCLUSIONS:In this Kenyan cohort, tenofovir-based first-line ART resulted in good (90%) virologic suppression including high suppression (99%) after switch from non-tenofovir-based ART. Lower virologic suppression (85%) and high observed resistance levels (89%) in the tenofovir-only group impact future treatment options, support recommendations for widespread VL monitoring in such resource limited settings to identify early treatment failure and suggest consideration of individualized resistance testing to design effective subsequent regimens.

Project description:BackgroundPre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2-9%) or higher (≥10%) frequencies during efavirenz- vs. nevirapine-ART.MethodsWe conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA ≥400 copies/mL at month-12 of ART, was compared by PDR genotypes.FindingsPDR was detected in 59/1231 (4·8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69·2% (27/39) vs. wild-type 10·4% (70/674); p = 0·0001], whether detected as minority [66·7% (4/6)] or higher [69·7% (23/33)] frequencies in an individual's HIV quasispecies (p = 0·002 and p < 0·0001, respectively), or mutations at single [50·0% (12/24)] or multiple [100·0% (15/15)] codons (p < 0·0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25·0% (5/20) vs. wild-type 5·0% (25/498); p = 0·005], but only if detected at multiple drug-resistant codons [50·0% (3/6); p = 0·003] or high frequencies PDR [33·3% (5/15); p = 0·001].InterpretationThe risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz- compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings.FundingNIH, PEPFAR.

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HIV type 1 drug resistance patterns among patients failing first and second line antiretroviral therapy in Nairobi, Kenya.

Publications

HIV type 1 drug resistance patterns among patients failing first and second line antiretroviral therapy in Nairobi, Kenya.

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