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Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia.

ABSTRACT: BACKGROUND: The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Africa is sparse. METHODS: HIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line therapy in Jimma, Ethiopia. VL measurements were done at baseline and after 3 and 6 months. Genotypic HIV drug resistance (HIVDR) was performed on patients exhibiting virological failure (>1000 copies/mL at 6 months) or slow virological response (>5000 copies/mL at 3 months and <1000 copies/mL at 6 months). RESULTS: Two hundred sixty five patients had VL data available at baseline and at 6 months. Virological failure was observed among 14 (5.3%) participants out of 265 patients. Twelve samples were genotyped and six had HIV drug resistance (HIVDR) mutations at baseline. Among virological failures, 9/11 (81.8%) harbored one or more HIVDR mutations at 6 months. The most frequent mutations were K103N and M184VI. CONCLUSIONS: Our data confirm that the currently recommended first-line ART regimen is efficient in the vast majority of individuals initiating therapy in Jimma, Ethiopia eight years after the introduction of ART. However, the documented occurrence of transmitted resistance and accumulation of acquired HIVDR mutations among failing patients justify increased vigilance by improving the availability and systematic use of VL testing to monitor ART response, and underlines the need for rapid, inexpensive tests to identify the most common drug resistance mutations.

SUBMITTER: Abdissa A

PROVIDER: S-EPMC4234735 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia.

Abdissa Alemseged A Abdissa Alemseged A Yilma Daniel D Fonager Jannik J Audelin Anne M AM Christensen Lone H LH Olsen Mette F MF Tesfaye Markos M Kaestel Pernille P Girma Tsinuel T Aseffa Abraham A Friis Henrik H Pedersen Court C Andersen Aase B AB

BMC infectious diseases 20140404

<h4>Background</h4>The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Africa is sparse.<h4>Methods</h4>HIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line ...[more]

PMID: 24708645

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Project description:First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART.We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance - Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ? 2 TAMs; or M184V+? 1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line.A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ? 1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ? 2 TAMs; and 32 with M184V+? 1 TAM. Factors associated with multi-NRTI RAMs were CD4 ? 200 cells/µL at genotyping (OR=4.43, 95% CI [1.59-12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39-16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ? 95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43-35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome.Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

Project description:The impact of minor drug-resistant variants of the type 1 immunodeficiency virus (HIV-1) on the failure of antiretroviral therapy remains unclear. We have evaluated the importance of detecting minor populations of viruses resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) during intermittent antiretroviral therapy, a high-risk context for the emergence of drug-resistant HIV-1. We carried out a longitudinal study on plasma samples taken from 21 patients given efavirenz and enrolled in the intermittent arm of the ANRS 106 trial. Allele-specific real-time PCR was used to detect and quantify minor K103N mutants during off-therapy periods. The concordance with ultra-deep pyrosequencing was assessed for 11 patients. The pharmacokinetics of efavirenz was assayed to determine whether its variability could influence the emergence of K103N mutants. Allele-specific real-time PCR detected K103N mutants in 15 of the 19 analyzable patients at the end of an off-therapy period while direct sequencing detected mutants in only 6 patients. The frequency of K103N mutants was <0.1% in 7 patients by allele-specific real-time PCR without further selection, and >0.1% in 8. It was 0.1%-10% in 6 of these 8 patients. The mutated virus populations of 4 of these 6 patients underwent further selection and treatment failed for 2 of them. The K103N mutant frequency was >10% in the remaining 2, treatment failed for one. The copy numbers of K103N variants quantified by allele-specific real-time PCR and ultra-deep pyrosequencing agreed closely (??=?0.89 P<0.0001). The half-life of efavirenz was higher (50.5 hours) in the 8 patients in whom K103N emerged (>0.1%) than in the 11 patients in whom it did not (32 hours) (P?=?0.04). Thus ultrasensitive methods could prove more useful than direct sequencing for predicting treatment failure in some patients. However the presence of minor NNRTI-resistant viruses need not always result in virological escape.ClinicalTrials.gov NCT00122551.

Project description:Stavudine (D4T), zidovudine (AZT), and tenofovir (TDF) along with lamivudine (3TC) are the most widely used HIV treatment regimens in China. China's National Free Antiretroviral Treatment Programme (NFATP) has replaced D4T with AZT or TDF in the standard first-line regimens since 2010. Few studies have evaluated the adherence, virological outcome, and drug resistance in HIV patients receiving first-line antiretroviral therapy (ART) from 2011 to 2015 due to changes in ART regimen.From 2011 to 2015, 2787 HIV patients were examined, with 364, 1453, and 970 patients having initiated D4T-, AZT-, and TDF-based first-line ART regimens, respectively. The Cochran-Armitage test was used to examine the trends in clinical and virological outcomes during 2011 to 2015. Logistic regression was used to examine the effects of different regimens after 9 to 24 months of ART.From 2011 to 2014-2015, adverse drug reactions decreased from 18.9% to 6.7%, missed doses decreased from 9.9% to 4.6%, virological failure decreased from 16.2% to 6.4%, and drug resistance rates also significantly decreased from 5.4% to 1.1%. These successes were strongly associated with the standardized use of TDF- or AZT-based regimens in place of the D4T-based regimen. Poor adherence decreased from 11.3% in patients who initiated D4T-based regimens to 4.9% in those who initiated TDF-based regimens, adverse drug reactions decreased from 32.4% to 6.7%, virological failure reduced from 18.7% to 8.6%, and drug resistance reduced from 5.8% to 2.9%. Compared with patients who initiated AZT-based regimens, patients who initiated TDF-based regiments showed significant reductions in adherence issues, adverse drug reactions, virological outcomes, and drug resistance. Significant differences were also observed between those who initiated D4T- and AZT-based regimens.The good control of HIV replication and drug resistance was attributed to the success of China's NFATP from 2011 to 2015. This study provided real world evidence for further scaling up ART and minimizing the emergence of drug resistance in the "Three 90" era.

Project description:IntroductionAntiretroviral treatment (ART) has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF) and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo.MethodsHIV viral load (VL) testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow-up visit (June to September 2014). Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA). Genotypic drug resistance was done for all samples with VL>1000 copies/ml.Results and discussionAmong 283 perinatally HIV-1-infected children and adolescents included, 167 (59%) were adolescents and 116 (41%) were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months). For 228 (80.6%), the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine and lamivudine) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine or efavirenz). Only 28 (9.9%) were on a protease inhibitor (PI)-based regimen. VL was below the detection limit (i.e. 40 copies/ml) for 102 (36%), between 40 and 1000 copies/ml for 35 (12.4%) and above 1000 copies/ml for 146 (51.6%). Genotypic drug-resistance testing was successful for 125/146 (85.6%); 110/125 (88.0%) were resistant to both NRTIs and NNRTIs, 1/125 (0.8%) to NRTIs only, 4/125 (3.2%) to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125) of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in their current ART regimen.ConclusionsOur study provided important information on virological outcome on lifelong ART in perinatally HIV-1-infected children and adolescents who were still on ART and continued to attend antiretroviral (ARV) clinics for follow-up visits. Actual conditions for scaling up and monitoring lifelong ART in children in resource-limited countries can have dramatic long-term outcomes and illustrate that paediatric ART receives inadequate attention.

Project description:IntroductionThe current expansion of antiretroviral treatment (ART) in the developing world without routine virological monitoring still raises concerns on the outcome of the strategy in terms of virological success and drug resistance burden. We assessed the virological outcome and drug resistance mutations in patients with 36 months' ART experience, and monitored according to the WHO public health approach in Cameroon.MethodsWe consecutively recruited between 2008 and 2009 patients attending a national reference clinic in Yaoundé - Cameroon, for their routine medical visits at month 36±2. Observance data and treatment histories were extracted from medical records. Blood samples were collected for viral load (VL) testing and genotyping of drug resistance when HIV-1 RNA ≥1000 copies/ml.ResultsOverall, 376 HIV-1 infected adults were recruited during the study period. All, but four who received PMTCT, were ART-naïve at treatment initiation, and 371/376 (98.7%) started on a first-line regimen that included 3TC +d4T/AZT+NVP/EFV. Sixty-six (17.6%) patients experienced virological failure (VL ≥1000 copies/ml) and 53 carried a resistant virus, thus representing 81.5% (53/65) of the patients who failed. Forty-two out of 53 were resistant to nucleoside and non-nucleoside reverse-transcriptase inhibitors (NRTIs+NNRTIs), one to protease inhibitors (PI) and NNRTIs, two to NRTIs only and eight to NNRTIs only. Among patients with NRTI resistance, 18/44 (40.9%) carried Thymidine Analog Mutations (TAMs), and 13/44 (29.5%) accumulated at least three NRTI resistance mutations. Observed NNRTI resistance mutations affected drugs of the regimen, essentially nevirapine and efavirenz, but several patients (10/51, 19.6%) accumulated mutations that may have compromised etravirine use.ConclusionsWe observed a moderate level of virological failure after 36 months of treatment, but a high proportion of patients who failed developed drug resistance. Although we found that for the majority of patients, second-line regimens recommended in Cameroon would be still effective, accumulated resistance mutations are of concern and may compromise future treatment strategies, stressing the need for virological monitoring in resource-limited settings.

Dataset Information

Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia.

Publications

Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia.

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