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Previous antiretroviral drug use compromises standard first-line HIV therapy and is mediated through drug-resistance.

ABSTRACT: In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess the associations between PAU, PDR and VF (defined as viral load ?400?cps/mL). Causal mediation analysis was used to assess the proportion of the effect of PAU on VF that could be eliminated by intervening on PDR. Of 2737 participants, 122 (4.5%) had a history of PAU. Participants with PAU had a 7.2-fold (95% CI 4.4-11.7) risk of carrying PDR and a 3.1-fold (95% CI 1.6-6.1) increased risk of VF, compared to antiretroviral-naïve participants. Controlling for PDR would eliminate nearly half the effect of PAU on the risk of VF. Patients with a history of PAU are at increased risk of ART failure, which is to a large extent attributable to PDR. These findings support the recent WHO recommendations for use of differentiated, non-NNRTI-based empiric first-line therapy in patients with PAU.

SUBMITTER: Inzaule SC

PROVIDER: S-EPMC6202366 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Previous antiretroviral drug use compromises standard first-line HIV therapy and is mediated through drug-resistance.

Inzaule Seth C SC Kityo Cissy M CM Siwale Margaret M Akanmu Alani Sulaimon AS Wellington Maureen M de Jager Marleen M Ive Prudence P Mandaliya Kishor K Stevens Wendy W Stevens Wendy W Boender T Sonia TS Ondoa Pascale P Sigaloff Kim C E KCE Naniche Denise D Rinke de Wit Tobias F TF Hamers Raph L RL

Scientific reports 20181025 1

In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess ...[more]

PMID: 30361640

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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: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:IntroductionThere are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.MethodsWe included children (<16 years at ART initiation) who initiated ?3 antiretrovirals between 2004-2014 with ?1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.ResultsWe included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.ConclusionsWhile stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

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.

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Previous antiretroviral drug use compromises standard first-line HIV therapy and is mediated through drug-resistance.

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Previous antiretroviral drug use compromises standard first-line HIV therapy and is mediated through drug-resistance.

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