Accumulation of HIV Drug Resistance Mutations in Patients Failing First-Line Antiretroviral Treatment in South Africa

Sigaloff, Kim C.E.; Ramatsebe, Tina; Viana, Raquel; Wit, Tobias F. Rinke de; Wallis, Carole L.; Stevens, Wendy

doi:10.1089/aid.2011.0136

Cited by 59 publications

(46 citation statements)

References 21 publications

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“…Despite this tendency to wait to switch on PIs, which hypothetically would result in more resistance mutations, we still saw less resistance accumulate in PI-higher compared to NNRTI-higher. These data are consistent with clinical trials and observational studies in adults, reporting fewer NRTI mutations on PIs than NNRTIs [8, 9], as well as additional reports on accumulation of NRTI resistance on NNRTIs [10–12]. …”

Section: Discussionsupporting

confidence: 87%

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Harrison

Melvin

Fiscus

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. Methods PENPACT-1 had a 2x2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART, and switch at a 1000c/ml versus 30000c/ml threshold. Switch-criteria were: not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or CDC-C event. Resistance tests were performed on samples ≥1000c/ml before switch, re-suppression and at 4-year/trial-end. Results Sixty-seven children started PI-based ART and were randomized to switch at 1000c/ml (PI-1000), 64 PIs and 30000c/ml (PI-30000), 67 NNRTIs and 1000c/ml (NNRTI-1000), and 65 NNRTI and 30000c/ml (NNRTI-30000). Ninety-four (36%) children reached the 1000c/ml switch-criteria during 5 years follow-up. In 30000c/ml threshold arms, median time from 1000c/ml to 30000c/ml switch-criteria was 58 (PI) versus 80 (NNRTI) weeks (P=0.81). In NNRTI-30000 more NRTI resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000c/ml (23% NNRTI-1000, 27% NNRTI-30000). Sixty-two children started abacavir+lamivudine, 166 lamivudine+zidovudine or stavudine, and 35 other NRTIs. The abacavir+lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30000, 64% NNRTI-1000 and 100% NNRTI-30000 were <400c/ml 24 weeks later. Conclusion Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet re-suppressed on second-line. An abacavir+lamivudine NRTI combination seemed protective against development of NRTI resistance.

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Section: Discussionsupporting

confidence: 87%

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Harrison

Melvin

Fiscus

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…A similar study from Rwanda revealed that even a threshold of less than 350 CD4 + T cells/μl to detect treatment failure had a very low sensitivity ranging from 19 to 32% [15]. The late detection of patients with treatment failure leads to the accumulation of drug resistances and dramatically limits treatment options [9,43]. The implementation and upscaling of viral load monitoring is essential to maintain treatment options and optimize health outcomes in resource-limited settings with restricted treatment possibilities [9,10,29].…”

Section: Discussionmentioning

confidence: 99%

Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania

Muri

Gamell

Ntamatungiro

et al. 2017

Aids

104

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Objective:To investigate the prevalence and determinants of virologic failure and acquired drug resistance-associated mutations (DRMs) in HIV-infected children and adolescents in rural Tanzania.Design:Prospective cohort study with cross-sectional analysis.Methods:All children 18 years or less attending the paediatric HIV Clinic of Ifakara and on antiretroviral therapy (ART) for at least 12 months were enrolled. Participants with virologic failure were tested for HIV-DRM. Pre-ART samples were used to discriminate acquired and transmitted resistances. Multivariate logistic regression analysis identified factors associated with virologic failure and the acquisition of HIV-DRM.Results:Among 213 children on ART for a median of 4.3 years, 25.4% failed virologically. ART-associated DRM were identified in 90%, with multiclass resistances in 79%. Pre-ART data suggested that more than 85% had acquired key mutations during treatment. Suboptimal adherence [odds ratio (OR) = 3.90; 95% confidence interval (CI) 1.11–13.68], female sex (aOR = 2.57; 95% CI 1.03–6.45), and current nonnucleoside reverse transcriptase inhibitor-based ART (aOR = 7.32; 95% CI 1.51–35.46 compared with protease inhibitor-based) independently increased the odds of virologic failure. CD4+ T-cell percentage (aOR = 0.20; 0.10–0.40 per additional 10%) and older age at ART initiation (aOR = 0.84 per additional year of age; 95% CI 0.73–0.97) were protective (also in predicting acquired HIV-DRM). At the time of virologic failure, less than 5% of the children fulfilled the WHO criteria for immunologic failure.Conclusion:Virologic failure rates in children and adolescents were high, with the majority of ART-failing children harbouring HIV-DRM. The WHO criteria for immunologic treatment failure yielded an unacceptably low sensitivity. Viral load monitoring is urgently needed to maintain future treatment options for the millions of African children living with HIV.

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“…NRTI mutations, especially TAMs, are significant in terms of their influence on the success of second-line regimens in resource-limited settings. Time on a failing ART regimen is thought to be a predictor of accumulation of TAMs, which then compromise second-line therapy [25],[26]. Data from Uganda demonstrating very early acquisition of M184V (1.5 months post initial viremia on ART) compared to TAMs (12 months post viremia) suggests if virologic failure is recognized early, prior to the accumulation of TAMs, second-line therapy may be more robust [27].…”

Section: Discussionmentioning

confidence: 99%

Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up

et al. 2014

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BackgroundIn Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up.MethodsThis was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained.Results161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01).ConclusionsAfter viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0567-3) contains supplementary material, which is available to authorized users.

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Accumulation of HIV Drug Resistance Mutations in Patients Failing First-Line Antiretroviral Treatment in South Africa

Cited by 59 publications

References 21 publications

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania

Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up

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