HIV-1 drug resistance at virological failure versus immunological failure among patients failing first-line antiretroviral therapy in a resource-limited setting

Sungkanuparph, Somnuek; Win, May Myat; Kiertiburanakul, Sasisopin; Phonrat, Benjaluck; Maek-a-nantawat, Wirach

doi:10.1258/ijsa.2011.011337

Cited by 14 publications

(14 citation statements)

References 18 publications

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“…Our findings were consistent with previous reports which showed that NNRTI RAMS were the most common, followed by NRTI and PI RAMs [6, 29, 30]. Our study also found that approximately one-third of the patients harboured multi-NRTI RAMs.…”

Section: Discussionsupporting

confidence: 93%

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HIV multi‐drug resistance at first‐line antiretroviral failure and subsequent virological response in Asia

Jiamsakul¹,

Sungkanuparph

Law³

et al. 2014

Journal of the International AIDS Society

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IntroductionFirst-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.MethodsWe 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.ResultsA 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.ConclusionsMulti-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.

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Section: Discussionsupporting

confidence: 93%

“…These studies demonstrated that the prevalence of RAMs in patients failing first-line ART ranged from 53 to 84% with 38–64% harbouring dual-class resistance [2–5]. The prevalence of RAMs in individuals experiencing first-line ART failure in Asia has ranged from 87 to 95% with 50–64% harbouring dual-class mutations [6–9]. …”

Section: Introductionmentioning

confidence: 99%

HIV multi‐drug resistance at first‐line antiretroviral failure and subsequent virological response in Asia

Jiamsakul¹,

Sungkanuparph

Law³

et al. 2014

Journal of the International AIDS Society

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“…Most first-line failure data in this HIV subtype are reported from Thailand, with NNRTI and NRTI resistance of 89-95% and 42-58% in adults and 97% and 98% in children, respectively. 13,[22][23][24][25][26][27] Data on drug resistance in Cambodian children failing ART are limited. In a recent systematic review of first-line ART failure among children, 28 within 30 reviewed studies on 3,241 children, only 265 (8%) were from Cambodia and only 74 (2%) of those had genotypes available, some available only in poster form and after second-line ART failure.…”

Section: Introductionmentioning

confidence: 99%

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

Coetzer

Westley

DeLong

et al. 2013

AIDS Research and Human Retroviruses

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Antiretroviral therapy in resource-limited settings is monitored clinically and immunologically according to WHO guidelines. Frequent misclassification of virologic failure is reported, mostly in adults, leading to early therapy switch or late failure diagnosis. Pediatric treatment monitoring and resistance data upon first-line failure are limited, particularly when the 2010-WHO pediatric guidelines are used without routine viral load monitoring. We previously reported high treatment failure misclassification rates by pediatric 2010 guidelines in Cambodian children on first-line therapy. Here we determine the extent and patterns of resistance, with yearly viral load and 6-monthly CD4. Drug resistance mutations were determined using the IAS-USA 2011 list. Predicted resistance interpretation was determined with Stanford Database tools. Fifty-one children with available genotypes met inclusion criteria. All but one (subtype B) were CRF01_AE. The most common regimen was stavudine, lamivudine, and nevirapine (96%), taken for a median of 2.2 years. Resistance was seen in 98%; 96% to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs); 51% with ‡ 4 mutations. The most common NRTI mutations were 184V/I and 67N and the most common NNRTI mutations were 181C/Y/I/V and 190A/S. A total of 22% had multiresistant mutations and 18% had predicted high-level resistance to subsequent therapy options didanosine, abacavir, etravirine, and tenofovir. In 98% of Cambodian children misclassified as nonfailing first-line therapy by 2010 guidelines, 51% had extensive drug resistance to current and 18% to subsequent antiretroviral therapy. Affordable routine viral load monitoring allowing for early and more accurate treatment failure diagnosis is desperately needed in resource-limited settings.

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“…Studies have shown that by using methods other than VL to assess ART response, there may be a delay in switching to second-line ART which has been shown to be associated with mortality. Furthermore, patients with immunological failure were shown to have higher VL and higher rates of HIV drug resistance mutations compared to those with virological failure, which could impact second-line treatment options[13, 14]. As TAHOD sites are located in high and low-income countries[15], the frequency of VL testing in TAHOD sites varies substantially from an average of less than once per year to more than three times per year[3].…”

Section: Discussionmentioning

confidence: 99%

The occurrence of Simpson's paradox if site-level effect was ignored in the TREAT Asia HIV Observational Database

Kerr

Chandrasekaran

Huelgas

et al. 2016

Journal of Clinical Epidemiology

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Background In multi-site HIV observational cohorts, clustering of observations often occur within sites. Ignoring clustering may lead to “Simpson's paradox” (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox-regression models. Methods Survival time from combination antiretroviral therapy (cART) initiation was analysed using four Cox models: (i) no site adjustment; (ii) site as a fixed effect; (iii) stratification through site; and (iv) shared frailty on site. Results A total of 6454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (i) shows the hazard ratio (HR) for years 2010-2014 was higher than the HR for 2006-2009, compared to 2003-2005 (HR = 0.68 vs 0.61). Models (ii)-(iv) consistently implied greater improvement in survival for those who initiated in 2010-2014 than 2006-2009 contrasting findings from Model (i). The effects of other significant covariates on survival were similar across four models. Conclusions Ignoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible.

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HIV-1 drug resistance at virological failure versus immunological failure among patients failing first-line antiretroviral therapy in a resource-limited setting

Cited by 14 publications

References 18 publications

HIV multi‐drug resistance at first‐line antiretroviral failure and subsequent virological response in Asia

HIV multi‐drug resistance at first‐line antiretroviral failure and subsequent virological response in Asia

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

The occurrence of Simpson's paradox if site-level effect was ignored in the TREAT Asia HIV Observational Database

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