Zidovudine impairs immunological recovery on first-line antiretroviral therapy

Wandeler, Gilles; Gsponer, Thomas; Mulenga, Lloyd; Garone, Daniela; Wood, Robin; Maskew, Mhairi; Prozesky, Hans; Hoffmann, Christopher J.; Ehmer, Jochen; Dickinson, Diana; Davies, Mary Ann; Egger, Matthias; Keiser, Olivia

doi:10.1097/qad.0b013e328362d887

Cited by 15 publications

(12 citation statements)

References 22 publications

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“…NNRTIs are known to be associated with a lower CD4 increase after the start of cART,[ 26 ] with particular evidence of this effect for zidovudine. [ 28 , 29 ] In our study, neither type of NNRTI (zidovudine or stavudine) was associated with either type of discordant treatment response.…”

Section: Discussionmentioning

confidence: 50%

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study

Kayigamba¹,

Franke

Bakker

et al. 2016

PLoS ONE

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IntroductionSome antiretroviral therapy naïve patients starting combination antiretroviral therapy (cART) experience a limited CD4 count rise despite virological suppression, or vice versa. We assessed the prevalence and determinants of discordant treatment responses in a Rwandan cohort.MethodsA discordant immunological cART response was defined as an increase of <100 CD4 cells/mm3 at 12 months compared to baseline despite virological suppression (viral load [VL] <40 copies/mL). A discordant virological cART response was defined as detectable VL at 12 months with an increase in CD4 count ≥100 cells/mm3. The prevalence of, and independent predictors for these two types of discordant responses were analysed in two cohorts nested in a 12-month prospective study of cART-naïve HIV patients treated at nine rural health facilities in two regions in Rwanda.ResultsAmong 382 patients with an undetectable VL at 12 months, 112 (29%) had a CD4 rise of <100 cells/mm3. Age ≥35 years and longer travel to the clinic were independent determinants of an immunological discordant response, but sex, baseline CD4 count, body mass index and WHO HIV clinical stage were not. Among 326 patients with a CD4 rise of ≥100 cells/mm3, 56 (17%) had a detectable viral load at 12 months. Male sex was associated with a virological discordant treatment response (P = 0.05), but age, baseline CD4 count, BMI, WHO HIV clinical stage, and travel time to the clinic were not.ConclusionsDiscordant treatment responses were common in cART-naïve HIV patients in Rwanda. Small CD4 increases could be misinterpreted as a (virological) treatment failure and lead to unnecessary treatment changes.

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Section: Discussionmentioning

confidence: 50%

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study

Kayigamba¹,

Franke

Bakker

et al. 2016

PLoS ONE

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“…Due to lower cost and comparable efficacy to TDF, nearly 40% of ART patients in sub‐Saharan Africa still receive an AZT‐containing first‐line regimen, and forecasts expect that about 30% will still be in 2016 . While several studies from sub‐Saharan Africa report lower rates of substitution, lower attrition from care and better immunological response for patients on TDF than AZT , virologic information comparing the two NRTIs in resource‐poor settings is very limited. A recent cohort analysis from South Africa comparing TDF to stavudine (d4T), a thymidine analogue closely related to AZT, found no significant differences in mortality, loss to follow‐up or virologic success .…”

Section: Introductionmentioning

confidence: 99%

Is zidovudine first‐line therapy virologically comparable to tenofovir in resource‐limited settings?

Labhardt

Bader

Lejone³

et al. 2015

Tropical Med Int Health

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Abstractobjective To compare virologic success between adult patients on tenofovir (TDF) and zidovudine (AZT)-containing first-line antiretroviral (ART) regimens in 10 rural clinics in Lesotho, Southern Africa.methods Multicentre cross-sectional study, patients ≥16 years, on first-line ART ≥6 months, receiving AZT/lamivudine (3TC) or TDF/3TC combined with efavirenz (EFV) or nevirapine (NVP). Patient characteristics and clinical/therapeutic history were collected on the day of blood draw for viral load (VL). Analysis was stratified for non-nucleoside reverse transcriptase inhibitor (EFV or NVP). A logistic regression model weighted for patients' baseline characteristics was used to assess the likelihood of virologic success (<80 copies/ml) in patients with TDF-as compared to AZTbackbones.results In total 1539 patients were included in the analysis. Most were clinically and immunologically stable (clinical failure: 2.7% (AZT) and 2.8% (TDF); immunological failure: 4.6% (AZT) and 4.8% (TDF)). In EFV-based regimens (n = 1162), TDF was significantly associated with higher rates of virologic suppression than AZT (93.8% vs. 88.1%; weighted odds ratio: 2.15 (95% CI: 1.29-3.58; P = 0.003)). In NVP-based regimens, a similar trend was observed, but not significant (89.4% vs. 86.7%; 1.99 (0.83-4.75, P = 0.121)).conclusion These findings support the WHO recommendation to use TDF/3TC/EFV as first-line regimen. They do, however, not support the recommendation that patients who are clinically stable on AZT should continue on this first-line regimen.

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“…Maskew et al 2013 used GLME with random slope and intercepts and specified an unstructured correlation matrix for repeated measures [ 33 ]. Mayanja et al 2012 and Wandeler et al 2013 used a GLME with functional polynomials [ 14 , 34 ]. Sarfo et al 2014 used GLME with a log-link and assumed a Poisson distribution for CD4 count response [ 35 ], while De Beaudrap et al 2009 applied a non-linear mixed effects model [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

“…Four variants of asymptote models, were found: 1. Factors associated with reaching a particular threshold CD4 count or not, analyzed using multivariate logistic regression [ 14 , 16 , 37 , 43 – 46 ], 2. Overall change in CD4 count, using multivariate linear regression [ 15 , 21 , 47 , 48 ], 3.…”

Section: Resultsmentioning

confidence: 99%

“…from ART initiation [ 13 , 16 , 21 ] and the others used the change in CD4 count between each subsequent visit [ 22 – 24 ]. Of the 11 studies that used GLMEs, 2 used the increase from the baseline as outcome [ 32 , 33 ], one used change in CD4 count between subsequent visits [ 27 ] and 8 used absolute change in CD4 counts over time [ 14 , 25 , 26 , 28 – 31 , 34 ]. Only one study used non-linear mixed effects regression [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Systematic review of statistically-derived models of immunological response in HIV-infected adults on antiretroviral therapy in Sub-Saharan Africa

2017

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IntroductionIn Sub-Saharan African (SSA) resource limited settings, Cluster of Differentiation 4 (CD4) counts continue to be used for clinical decision making in antiretroviral therapy (ART). Here, HIV-infected people often remain with CD4 counts <350 cells/μL even after 5 years of viral load suppression. Ongoing immunological monitoring is necessary. Due to varying statistical modeling methods comparing immune response to ART across different cohorts is difficult. We systematically review such models and detail the similarities, differences and problems.Methods‘Preferred Reporting Items for Systematic Review and Meta-Analyses’ guidelines were used. Only studies of immune-response after ART initiation from SSA in adults were included. Data was extracted from each study and tabulated. Outcomes were categorized into 3 groups: ‘slope’, ‘survival’, and ‘asymptote’ models. Wordclouds were drawn wherein the frequency of variables occurring in the reviewed models is indicated by their size and color.Results69 covariates were identified in the final models of 35 studies. Effect sizes of covariates were not directly quantitatively comparable in view of the combination of differing variables and scale transformation methods across models. Wordclouds enabled the identification of qualitative and semi-quantitative covariate sets for each outcome category. Comparison across categories identified sex, baseline age, baseline log viral load, baseline CD4, ART initiation regimen and ART duration as a minimal consensus set.ConclusionMost models were different with respect to covariates included, variable transformations and scales, model assumptions, modelling strategies and reporting methods, even for the same outcomes. To enable comparison across cohorts, statistical models would benefit from the application of more uniform modelling techniques. Historic efforts have produced results that are anecdotal to individual cohorts only. This study was able to define ‘prior’ knowledge in the Bayesian sense. Such information has value for prospective modelling efforts.

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Zidovudine impairs immunological recovery on first-line antiretroviral therapy

Cited by 15 publications

References 22 publications

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study

Is zidovudine first‐line therapy virologically comparable to tenofovir in resource‐limited settings?

Systematic review of statistically-derived models of immunological response in HIV-infected adults on antiretroviral therapy in Sub-Saharan Africa

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