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Comparative effectiveness of initial antiretroviral therapy regimens: ACTG 5095 and 5142 clinical trials relative to ART-CC cohort study.

ABSTRACT: BACKGROUND:The generalizability of antiretroviral therapy (ART) clinical trial efficacy findings to routine care settings is not well studied. We compared the relative effectiveness of initial ART regimens estimated in AIDS Clinical Trial Group (ACTG) randomized controlled trials with that among patients receiving ART at Antiretroviral Therapy Cohort Collaboration (ART-CC) study sites. METHODS:Treatment-naive HIV-infected patients initiating identical ART regimens in ACTG trials (A5095 and A5142) and at 15 ART-CC cohort study sites were included. Virological failure (HIV-1 RNA >200 copies/mL) at 24 and 48 weeks, incident AIDS-defining events and mortality were measured according to study design (ART-CC cohort vs. ACTG trial) and stratified by third drug [abacavir (ABC), efavirenz (EFV), and lopinavir/r (LPV/r)]. We used logistic regression to estimate and compare odds ratios (OR) for virological failure between different regimens and study designs, and used Cox models to estimate and compare hazard ratios for AIDS and death. RESULTS:Compared with patients receiving ABC, those receiving EFV had roughly half the odds of 24-week virologic failure (>200 copies/mL) in both ACTG 5095 (OR = 0.53, 95% confidence interval: 0.36 to 0.79) and ART-CC (0.46, 0.37 to 0.57). Virologic superiority of EFV (vs. ABC) seemed comparable in ART-CC and ACTG 5095 (ratio of ORs 0.86, 95% confidence interval: 0.54 to 1.35). Odds ratios for 48-week virologic failure, comparing EFV with LPV/r, were also comparable in ACTG 5142 and ART-CC (ratio of ORs: 0.87, 0.45 to 1.69). CONCLUSIONS:Between ART regimen virologic efficacy of third drugs ABC, EFV, and LPV/r observed in the ACTG 5095 and 5142 trials seem generalizable to the routine care setting of ART-CC clinical cohorts.

SUBMITTER: Mugavero MJ

PROVIDER: S-EPMC3196673 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Comparative effectiveness of initial antiretroviral therapy regimens: ACTG 5095 and 5142 clinical trials relative to ART-CC cohort study.

Mugavero Michael J MJ May Margaret M Ribaudo Heather J HJ Gulick Roy M RM Riddler Sharon A SA Haubrich Richard R Napravnik Sonia S Abgrall Sophie S Phillips Andrew A Harris Ross R Gill M John MJ de Wolf Frank F Hogg Robert R Günthard Huldrych F HF Chêne Geneviève G D'Arminio Monforte Antonella A Guest Jodie L JL Smith Colette C Murillas Javier J Berenguer Juan J Wyen Christoph C Domingo Pere P Kitahata Mari M MM Sterne Jonathan A C JA Saag Michael S MS

Journal of acquired immune deficiency syndromes (1999) 20111101 3

<h4>Background</h4>The generalizability of antiretroviral therapy (ART) clinical trial efficacy findings to routine care settings is not well studied. We compared the relative effectiveness of initial ART regimens estimated in AIDS Clinical Trial Group (ACTG) randomized controlled trials with that among patients receiving ART at Antiretroviral Therapy Cohort Collaboration (ART-CC) study sites.<h4>Methods</h4>Treatment-naive HIV-infected patients initiating identical ART regimens in ACTG trials ( ...[more]

PMID: 21857357

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Project description:ImportanceMaternal antiretroviral treatment (ART) started before conception may increase the risk for adverse birth outcomes among women with human immunodeficiency virus (HIV) infection, but whether the risk differs by ART regimen is unknown.ObjectiveTo compare the risk for selected birth outcomes by maternal ART regimen.Design, setting, and participantsThis observational birth outcomes surveillance study compared all live births and stillbirths with a gestational age of at least 24 weeks in 8 geographically dispersed government hospitals throughout Botswana (approximately 45% of births nationwide). Data were collected from August 15, 2014, through August 15, 2016.ExposuresBirths among HIV-infected women who started 3-drug ART regimens before their last menstrual period and did not switch or stop ART in pregnancy were considered to be ART exposed from conception.Main outcomes and measuresThe primary outcomes were any adverse birth outcome, including stillbirth, preterm birth (<37 weeks), small size for gestational age (SGA; <10th percentile of weight for gestational age) or neonatal death (<28 days from delivery), and any severe adverse outcome, including very preterm birth (<32 weeks), very SGA (<3rd percentile of weight for gestational age), stillbirth, and neonatal death.ResultsInformation was available for 47?027 of 47?124 births (99.8%) at surveillance maternity hospitals (mean [SD] age of mothers, 26.86 [6.45] years). Among 11?932 HIV-exposed infants, 5780 (48.4%) were ART exposed from conception. Adverse birth outcomes were more common among HIV-exposed infants than HIV-unexposed infants (39.6% vs 28.9%; adjusted relative risk [ARR], 1.40; 95% CI, 1.36-1.44). The risk for any adverse birth outcome was lower among infants exposed from conception to tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TDF-FTC-EFV) (901 of 2472 [36.4%]) compared with TDF-FTC and nevirapine (NVP) (317 of 760 [41.7%]; ARR, 1.15; 95% CI, 1.04-1.27); TDF-FTC and lopinavir-ritonavir (TDF-FTC-LPV-R) (112 of 231 [48.5%]; ARR, 1.31; 95% CI, 1.13-1.52); zidovudine, lamivudine, and NPV (ZDV-3TC-NVP) (647 of 1365 [47.4%]; ARR, 1.30; 95% CI, 1.20-1.41); or ZDV-3TC-LPV-R (75 of 167 [44.9%]; ARR, 1.21; 95% CI, 1.01-1.45). The risk for any severe adverse outcome was also lower among infants exposed from conception to TDF-FTC-EFV (303 of 2472 [12.3%]) compared with TDF-FTC-NVP (136 of 760 [17.9%]; ARR, 1.44; 95% CI, 1.19-1.74), TDF-FTC-LPV-R (45 of 231 [19.5%]; ARR, 1.58; 95% CI, 1.19-2.11), ZDV-3TC-NVP (283 of 1365 [20.7%]; ARR, 1.68; 95% CI, 1.44-1.96), or ZDV-3TC-LPV-R (39 of 167 [23.4%]; ARR, 1.93; 95% CI, 1.43-2.60) from conception. Compared with TDF-FTC-EFV, all other regimens were associated with higher risk for SGA; ZDV-3TC-NVP was associated with higher risk of stillbirth, very preterm birth, and neonatal death; and ZDV-3TC-LPV-R was associated with higher risk for preterm birth, very preterm birth, and neonatal death.Conclusions and relevanceAmong infants exposed to ART from conception, TDF-FTC-EFV was associated with a lower risk for adverse birth outcomes than other ART regimens.

Project description:Personalized medicine is a high priority for the future of health care. The idea of tailoring an individual's wellness plan to their unique genetic code is one which we hope to realize through the use of pharmacogenomics. There have been examples of tremendous success in pharmacogenomic associations however there are many such examples in which only a small proportion of trait variance has been explained by the genetic variation. Although the increased use of GWAS could help explain more of this variation, it is likely that a significant proportion of the genetic architecture of these pharmacogenomic traits are due to complex genetic effects such as epistasis, also known as gene-gene interactions, as well as gene-drug interactions. In this study, we utilize the Biofilter software package to look for candidate epistasis contributing to risk for virologic failure with efavirenz-containing antiretroviral therapy (ART) regimens in treatment-naïve participants of AIDS Clinical Trials Group (ACTG) randomized clinical trials. A total of 904 individuals from three ACTG trials with data on efavirenz treatment are analyzed after race-stratification into white, black, and Hispanic ethnic groups. Biofilter was run considering 245 candidate ADME (absorption, distribution, metabolism, and excretion) genes and using database knowledge of gene and protein interaction networks to produce approximately 2 million SNP-SNP interaction models within each ethnic group. These models were evaluated within the PLATO software package using pair wise logistic regression models. Although no interaction model remained significant after correction for multiple comparisons, an interaction between SNPs in the TAP1 and ABCC9 genes was one of the top models before correction. The TAP1 protein is responsible for intracellular transport of antigen to MHC class I molecules, while ABCC9 codes for a transporter which is part of the subfamily of ABC transporters associated with multi-drug resistance. This study demonstrates the utility of the Biofilter method to prioritize the search for gene-gene interactions in large-scale genomic datasets, although replication in a larger cohort is required to confirm the validity of this particular TAP1-ABCC9 finding.

Dataset Information

Comparative effectiveness of initial antiretroviral therapy regimens: ACTG 5095 and 5142 clinical trials relative to ART-CC cohort study.

Publications

Comparative effectiveness of initial antiretroviral therapy regimens: ACTG 5095 and 5142 clinical trials relative to ART-CC cohort study.

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