Heather J Ribaudo

Harvard University, Cambridge, Massachusetts, United States

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Publications (71)648.71 Total impact

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    ABSTRACT: Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n=786) regimens in ACTG protocols 384, A5142, A5095, and A5202. Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P<5×10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.
    Pharmacogenetics and Genomics 11/2014; · 3.45 Impact Factor
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    ABSTRACT: Background : Cellular markers of immune activation are strong predictors of disease progression and comorbidities in HIV infection. It is unclear whether soluble biomarkers of T cell (sIL-2r) and monocyte (MNC) activation (sCD14, sCD163) represent robust surrogate markers of cellular immune activation during the course of antiretroviral therapy (ART). Methods : In the ACTG A5260s study, Spearman correlations between biomarkers of T-cell and MNC activation and proinflammatory MNC (pMNCs) subsets were estimated at entry and 96 weeks in 328 HIV-infected treatment-naive subjects randomized equally to tenofovir/emtricitabine plus raltegravir or ritonavir-boosted atazanavir or darunavir. Analyses were restricted to 234 (71%) subjects who had HIV-1 RNA <50 copies/ml by week 24 and thereafter. Plasma and cellular immune markers were determined by ELISA and flow cytometry, respectively. Results: sIL-2r and sCD163 were significantly associated with T cell activation (% CD38+DR+ CD8 T cells) at entry and 96 weeks. sCD163 was also associated with both T cell activation and pMNCs (% CD14+CD16+ MNCs) after successful ART. sCD14 was significantly associated with T cell activation and pMNCs only at entry. After 96 weeks of ART, sIL-2r and sCD14 were not associated with cellular markers of pMNCs (Table). Conclusion: There were modest associations between all plasma markers of immune activation and cellular markers of T activation in viremic subjects. However, after successful ART, only sCD163 had a modest association with cellular markers of T cell activation. Plasma markers of immune activation may reflect different immune activation pathways with differential dependence on viral replication versus immune dysregulation that is not reversed with viral suppression by ART. Plasma Markers Week 0 Week 96 Cellular Markers sIL-2r sCD14 sCD163 sIL-2r sCD14 sCD163 % CD38+DR+ of CD8+ T cells (T cell activation) 0.36 (<0.001) 0.25 (<0.001) 0.38 (<0.001) 0.18 (0.011) 0.11 (0.11) 0.40 (<0.001) % CD14+CD16+ of MNCs (pMNCs) 0.07 (0.30) 0.27 (<0.001) 0.06 (0.38) -0.06 (0.40) 0.07 (0.32) 0.16 (0.022) % CD163+ of MNCs (pMNCs) -0.01 (0.90) 0.03 (0.65) -0.02 (0.78) -0.07 (0.29) -0.02 (0.81) -0.05 (0.52) 1Similar correlations on CD4+; 2associations with CD16 (h) CD14 (l) not apparent.
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.
    Annals of internal medicine 10/2014; 161(7):461-471. · 16.10 Impact Factor
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    ABSTRACT: Background. The development of drug resistance to nucleoside (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) has been associated with baseline HIV-1 RNA level (VL), CD4 cell counts (CD4), subtype, or treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in subjects from Thailand, South Africa, India, Malawi and Tanzania. Methods. CD4 and VL were captured at ACTG5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on a NNRTI regimen. HIV drug resistance mutation associations with subtype, site, study entry VL and CD4 were evaluated by Fisher's exact and Kruskall-Wallis tests. Results. Of the 207 individuals that were screened for A5230, sequence data were available for 148 subjects. Subtypes observed were subtype C (n=97, 66%) followed by AE (n=27, 18%); A1 (n=12, 8%) and D (n=10, 7%). Of the 148 subjects, 93% (n=138) and 96% (n=142) had at least one RT mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (p<0.001). Differences in drug resistant patterns in both NRTI and NNRTI were observed by site. Conclusions. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry; only 32% of subjects remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.
    Clinical Infectious Diseases 05/2014; · 9.42 Impact Factor
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    ABSTRACT: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. US National Institute of Allergy and Infectious Diseases.
    The Lancet Infectious Diseases 03/2014; · 19.45 Impact Factor
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    ABSTRACT: To evaluate the relationship between incomplete antiretroviral therapy (ART) adherence and levels of residual HIV-1 viremia. Medication adherence and residual viremia less than 50 copies/ml were quantified in participants of a cohort of homeless and marginally housed individuals with HIV/AIDS. Participants had at least 6 months of virologic suppression of less than 50 copies/ml and were in the adherence monitoring cohort with monthly unannounced pill counts. Residual viremia was measured by the single-copy assay. The median average ART adherence over the prior 1 and 2 months were 94% [interquartile range (IQR) 79-100%] and 93% (IQR 82-98%), respectively. Average ART adherence over the past 2 months was significantly associated with levels of residual HIV viremia (Spearman r = -0.25, P = 0.04). One-third of participants with 100% ART adherence over the past 2 months had detectable residual viremia. On multivariate regression analysis, ART adherence over the past 2 months, but not duration of virologic suppression, CD4 T-cell count or ART regimen, was significantly associated with levels of residual HIV viremia. Detectable residual viremia was associated with virologic failure (>50 copies/ml) on univariate Cox proportional hazard analysis (hazard ratio 2.08, P = 0.02). However, on multivariate analysis, only ART adherence was associated with risk of virologic failure. Incomplete ART adherence is associated with higher levels of residual HIV-1 viremia, but detectable residual viremia can be present despite 100% measured ART adherence.
    AIDS (London, England) 12/2013; · 6.56 Impact Factor
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    ABSTRACT: Background. In the U.S., HIV-infected blacks have higher rates of virologic failure on antiretroviral therapy (ART) and of death compared to whites. The cause for these disparities is uncertain. We sought to examine differences in virologic outcomes among antiretroviral-naïve clinical trial participants starting randomized ART and to investigate factors to explain the differences. Methods. Individual-level data from participants initiating ART in 5 AIDS Clinical Trials Group (ACTG) studies were analyzed. Included studies were those conducted 1998-2006 with a primary outcome of virologic failure. The primary outcome measure was time to virologic failure, regardless of ART changes. Results. 2495 individuals (1151 black; 1344 white) were included with a median follow-up of 129 weeks. Compared to whites, blacks had an increased hazard of virologic failure (hazard ratio [95% confidence interval]: 1.7 [1.4, 1.9], P<0.001), with no evidence of heterogeneity across regimens (P=0.97); the association remained after adjustment for measured confounders (1.4 [1.2-1.6]; P<0.001). Increased hazard of virologic failure was associated with younger age, higher pre-treatment HIV-1 RNA level, lower pre-treatment CD4 cell count, hepatitis C antibody, less education, and recent non-adherence. Sensitivity analyses with different endpoint definitions demonstrated similar results. Conclusions. In this analysis, blacks had a 40% higher virologic failure risk than whites that was not explained by measured confounders. The observation was consistent over a range of regimens suggesting the difference may be driven by social factors but biological factors cannot be ruled out. Further research should identify the sources of racial disparities and develop strategies to reduce them.
    Clinical Infectious Diseases 09/2013; · 9.42 Impact Factor
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    ABSTRACT: Modeling clinical endpoints as a function of change in antiretroviral therapy (ART) attempts to answer one simple but very challenging question: was the change in ART beneficial or not? We conceive a similar scientific question of interest in the current manuscript except that we are interested in modeling the time of ART regimen change rather than a comparison of two or more ART regimens. The answer to this scientific riddle is unknown and has been difficult to address clinically. Naturally, ART regimen change is left to a participant and his or her provider and so the date of change depends on participant characteristics. There exists a vast literature on how to address potential confounding and those techniques are vital to the success of the method here. A more substantial challenge is devising a systematic modeling strategy to overcome the missing time of regimen change for those participants who do not switch to second-line ART within the study period even after failing the initial ART. In this article, we adopt and apply a statistical method that was originally proposed for modeling infusion trial data, where infusion length may be informatively censored, and argue that the same strategy may be employed here. Our application of this method to therapeutic HIV/AIDS studies is new and interesting. Using data from the AIDS Clinical Trials Group (ACTG) Study A5095, we model immunological endpoints as a polynomial function of a participant's switching time to second-line ART for 182 participants who already failed the initial ART. In our analysis, we find that participants who switch early have somewhat better sustained suppression of HIV-1 RNA after virological failure than those who switch later. However, we also found that participants who switched very late, possibly censored due to the end of the study, had good HIV-1 RNA suppression, on average. We believe our scientific conclusions contribute to the relevant HIV literature and hope that the basic modeling strategy outlined here would be useful to others contemplating similar analyses with partially missing treatment length data.
    Biometrics 07/2013; · 1.52 Impact Factor
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    ABSTRACT: Objective. Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4, We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and HIV-1 drug resistance mutations in pregnant women following single-dose intrapartum nevirapine.Methods. In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor, and were randomized to lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir, for 7 or 21 days. Plasma nevirapine was quantified at post-partum day 1 and weeks 1, 3 and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters included elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine below quantification limit.Results. Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and randomization to lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T→C (p=0.004) but not with CYP2B6 516G→T (p=0.8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G→T (p=0.04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype.Conclusions. Effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T→C than 516G→T, and are less pronounced than at steady state.
    The Journal of Infectious Diseases 05/2013; · 5.85 Impact Factor
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    ABSTRACT: OBJECTIVE:: To determine the association between bone mineral density (BMD), inflammatory markers, and alterations in fat and lean mass in untreated HIV-infected individuals. DESIGN:: Cross-sectional analysis of antiretroviral therapy (ART)-naïve persons enrolled into a randomized clinical trial METHODS:: Dual energy x-ray absorptiometry (DXA) for BMD, lean and fat mass, and a laboratory assessment were performed. Soluble biomarkers included adipocytokines (leptin, adiponectin), inflammatory markers (hsCRP, IL-6), and markers related to bone metabolism (osteoprotegerin (OPG)), receptor activator of NFκB Ligand (RANKL)). BMD at the lumbar spine, total hip, and femoral neck was expressed as a Z-score (number of standard deviations away from an age-, race-, sex-matched reference population). RESULTS:: 331 subjects had a median (Q1, Q3) age of 36 (28,45) years, were 89% male, and 44% white. The prevalence of low BMD (Z-score ≤ -2 at any of the 3 sites) was 10%. No associations were detected between Z-scores and hsCRP, IL-6, or RANKL (P≥0.1). In a linear model adjusting for age, gender, race, and total fat mass, lower lumbar spine Z-scores were associated with lower total lean mass, higher serum adiponectin, and lower OPG. Results at the total hip or femoral neck were similar. CONCLUSIONS:: Among ART-naïve HIV-infected individuals, lower BMD was associated with lower lean mass, higher adiponectin, and lower OPG, but not HIV disease variables or any of the inflammatory markers. These findings may have implications for bone metabolism in untreated HIV, in which hypoadiponectinemia and higher OPG may mitigate bone loss.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2013; · 4.39 Impact Factor
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    ABSTRACT: BACKGROUND: Homozygosity for UGT1A1*28/*28 (Gilbert's variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually. RESULTS: Initiating atazanavir-based ART at CD4 <500/µl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinemia by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario. CONCLUSIONS: Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
    Antiviral therapy 12/2012; · 3.14 Impact Factor
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    ABSTRACT: Drug-resistant HIV-1 minority variants increase the risk of virologic failure for first-line NNRTI-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and pre-existing NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.
    The Journal of Infectious Diseases 12/2012; · 5.85 Impact Factor
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    ABSTRACT: OBJECTIVE:: To evaluate associations between traditional cardiovascular disease (CVD) risk factors, inflammatory markers, and markers of HIV disease activity with ultrasonographic measures of CVD risk in patients with HIV who are not receiving antiretroviral therapy (ART). DESIGN:: Cross-sectional, baseline evaluation of ART-naïve HIV-infected individuals without known CVD or diabetes mellitus enrolled in a randomized ART treatment trial. METHODS:: Prior to ART initiation, carotid artery intima-media thickness (CIMT) and brachial artery flow-mediated dilation (FMD) were measured. Additional parameters included CD4 cell count, HIV viral load, body composition, lipoproteins, and inflammatory markers. Associations with common CIMT, bifurcation CIMT, presence of carotid artery lesions, and brachial artery FMD were evaluated. RESULTS:: The 331 enrolled subjects were a median (1st-3rd quartile) of 36 (28-45) years old. Common and bifurcation CIMT values were higher and lesions more prevalent with older age (p < 0.001). FMD was lower with older age (p = 0.009). Those with a Framingham Risk Score >6%/10 years (N = 44) had higher common and bifurcation CIMT (p < 0.001), carotid lesion prevalence (p < 0.001), and lower FMD (p = 0.035). Independent associations with common CIMT were identified for increasing age, height, weight, small LDL particles, and black race; these were similar for bifurcation CIMT. Presence of carotid artery lesions was associated with increasing age, presence of metabolic syndrome, interleukin-6, and lower HIV-1 RNA. CONCLUSIONS:: In a contemporary cohort of ART-naive HIV-infected individuals, ultrasonographic measures of CVD risk were more strongly associated with traditional risk factors than CD4 cell counts, HIV replication, or inflammatory markers.
    AIDS (London, England) 11/2012; · 6.56 Impact Factor
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    ABSTRACT: The UGT1A1*28 variant has been associated with hyperbilirubinemia and atazanavir discontinuation. Protocol A5202 randomized HIV-1-infected patients to atazanavir/ritonavir (atazanavir/r) or efavirenz, with tenofovir/emtricitabine or abacavir/lamivudine. A total of 646 atazanavir/r recipients were evaluable for UGT1A1. Homozygosity for *28/*28 was present in 8% of whites, 24% of blacks, and 18% of Hispanics, and was associated with increased bilirubin concentrations. There was an association between *28/*28 and increased atazanavir/r discontinuation among Hispanic participants (P=0.005), but not among white or black participants (p=0.79, p=0.46, respectively). The positive predictive value of 28*/28* for atazanavir/r discontinuation among Hispanic participants was only 32% (95% CI: 16-52%).
    The Journal of Infectious Diseases 11/2012; · 5.85 Impact Factor
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    ABSTRACT: Purpose: We assessed the potential cost-effectiveness of UGT1A1 genetic testing to inform choice of the initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-nave HIV-infected individuals. Homozygosity for UGT1A1*28/*28 (Gilbert's variant) has been reported to predict abnormal liver tests and mild jaundice (hyperbilirubinemia) associated with the protease inhibitor drug atazanavir and premature atazanavir discontinuation. Methods: The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model projected quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using the protease inhibitor darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates as reported in the Swiss HIV Cohort study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these inputs, hyperbilirubinemia impact on quality of life, and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually. Results: Initiating atazanavir-based ART among patients eligible for ART (<500 CD4 cells/mm3)without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $530,700 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY) in the base case. Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost was reduced to $10 (Figure) or if avoiding toxicity by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario. Conclusions: Testing for UGT1A1 may be cost effective if assay cost is low and if testing improves retention in care, but only if the comparator regimens have the same drug cost and efficacy.
    The 34th Annual Meeting of the Society for Medical Decision Making; 10/2012
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    ABSTRACT: OBJECTIVES: Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics. MATERIALS AND METHODS: Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry. RESULTS: Among 856 individuals, CYP2B6 516G→T was associated with efavirenz estimated Cmin (P=8.5×10). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P=9.9×10). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms. CONCLUSION: Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization.
    Pharmacogenetics and Genomics 10/2012; · 3.45 Impact Factor
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    ABSTRACT: Background. It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings.Methods. We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)-infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4(+) lymphocyte cell count.Results. Of 33 148 women, 32 113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4(+) was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB.Conclusions. HAART receipt during pregnancy was associated with increased PTD, SGA, and SB.
    The Journal of Infectious Diseases 10/2012; · 5.85 Impact Factor
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    ABSTRACT: Despite viral suppression, antiretroviral therapy (ART) does not restore CD4(+) T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1). In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4(+) T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/µL in the CD4(+) T-cell count. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4(+) T-cell count was 153 cells/µL. The median increase in CD4(+) T-cell count from baseline to week 22/24 was 12 cells/µL (90% confidence interval, 1-22). A CD4(+) T-cell count increase of at least 20 cells/µL was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4(+) T-cell counts of at least 20 cells/µL. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted. Clinical Trials Registration. NCT 00709111.
    The Journal of Infectious Diseases 06/2012; 206(4):534-42. · 5.85 Impact Factor
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    ABSTRACT: The current goal of initial antiretroviral (ARV) therapy is suppression of plasma human immunodeficiency virus (HIV)-1 RNA levels to below 200 copies per milliliter. A proportion of HIV-infected patients who initiate antiretroviral therapy in clinical practice or antiretroviral clinical trials either fail to suppress HIV-1 RNA or have HIV-1 RNA levels rebound on therapy. Frequently, these patients have sustained CD4 cell counts responses and limited or no clinical symptoms and, therefore, have potentially limited indications for altering therapy which they may be tolerating well despite increased viral replication. On the other hand, increased viral replication on therapy leads to selection of resistance mutations to the antiretroviral agents comprising their therapy and potentially cross-resistance to other agents in the same class decreasing the likelihood of response to subsequent antiretroviral therapy. The optimal time to switch antiretroviral therapy to ensure sustained virologic suppression and prevent clinical events in patients who have rebound in their HIV-1 RNA, yet are stable, is not known. Randomized clinical trials to compare early versus delayed switching have been difficult to design and more difficult to enroll. In some clinical trials, such as the AIDS Clinical Trials Group (ACTG) Study A5095, patients randomized to initial antiretroviral treatment combinations, who fail to suppress HIV-1 RNA or have a rebound of HIV-1 RNA on therapy are allowed to switch from the initial ARV regimen to a new regimen, based on clinician and patient decisions. We delineate a statistical framework to estimate the effect of early versus late regimen change using data from ACTG A5095 in the context of two-stage designs.In causal inference, a large class of doubly robust estimators are derived through semiparametric theory with applications to missing data problems. This class of estimators is motivated through geometric arguments and relies on large samples for good performance. By now, several authors have noted that a doubly robust estimator may be suboptimal when the outcome model is misspecified even if it is semiparametric efficient when the outcome regression model is correctly specified. Through auxiliary variables, two-stage designs, and within the contextual backdrop of our scientific problem and clinical study, we propose improved doubly robust, locally efficient estimators of a population mean and average causal effect for early versus delayed switching to second-line ARV treatment regimens. Our analysis of the ACTG A5095 data further demonstrates how methods that use auxiliary variables can improve over methods that ignore them. Using the methods developed here, we conclude that patients who switch within 8 weeks of virologic failure have better clinical outcomes, on average, than patients who delay switching to a new second-line ARV regimen after failing on the initial regimen. Ordinary statistical methods fail to find such differences. This article has online supplementary material.
    Journal of the American Statistical Association 06/2012; 107(498):542-554. · 2.11 Impact Factor
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    ABSTRACT: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000  copies/ml. Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100  mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400  copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40  copies/ml and 30 had levels 40-200  copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400  copies/ml. In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.
    AIDS (London, England) 03/2012; 26(11):1345-54. · 6.56 Impact Factor

Publication Stats

4k Citations
648.71 Total Impact Points


  • 2000–2013
    • Harvard University
      • Department of Biostatistics
      Cambridge, Massachusetts, United States
  • 1999–2013
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2012
    • University of Southern California
      Los Angeles, California, United States
  • 2007–2012
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, MA, United States
    • University of Hawaiʻi at Mānoa
      Honolulu, Hawaii, United States
  • 2011
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
    • Beth Israel Deaconess Medical Center
      • Division of Infectious Diseases
      Boston, MA, United States
  • 2005–2010
    • University of Washington Seattle
      • Department of Neurology
      Seattle, Washington, United States
  • 2004–2007
    • Weill Cornell Medical College
      • Department of Public Health
      New York City, New York, United States
  • 2006
    • Case Western Reserve University
      Cleveland, Ohio, United States