Paul E Sax

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (177)1260.76 Total impact

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    ABSTRACT: In two double-blinded Phase 3 trials, 1733 antiretroviral-naïve participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug vs. tenofovir disoproxil fumarate (TDF), each co-formulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA <50 c/mL (difference 1.5%; 95%CI [-1.8%, 4.8%]). With TAF, there smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared to 2 for TDF. These longer-term data support E/C/F/TAF as a safe, well-tolerated and durable regimen for initial HIV-1 treatment.
    No preview · Article · Feb 2016 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Background: Recommended HIV treatment regimens in the US contain three antiretroviral agents, costing > $30,000/person/year. Pilot studies are evaluating the efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG+3TC regimens in the US. Methods: Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)-naïve patients under four strategies: 1) No ART (for modeling comparison); 2) Two-drug: initial regimen of DTG+3TC; 3) Induction-maintenance: 48-week induction regimen of three drugs (DTG/abacavir(ABC)/3TC), followed by DTG+3TC maintenance if virologically suppressed; and 4) Standard of care: three-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included: 48-week virologic suppression (88-93%), subsequent virologic failure (0.1%-0.6%/month), and Medicaid-discounted ART costs ($15,200/year-$39,600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was <$100,000 per quality-adjusted life year (QALY). Results: The three ART strategies had the same 5-year survival rates (90%). The ICER for induction-maintenance was $22,500/QALY and for standard of care was >$500,000/QALY. Two-drug was the preferred strategy only when DTG+3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or two-drug for ART-naïve patients, cost savings totaled $550 million and $800 million, respectively, within five years; savings reached greater than $3 billion if 25% of currently suppressed patients were switched to DTG+3TC maintenance. Conclusions: Should DTG+3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save over $500 million in ART costs in the US over five years.
    No preview · Article · Dec 2015 · Clinical Infectious Diseases
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    ABSTRACT: Background. Influenza and pneumococcal vaccinations are recommended for elderly and high-risk patients; however, rates of adherence are low. We sought to implement influenza and pneumococcal vaccine initiatives in 4 different ambulatory specialty practices, using 3 unique approaches. Methods. Four specialties with high-risk patient populations were selected for intervention: allergy (asthma), infectious disease (ID) (human immunodeficiency virus), pulmonary (chronic lung disease), and rheumatology (immunocompromised). Allergy and ID focused on influenza vaccination, and pulmonary and rheumatology focused on pneumococcal vaccination. We used 3 strategies for quality improvement: physician reminders, patient letters, and a nurse-driven model. Physicians were provided their performance data on a monthly basis and presented trended data on a quarterly basis at staff meetings. Results. All 4 specialties developed processes for improving vaccination rates with all showing some increase. Higher rates were achieved with pneumococcal vaccine than influenza. Pneumococcal vaccine rates showed steady improvement from year to year while influenza vaccine rates remained relatively constant. Allergy's influenza rate was 59% in 2011 and 64% in the 2014 flu season. Infectious disease influenza rates moved from 74% in the 2011 flu season to 86% for the 2014 season. Pneumococcal vaccine in pulmonary patients' rate was 52% at the start of intervention in February 2009 and 79% as of January 2015. Rheumatology rates rose from 50% in February 2009 to 87% in January 2015. Conclusions. Integrated routine workflow and performance data sharing can effectively engage specialists and staff in vaccine adherence improvement. Influenza vaccination may require other approaches to achieve the rates seen with pneumococcal vaccine.
    Preview · Article · Dec 2015 · Open Forum Infectious Diseases
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    ABSTRACT: Background: Value of Information (VOI) analysis examines whether to acquire information before making a decision. We introduced VOI to the HIV audience, using the example of generic antiretroviral therapy (ART) in the US. Methods and findings: We used a mathematical model and probabilistic sensitivity analysis (PSA) to generate probability distributions of survival (in quality-adjusted life years, QALYs) and cost for three potential first-line ART regimens: three-pill generic, two-pill generic, and single-pill branded. These served as input for a comparison of two hypothetical two-arm trials: three-pill generic versus single-pill branded; and two-pill generic versus single-pill branded. We modeled pre-trial uncertainty by defining probability distributions around key inputs, including 24-week HIV-RNA suppression and subsequent ART failure. We assumed that, without a trial, patients received the single-pill branded strategy. Post-trial, we assumed that patients received the most cost-effective strategy. For both trials, we quantified the probability of changing to a generic-based regimen upon trial completion and the expected VOI in terms of improved health outcomes and costs. Assuming a willingness to pay (WTP) threshold of $100 000/QALY, the three-pill trial led to more treatment changes (84%) than the two-pill trial (78%). Estimated VOI was $48 000 (three-pill trial) and $35 700 (two-pill trial) per future patient initiating ART. Conclusions: A three-pill trial of generic ART is more likely to lead to post-trial treatment changes and to provide more value than a two-pill trial if policy decisions are based on cost-effectiveness. Value of Information analysis can identify trials likely to confer the greatest impact and value for HIV care.
    No preview · Article · Sep 2015 · HIV Clinical Trials
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    ABSTRACT: Background: Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. Methods: We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results: Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. Conclusions: Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).
    Full-text · Article · Jul 2015 · New England Journal of Medicine
  • Daniel A Solomon · Paul E Sax
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    ABSTRACT: We aim to review the strengths and weaknesses of current antiretroviral therapy (ART), and describe ongoing research to address limitations to current therapy. Current ART is highly effective and well tolerated. As a result of a decrease in medication side-effects and pill burden, and the known health effects of uncontrolled viremia, ART is now recommended at all CD4 cell counts in the USA. Novel medications are being developed to further decrease side-effects and offer alternative options for patients with multiclass resistance. New combination pills will further decrease pill burden. Current treatment for HIV is characterized by highly potent oral antiretroviral medications, which are well tolerated, resulting in outstanding rates of virologic suppression in patients who are adherent to therapy. Despite the marked improvement in therapeutic options, limitations to therapy still exist including reliance on daily adherence, long-term toxicity of medications, drug-drug interactions, long-term effects of HIV even in the setting of viral suppression, high lifetime cost of treatment, and limited options for some patients with multiclass resistance. Emerging alternative treatment strategies include nucleoside reverse transcriptase inhibitor-sparing or limiting regimens and long-acting injectable combination therapy.
    No preview · Article · Jul 2015 · Current opinion in HIV and AIDS
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    ABSTRACT: Among patients with HIV infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation. ACTG A5224s was a substudy of A5202, which randomly assigned ART-naive HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or ritonavir-boosted atazanavir. This analysis explored changes in cystatin C from 0 to 96 weeks. Of the 269 subjects, 85% were male and 66% white non-Hispanics; baseline mean CD4 count was 236 cells per cubic millimeter and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ritonavir-boosted atazanavir attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline body mass index and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high-sensitivity C-reactive protein (Spearman r = 0.25), interleukin 6 (r = 0.34), soluble intercellular adhesion molecule (r = 0.36), soluble vascular cell adhesion molecule (r = 0.54), tumor necrosis factor α (r = 0.57), and soluble TNF-α receptor I (r = 0.70, all P < 0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r = 0.39-0.58, P < 0.001) except for high-sensitivity C-reactive protein (r = 0.01, P = 0.89) and IL-6 (r = 0.08, P = 0.24). The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation.
    No preview · Article · Jun 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment. Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir. Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m2 compared to the group with baseline eGFR ≥ 90 mL/min/1.73m2 (12 vs. 18 mL/min/1.73m2, P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m2 decrease in estimated glomerular filtration rate at twelve months in an adjusted model. Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m2 as previously reported.
    Preview · Article · Apr 2015 · PLoS ONE
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    ABSTRACT: Background Off-target renal and bone side effects may occur with tenofovir disoproxil fumarate (TDF) use. Compared with TDF, tenofovir alafenamide (TAF) results in significantly reduced plasma tenofovir (TFV) and may have less renal and bone toxicity.
    No preview · Article · Apr 2015 · Journal of the International AIDS Society
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    ABSTRACT: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Gilead Sciences. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Apr 2015 · The Lancet
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    ABSTRACT: Background: Long-acting antiretroviral therapy (LA-ART) is currently under development and could improve outcomes for human immunodeficiency virus (HIV)-infected individuals with poor daily ART adherence. Methods: We used a computer simulation model to evaluate the cost-effectiveness of 3 LA-ART strategies vs daily oral ART for all: (1) LA-ART for patients with multiple ART failures; (2) second-line LA-ART for those failing first-line therapy; and (3) first-line LA-ART for ART-naive patients. We calculated the maximum annual cost of LA-ART at which each strategy would be cost-effective at a willingness to pay of $100 000 per quality-adjusted life-year. We assumed HIV RNA suppression on daily ART ranged from 0% to 91% depending on adherence, vs 91% suppression on LA-ART regardless of daily ART adherence. In sensitivity analyses, we varied adherence, efficacy of LA-ART and daily ART, and loss to follow-up. Results: Relative to daily ART, LA-ART increased overall life expectancy by 0.15-0.24 years, and by 0.51-0.89 years among poorly adherent patients, depending on the LA-ART strategy. LA-ART after multiple failures became cost-effective at an annual drug cost of $48 000; in sensitivity analysis, this threshold varied from $40 000-$70 000. Second-line LA-ART and first-line LA-ART became cost-effective at an annual drug cost of $26 000-$31 000 and $24 000-$27 000, vs $28 000 and $25 000 for current second-line and first-line regimens. Conclusions: LA-ART could improve survival of HIV patients, especially those with poor daily ART adherence. At an annual cost of $40 000-$70 000, LA-ART will offer good value for patients with multiple prior failures. To be a viable option for first- or second-line therapy, however, its cost must approach that of currently available regimens.
    No preview · Article · Jan 2015 · Clinical Infectious Diseases
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    ABSTRACT: HIV genotype-resistance testing can help identify more effective antiretroviral treatment (ART) regimens for patients, substantially increasing the likelihood of viral suppression and immune recovery. We sought to evaluate the cost-effectiveness of genotype-resistance testing prior to 1st-line ART initiation in Brazil. We used a previously published microsimulation of HIV disease (CEPAC-International) and data from Brazil to compare the clinical impact, costs, and cost-effectiveness of initial genotype testing (Genotype) to no initial genotype testing (No genotype). Model parameters were derived from the HIV Clinical Cohort at the Evandro Chagas Clinical Research Institute and from published data, using Brazilian sources whenever possible. Baseline patient characteristics included: 69% male, mean age 36 years (SD 10 years), mean CD4 count 347/µL (SD 300/µL) at ART initiation, annual ART costs from 2012 US$1,400 to US$13,400, genotype test cost of US$230, and primary resistance prevalence of 4.4%. Life expectancy and costs were discounted 3%/year. Genotype was defined as "cost-effective" compared to No Genotype if its incremental cost-effectiveness ratio was less than 3x the 2012 Brazilian per capita GDP of US$12,300. Compared to No genotype, Genotype increased life-expectancy from 18.45 to 18.47 years and reduced lifetime cost from US$45,000 to $44,770; thus, in the base case, Genotype was cost-saving. Genotype was cost-effective at primary resistance prevalences as low as 1.4% and remained cost-effective when subsequent-line ART costs decreased to 30% of baseline value. Cost-inefficient results were observed only when simultaneously holding multiple parameters to extremes of their plausible ranges. Genotype-resistance testing in ART-naïve individuals in Brazil will improve survival and decrease costs and should be incorporated into HIV treatment guidelines in Brazil.
    Full-text · Article · Nov 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Background We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART). Methods We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY. Results For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving. Conclusions Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.
    Preview · Article · Nov 2014 · PLoS ONE
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    ABSTRACT: Background: Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods: We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Results: At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. Conclusions: In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.
    No preview · Article · Sep 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes
  • Jennifer A Johnson · Paul E Sax
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    ABSTRACT: In this article, we review the options for initial antiretroviral therapy, including the data from clinical trials to support these choices and the factors to consider in selection of a regimen to best fit each patient.
    No preview · Article · Sep 2014 · Infectious Disease Clinics of North America
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    ABSTRACT: Objectives: It is uncertain whether HIV-1 antiretroviral exposure and clinical response varies between males and females or different race/ethnic groups. We describe ritonavir-enhanced atazanavir pharmacokinetics in relation to virological failure, safety and tolerability in treatment-naive individuals to investigate potential differences. Methods: Plasma samples were collected from participants in AIDS Clinical Trials Group Study A5202 for measurement of antiretroviral concentrations. Individual estimates of apparent oral clearance of atazanavir (L/h) were calculated from a one-compartment model and divided into tertiles as slow (<7), middle (7 to <9; reference group) and fast (≥9). Associations between atazanavir clearance and clinical outcomes were estimated with a hazard ratio (HR) from Cox proportional hazards models. Interactions between atazanavir clearance and sex, race/ethnicity and NRTIs were investigated for each of the outcomes. Results: Among 786 participants, average atazanavir clearance was slower in females (n = 131) than males (n = 655). Atazanavir clearance was associated with time to virological failure (P = 0.053) and this relationship differed significantly by sex (P = 0.003). Females in the fast atazanavir clearance group had shorter time to virological failure (HR 3.49; 95% CI 1.24-9.84) compared with the middle (reference) atazanavir clearance group. Among males, the slow atazanavir clearance group had a higher risk of virological failure (HR 2.10; 95% CI 1.16-3.77). Conclusions: Atazanavir clearance differed by sex. Females with fast clearance and males with slow clearance had increased risk of virological failure.
    No preview · Article · Aug 2014 · Journal of Antimicrobial Chemotherapy

  • No preview · Article · Aug 2014 · Annals of internal medicine
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    ABSTRACT: The relationship between efavirenz use and suicidality is not well-defined.
    No preview · Article · Jul 2014 · Annals of internal medicine
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    Full-text · Article · Jun 2014 · AIDS (London, England)
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    ABSTRACT: Objectives: To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection. Design: Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. Methods: Antiretroviral naive adults with HIV-1 RNA 5000 copies per milliliter and a CD4 count 50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. Results: Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (<50 HIV copies per milliliter) at week 24 (86.6%; 89.7%) and at week 48 (88.4%; 87.9%), and had similar improvements in CD4 at week 48 (177; 204), respectively. Both treatments were well tolerated, and most adverse events were self-limiting and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had smaller reductions in estimated creatinine clearance (-5.5 vs.-10.1 mL/min, P = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip (-0.62% vs.-2.39%, P < 0.001) and spine (-1.00% vs.-3.37%, P < 0.001). Patients on E/C/F/TAF had higher increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. Conclusions: Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density.
    No preview · Article · May 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes

Publication Stats

8k Citations
1,260.76 Total Impact Points

Institutions

  • 1999-2015
    • Brigham and Women's Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1995-2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2009
    • The Richard Stockton College of New Jersey
      New Jersey, United States
  • 1999-2007
    • Massachusetts General Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
  • 2006
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2001-2006
    • Boston University
      Boston, Massachusetts, United States