Paul E Sax

Harvard Medical School, Boston, Massachusetts, United States

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Publications (163)1102.78 Total impact

  • [Show abstract] [Hide abstract]
    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.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2015; 69(2). DOI:10.1097/QAI.0000000000000557 · 4.39 Impact Factor
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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.
    PLoS ONE 04/2015; 10(4):e0124139. DOI:10.1371/journal.pone.0124139 · 3.53 Impact Factor
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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, 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.
    The Lancet 04/2015; DOI:10.1016/S0140-6736(15)60616-X · 39.21 Impact Factor
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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.
    Clinical Infectious Diseases 01/2015; DOI:10.1093/cid/ciu1159 · 9.42 Impact Factor
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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.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2014; 68(2). DOI:10.1097/QAI.0000000000000426 · 4.39 Impact Factor
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    ABSTRACT: 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).
    PLoS ONE 11/2014; 9(11):e113031. DOI:10.1371/journal.pone.0113031 · 3.53 Impact Factor
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    ABSTRACT: 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.
  • 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.
    Infectious Disease Clinics of North America 09/2014; 28(3):421-438. DOI:10.1016/j.idc.2014.06.003 · 2.31 Impact Factor
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    ABSTRACT: 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.
    Journal of Antimicrobial Chemotherapy 08/2014; · 5.44 Impact Factor
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    ABSTRACT: The relationship between efavirenz use and suicidality is not well-defined.
    Annals of internal medicine 07/2014; 161(1):1-10. DOI:10.7326/M14-0293 · 16.10 Impact Factor
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    AIDS (London, England) 06/2014; 28(10):1539-1541. DOI:10.1097/QAD.0000000000000268 · 6.56 Impact Factor
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    ABSTRACT: To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single tablet regimen (STR) for initial treatment of HIV-1 infection.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2014; DOI:10.1097/QAI.0000000000000225 · 4.39 Impact Factor
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    ABSTRACT: Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown. Methods. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed. Results. Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4(+) cell counts (median, 275 vs 213 cells/mu L; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32-8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs >= 10 000 copies/mL, 3.35 [95% CI, 1.40-8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15-.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression. Conclusions. For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success.
    Clinical Infectious Diseases 05/2014; 59(6). DOI:10.1093/cid/ciu367 · 9.42 Impact Factor
  • Paul E Sax
    The Lancet Infectious Diseases 04/2014; 14(7). DOI:10.1016/S1473-3099(14)70753-4 · 19.45 Impact Factor
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    ABSTRACT: Prior studies have found that early HIV protease inhibitors contribute to glucose dysregulation. Few randomized trials have evaluated glucose indices in antiretroviral-naive individuals on newer antiretroviral therapy (ART). A5224s was a substudy of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). Analyses used two-sample t-tests, Spearman correlation coefficients and linear regression. A5224s included 269 nondiabetic individuals: 85% men, 47% white non-Hispanic, baseline median age 38 years, HIV-1 RNA 4.6 log10 copies/ml and CD4 cell count 233 cells/μl. Overall, significant 96-week increases occurred in fasting glucose, insulin and the homeostatic model assessment of insulin resistance (HOMA-IR), P ≤ 0.004. Assignment to EFV (versus ATV/r) resulted in significantly greater glucose increase [mean difference 4.4; 95% confidence interval (CI) 1.3, 7.5 mg/dl; P = 0.006] but not insulin or HOMA-IR (P ≥ 0.72). Glucose indices were not significantly different between ABC/3TC and TDF/FTC arms, P ≥ 0.18. Significant correlations were detected between changes in glucose indices and changes in BMI; all r ≥ 0.23, P ≤ 0.001. In multivariable analyses, in addition to the EFV effect, higher baseline HIV-1 RNA and greater BMI change were significant independent factors associated with greater glucose increase. Changes in glucose metabolism were not significantly different between TDF/FTC and ABC/3TC-based regimens. A small but significantly greater increase in glucose was observed in those assigned to EFV. As glucose dysregulation may increase with time on ART, longer term studies will be needed to further clarify the clinical significance of these findings.
    AIDS (London, England) 03/2014; 28(10). DOI:10.1097/QAD.0000000000000266 · 6.56 Impact Factor
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    ABSTRACT: The effects of antiretrovirals on cystatin C-based renal function estimates are unknown. We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz. Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were -8.3 (-14.0, -2.6) mL/min with Cockcroft-Gault; -14.9 (-19.7, -10.1) mL/min per 1.73(2) with Modification of Diet in Renal Disease; -12.8 (-16.5, -9.0) mL/min per 1.73(2) with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.73(2) with 2012 CKD-EPI cystatin C; and -1.2 (-5.1, 2.6) mL/min per 1.73(2) with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation. Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used.
    03/2014; 1(1):ofu003. DOI:10.1093/ofid/ofu003
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    Paul E Sax
    03/2014; 1(1):ofu001. DOI:10.1093/ofid/ofu001
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    ABSTRACT: Background. Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes. Methods. A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool. Results. Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates (P = .004) and worse virological suppression (P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing. Conclusions. Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.
    Clinical Infectious Diseases 01/2014; 58(9). DOI:10.1093/cid/ciu046 · 9.42 Impact Factor
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    JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2014; 65(3):e118-e120. DOI:10.1097/QAI.0000000000000057 · 4.39 Impact Factor
  • AIDS (London, England) 11/2013; 27(18):2967-2968. DOI:10.1097/QAD.0000000000000018 · 6.56 Impact Factor

Publication Stats

7k Citations
1,102.78 Total Impact Points


  • 2001–2015
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1995–2015
    • Brigham and Women's Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
  • 2014
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1999–2014
    • Harvard University
      • Center for AIDS Research
      Cambridge, Massachusetts, United States
  • 2013
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2011
    • Case Western Reserve University
      • Rainbow Babies and Children's Hospital
      Cleveland, OH, United States
  • 2009
    • The Richard Stockton College of New Jersey
      New Jersey, United States
  • 2006–2008
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2003–2007
    • Massachusetts General Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
  • 2004–2006
    • Boston University
      • Department of Biostatistics
      Boston, Massachusetts, United States
  • 2005
    • Partners HealthCare
      Boston, Massachusetts, United States