Sharon A Riddler

Harvard University, Cambridge, Massachusetts, United States

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Publications (97)

  • [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Previous studies suggest that non-nucleoside-reverse-transcriptase inhibitors (NNRTI) cause faster virologic suppression while ritonavir-boosted-protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS: We searched databases (up to February 2016) to identify randomised trials comparing NNRTI- vs PI/r-based initial therapy. A meta-analysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were: death, progression to AIDS and treatment discontinuation. We calculated RR of virologic suppression and MD for increase of CD4 cells at week 48. RESULTS: We included 29 trials with 9047 participants. In intention-to-treat analyses, death or progression to AIDS occurred in 226 participants in the NNRTI arm and 221 in the PI/r arm (RR: 1.03 [95%CI: 0.87-1.22], 12 trials; n=3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04 [0.86-1.25]; 22 trials; n=8311) and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00 [0.80-1.25]; 13 trials; n=4740) Overall treatment discontinuation (1.12 [0.93-1.35], 24 trials, n=8249) and from toxicity (1.21 [0.87-1.68], 21 trials; n=6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58 [0.91-2.74], 17 trials; n=5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR: 1.03 [0.98-1.09]) or CD4+recovery (MD: -4.7 cells [-14.2 to 4.8]) CONCLUSIONS: In this comprehensive meta-analysis, we found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.
    Article · Apr 2016 · Clinical Infectious Diseases
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    Bernard J.C. Macatangay · Sharon A Riddler · Nicole D Wheeler · [...] · Charles R Rinaldo
    [Show abstract] [Hide abstract] ABSTRACT: Background: We report the results of a phase I/II, open label, single-arm, clinical trial to evaluate the safety and anti-HIV efficacy of an autologous dendritic cell (DC)-based HIV-1 vaccine loaded with autologous HIV-1-infected apoptotic cells. Methods: Antiretroviral therapy (ART)-naïve individuals were enrolled and viremia was suppressed on ART prior to receiving 4 doses of DC-based vaccine. Participants underwent treatment interruption 6 weeks after the 3(rd) vaccine dose. Plasma HIV-1 RNA 12 weeks after treatment interruption was compared to the pre-ART baseline. Results: The vaccine was safe and well-tolerated, but did not prevent viral rebound during treatment interruption. Vaccination resulted in a modest but significant decrease in plasma viremia from the pre-ART baseline (from 4.53 log10 cps/mL to 4.27 log10 cps/mL; p=0.05). Four of the ten participants had a greater than 0.70log10 increase in HIV-1 RNA in plasma following vaccination despite continuous ART. Single molecule sequencing of HIV-1 RNA in plasma pre- and post-vaccination revealed increases in G>A hypermutants in gag and pol after vaccination which suggests cytolysis of infected cells. Conclusion: A DC-apoptotic body-based therapeutic HIV vaccine was safe and induced T-cell activation and cytolysis, including HIV-1-infected cells in a subset of study participants.
    Full-text Article · Dec 2015 · The Journal of Infectious Diseases
  • Nyaradzo M Mgodi · Cliff Kelly · Brenda Gati · [...] · Sharon A Riddler
    [Show abstract] [Hide abstract] ABSTRACT: Summary There is a paucity of normative bone mineral density (BMD) data in healthy African women. Baseline total hip and lumbar spine BMD was measured in premenopausal women. BMD distribution was comparable to that of a reference population and was impacted by several factors including contraception and duration of lactation. Introduction Normative data on bone mineral density (BMD) and the cumulative impact of lactation, contraceptive use, and other factors on BMD in healthy African women have not been well studied. Objectives The objective of this study was to determine the factors associated with BMD in healthy premenopausal women in Uganda and Zimbabwe. Methods Baseline total hip (TH) and lumbar spine (LS) BMD was measured by dual x-ray absorptiometry in 518 healthy, premenopausal black women enrolling in VOICE, an HIV-1 chemoprevention trial, at sites in Uganda and Zimbabwe. Contraceptive and lactation histories, physical activity assessment, calcium intake, and serum vitamin D levels were assessed. Independent factors associated with BMD were identified using an analysis of covariance model. Results The study enrolled 331 women from Zimbabwe and 187 women from Uganda. Median age was 29 years (IQR 25, 32) and median body mass index (BMI) was 24.8 kg/m2 (IQR 22.2, 28.6). In univariate analyses, lower TH BMD values were associated with residence in Uganda (p p Conclusions Among healthy premenopausal women, TH and LS BMD was higher in Zimbabwe than Uganda. Additional factors independently associated with BMD included BMI, physical activity level, contraceptive use, and lactation.
    Article · Dec 2015 · Archives of Osteoporosis
  • Sharon A Riddler · Evgenia Aga · Ronald J Bosch · [...] · John W Mellors
    [Show abstract] [Hide abstract] ABSTRACT: We measured plasma HIV-1 RNA by single copy assay from participants (N=334) with viral suppression on antiretroviral therapy (ART). Residual viremia ≥1 copy/mL after 4 years of ART was predicted by higher pre-ART HIV-1 RNA, higher on-treatment CD8 cell count, and lower on-treatment CD4/CD8 ratio, but not by initial ART regimen. In a longitudinal subset (N=64), continued decay of plasma HIV-1 RNA was observed, averaging 6% decline per year and with an estimated half-life of 11.5 years. In contrast to prior reports, persistent viremia continues to slowly decline during years 4-12 of suppressive ART. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Article · Sep 2015 · The Journal of Infectious Diseases
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    Brenda G. Mirembe · Clifton W. Kelly · Nyaradzo Mgodi · [...] · Sharon A. Riddler
    [Show abstract] [Hide abstract] ABSTRACT: Background: Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial. Methods: HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks. Results: Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH. Conclusions: TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.
    Full-text Article · Sep 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    G. Wang · E. Li · Z. Mesbah · [...] · S. Eppes
    Full-text Article · Oct 2014 · Open Forum Infectious Diseases
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    Full-text Article · Oct 2014 · AIDS Research and Human Retroviruses
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    Brenda G Mirembe · Cliff Kelly · Mgodi Nyaradzo · [...] · Sharon Riddler
    Full-text Article · Oct 2014 · AIDS Research and Human Retroviruses
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    Sharon Riddler · Marla Husnik · Arendevi Pather · [...] · Jennifer Balkus
    Full-text Article · Oct 2014 · AIDS Research and Human Retroviruses
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. Methods: Blood mononuclear cells obtained during 7-12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. Results: Thirty participants were studied. HIV-1 DNA decreased significantly from years 0-1 and 1-4 of ART with median decay slopes of -0.86 (interquartile range, -1.05, -0.59) and -0.11 (-0.17, -0.06) log10(copies/10(6) CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4-7 (-0.02 [-0.06, 0.02]; P = .09) or after year 7 of ART (-0.006 [-0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10(6) CD4+ T-cells; range: 7-2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1-4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. Conclusions: Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1-4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.
    Article · Jul 2014 · Clinical Infectious Diseases
  • [Show abstract] [Hide abstract] 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/µL; 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.
    Article · May 2014 · Clinical Infectious Diseases
  • Conference Paper · Jan 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Peripheral neuropathy (PN) is a common neurological complication of HIV infection that has debilitating effects on quality of life. While there has been a comprehensive evaluation of the prevalence of neuropathic signs/symptoms and risk factors (RFs) for PN or symptomatic PN (SPN) with initiation of combination antiretroviral therapy (cART) in ART-naïve patients, similar evaluation in ART-experienced patients is limited. This study investigated the prevalence and RFs for PN/SPN in ART-experienced patients enrolled in clinical salvage therapy studies. Between February 2000 and June 2007, 522 ART-experienced participants who experienced virologic failure with a prior regimen and started new regimens were followed longitudinally and annually screened for signs and symptoms of PN. Rates of PN/SPN at 3 years since parent study entry were 52.8 and 24.0 %, respectively. Aging, taller height, protease inhibitor use, and female sex were significant RFs for PN/SPN. The use of statin drugs was significantly associated with lower odds of SPN, and it may prevent progression from no SPN to SPN.
    Article · Dec 2013 · Journal of NeuroVirology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: In the United States, black individuals infected with human immunodeficiency virus (HIV) have higher rates of virologic failure on antiretroviral therapy (ART) and of death compared to white individuals. The cause for these disparities is uncertain. We sought to examine differences in virologic outcomes among antiretroviral-naive 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 studies were analyzed. Included studies were those conducted during 1998-2006 with a primary outcome of virologic failure. The primary outcome measure was time to virologic failure, regardless of ART changes. Results: A total of 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 [HR]; 1.7; 95% confidence interval [CI], 1.4-1.9; P < .001), with no evidence of heterogeneity across regimens (P = .97); the association remained after adjustment for measured confounders (HR, 1.4; 95% CI, 1.2-1.6; P < .001). Increased hazard of virologic failure was associated with younger age, higher pretreatment HIV type 1 RNA level, lower pretreatment CD4 cell count, hepatitis C antibody, less education, and recent nonadherence to treatment. 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 that the difference may be driven by social factors; however, biological factors cannot be ruled out. Further research should identify the sources of racial disparities and develop strategies to reduce them.
    Article · Sep 2013 · Clinical Infectious Diseases
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To compare the longitudinal changes in total bone mineral density (TBMD) across antiretroviral (ARV) regimens. Methods: A5142 was an open-label study comparing 3 ARV regimens for the initial treatment of HIV-1. Subjects were randomized equally to efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir (LPV/r) plus 2 NRTIs, or LPV/r plus EFV without NRTI. The NRTI regimen (lamivudine [3TC] plus zidovudine [ZDV], stavudine [d4T], or tenofovir [TDF]) was selected prior to randomization. TBMD was assessed via whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 48 and 96 weeks. Analysis was modified intent-to-treat (ITT) ignoring regimen changes using all evaluations. Results: Significant mean declines in TBMD at week 48 were observed among subjects. In repeated-measures analysis of changes (including randomized regimen, NRTI used, and time), there was a significant difference in the NRTI-containing arms in mean percentage change in TBMD at week 48 according to NRTI used (P < .001). Subjects taking ZDV had similar changes to those taking d4T (P = .970), whereas those taking TDF had larger declines (P < .001). There was a nonsignificant trend toward greater mean declines among subjects taking LPV/r versus EFV (P = .080). Overall, TDF-containing regimens demonstrated the greatest losses in TBMD, while EFV regimens without TDF had lesser TBMD reductions even compared to the NRTI-sparing arm. From week 48 to 96, all treatment groups continued to lose TBMD at similar rates. Conclusions: Among NRTI-containing arms, NRTI selection, especially use of TDF, had a greater effect on TBMD change than randomized regimen. The long-term clinical significance remains to be demonstrated.
    Article · Sep 2013 · HIV Clinical Trials
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. Methods: We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. Results: The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/µL lost significantly more BMD compared to those with CD4(+) ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. Conclusions: Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.
    Article · Aug 2013 · Clinical Infectious Diseases
  • [Show abstract] [Hide abstract] ABSTRACT: The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4 T cells in HIV-1 infection is unclear. We evaluated the frequency and numbers of CD4CD39 and CD4CD73 T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP by ectoenzyme-expressing CD4 T cells, whereas cyclic adenosine monophosphate (cAMP) levels were measured using enzyme immunoassay. Suppression of T-cell function by exogenous ADO and CD4CD73 T cells was tested by flow cytometry. CD39 and CD73 are expressed in different CD4 T-cell subsets. CD4CD73 T cells do not express CD25 and FOXP3, and their frequency and numbers were lower in HIV-1-positive individuals regardless of virologic suppression (P = 0.005 and P < 0.001, respectively). CD4CD73 numbers inversely correlated with CD4CD38DR (P = 0.002), CD8CD38DR T-cell frequency (P = 0.05), and plasma CRP levels (P = 0.01). Both subsets are required for hydrolysis of exogenous ATP to ADO and can increase CD4 T-cell cAMP levels when incubated with exogenous ATP. Low-level viremia did not correlate with activated T-cell frequency. In vitro, ADO suppressed T-cell activation and cytokine expression. CD4CD73 T cells suppressed T-cell proliferation only in the presence of exogenous 5'-AMP. The ADO-producing CD4CD73 subset of T cells is depleted in HIV-1-positive individuals regardless of viral suppression and may play a key role in controlling HIV-1-associated immune activation.
    Article · Jun 2013 · AIDS (London, England)
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE:: To facilitate collection of cumulative data on longitudinal HIV disease outcomes during HIV prevention studies by developing recommendations for follow-up of the relatively few study participants with breakthrough infections. DESIGN:: We formed a working group to compare and contrast the various approaches taken in recent HIV prevention trials, to summarize the advantages and disadvantages associated with each, and to explore the feasibility of developing protocols for the long-term follow-up of seroconverters. METHODS:: We reviewed study designs, objectives, and assessments in 15 interventional studies that followed HIV seroconverters. Protocol team members joined discussions of the various approaches and developed recommendations. RESULTS:: Most HIV prevention clinical trials share a core set of objectives, including the description/comparison of virological, immunological and clinical course of HIV, and sometimes a comparison of pre-and post-seroconversion behavior. Long-term follow-up of seroconverters can be conducted in separate studies if the transition from parent protocol is effectively managed. CONCLUSION:: We recommend the development of harmonized seroconverter protocols. Although specific research questions in the post-seroconversion period may differ depending on prevention modality, harmonizing key evaluations would create an opportunity to ask overarching questions that inform the prevention field with respect to design and implementation of future combination prevention studies. Follow-up immediately post-seroconversion should be conducted in the parent protocol before rollover into a follow-up protocol. Development of specimen repositories with ample volumes for future assays, standardized definitions of infection, diagnosis and seroconversion dates, and harmonization of study objectives and sample collections at key time points are important.
    Article · Dec 2012 · AIDS (London, England)
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    [Show abstract] [Hide abstract] ABSTRACT: HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1888 treatment-naïve, chronically-infected individuals using phylogenetically-informed methods, and identified characteristics of HLA-associated immune pressures that differentiate protective and non-protective alleles. Over 2100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally-defined CTL epitope. Differential CTL escape patterns between closely related HLA alleles were common, and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly twofold more frequently than expected by chance, and were computationally predicted to reduce peptide-HLA binding nearly tenfold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multi-site and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. Study results provide new information to guide vaccine design and immunogenicity studies.
    Full-text Article · Oct 2012 · Journal of Virology
  • Conference Paper · Jan 2012