Susan H Eshleman

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (145)843.11 Total impact

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    ABSTRACT: Analysis of samples from Uganda using serologic HIV incidence assays reveal that individuals with subtype D infection often have weak humoral immune responses to HIV infection. It is unclear whether this reflects a poor initial response to infection or a waning antibody response later in infection. Samples (N = 2614) were obtained from 114 women aged 18-45 years in the Ugandan Genital Shedding and Disease Progression Study cohort (2001-2009; 82 subtype A, 32 subtype D; median 23 samples/women, range 3-41 samples, median follow-up of 6.6 years). Samples were analyzed using the BED capture immunoassay (cutoff, 0.8 OD-n) and the avidity assay (cutoff, 90% Avidity Index). Antibody maturation was assessed by having the BED capture enzyme immunoassay (BED-CEIA) or avidity value exceed the assay cutoff 1 or 2 years after infection. The waning antibody response was measured by having the BED-CEIA or avidity value fall >20% below the maximum value. For the BED-CEIA, 8 women with subtype A infection and 3 women with subtype D infection never progressed previously the cutoff value (median, 5.9 years follow-up after infection). Six women with subtype D infection never achieved an avidity index >90%. Subtype did not impact the proportion of women whose assay values regressed by >20% of the maximal value (for BED-CEIA: 33% for A, 41% for D, P = 0.51; for avidity: 1% for A, 6% for D, P = 0.19). The higher frequency of misclassification of individuals with long-term subtype D infection as recently infected using serologic incidence assays reflects a weak initial antibody response to HIV infection that is sustained over time.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2014; 65(4):390-6. · 4.65 Impact Factor
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    ABSTRACT: Antiretroviral drugs are used for the treatment and prevention of HIV infection. Non-adherence to antiretroviral drug regimens can compromise their clinical efficacy and lead to emergence of drug-resistant HIV. Clinical trials evaluating antiretroviral regimens for HIV treatment and prevention can also be compromised by poor adherence and non-disclosed off-study antiretroviral drug use. This report describes the development and validation of a high throughput, qualitative method for the identification of antiretroviral drugs using high-resolution mass spectrometry (HRMS) for the retrospective assessment of off-study antiretroviral drug use and the determination of potential antiretroviral therapy (ART) non-compliance. Serum standards were prepared that contained 15 antiretroviral drugs: 9 protease inhibitors (PIs), 4 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs), and 2 non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs). Analytical separation was achieved on a Hypersil Gold PFP (100×3 mm) column and the eluent was analyzed using the Thermo Exactive Orbitrap mass spectrometer (Exactive-MS) operated in full scan mode. Limit of identification, signal intensity precision, retention time analysis, selectivity, and carryover studies were conducted. Concordance with liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods was evaluated using remnant plasma samples from a clinical trial. The limit of identification ranged from 5-10 ng/ml for 14 drugs (9 PIs, 1 NNRTI, 4 NRTIs) and was 150 ng/ml for 1 NNRTI. Precision studies with high and low control mixtures revealed signal intensity coefficients of variation of 3.0-27.5%. The Exactive-MS method was selective for the compounds of interest. Overall, concordance ranged from 89.1%-100% for the screening of antiretroviral drugs in clinical plasma specimens as compared to LC-MS/MS methods. Using the Exactive-MS, we developed and validated a highly selective, robust method for the multiplexed detection of 15 antiretroviral drugs.
    Clinica chimica acta; international journal of clinical chemistry 03/2014; · 2.54 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; · 19.97 Impact Factor
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    ABSTRACT: BACKGROUND: HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18-month outcomes. METHODS: Randomized, placebo-controlled trial in 4 African countries. Infant diagnostic HIV testing was performed regularly from birth through 18 months. Kaplan-Meier analysis was used to assess 18-month cumulative infant HIV infection, HIV infection/or death, and mortality rates. RESULTS: Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower among infants receiving daily NVP from 6 weeks to 6 months 1.1% [95% confidence interval (CI): 0.2% to 1.8%], compared with placebo 2.4% (95% CI: 1.3% to 2.6%), P = 0.049, but not significantly lower thereafter. Eighteen-month postnatal infection rates were low: 2.2% (95% CI: 1.1% to 3.3%) versus 3.1% (95% CI: 1.9% to 4.4%), respectively, P = 0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18-month postnatal infection rates (0.5%, 95% CI: 0.0% to 1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI: 1.9% to 5.5%), and infants of mothers with CD4 counts of ≥ 350 cells per cubic millimeter not receiving ART (4.8%, 95% CI: 2.7% to 6.8%; P = 0.46). There were no differences in adverse events between study arms. CONCLUSIONS: This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age 6 weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.
    J Acquir Immune Defic Syndr. 03/2014; 65(3):366-74.
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    ABSTRACT: To evaluate factors associated with misclassification by the limiting-antigen avidity (LAg-avidity) assay among individuals with long-standing HIV infection. Samples were obtained from the Multicenter AIDS Cohort Study and AIDS Linked to the IntraVenous Experience cohort (1089 samples from 667 individuals, 595 samples collected 2-4 years and 494 samples collected 4-8 years after HIV seroconversion). Paired samples from both time points were available for 422 (63.3%) of the 667 individuals. Samples were considered to be misclassified if the LAg-avidity assay result was 1.5 or less normalized optical density (OD-n) units. Overall, 4.8% (52/1089) of the samples were misclassified, including 1.8% [16/884, 95% confidence interval (CI) 1.09-3.06%] of samples from individuals with viral loads above 400 copies/ml and 1.4% (10/705) of samples from individuals with viral loads above 400 copies/ml and CD4 cell counts above 200 cells/μl (95% CI 0.68-2.60%). Age, race, sex, and mode of HIV acquisition were not associated with misclassification. In an adjusted analysis, viral load below 400 copies/ml [adjusted odds ratio (aOR) 3.72, 95% CI 1.61-8.57], CD4 cell count below 50 cells/μl (aOR 5.41, 95% CI 1.86-15.74), and low LAg-avidity result (≤1.5 OD-n) from the earlier time point (aOR 5.60, 95% CI 1.55-20.25) were significantly associated with misclassification. The manufacturer of the LAg-avidity assay recommends excluding individuals from incidence surveys who are receiving antiretroviral therapy, are elite suppressors, or have AIDS (CD4 cell count <200 cells/μl). The results of this study indicate that those exclusions do not remove all sources of assay misclassification among individuals with long-standing HIV infection.
    AIDS (London, England) 02/2014; · 4.91 Impact Factor
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    ABSTRACT: Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence.
    PLoS ONE 01/2014; 9(6):e101043. · 3.73 Impact Factor
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    ABSTRACT: American Black men who have sex with men (MSM) are disproportionately affected by HIV, but the factors associated with this concentrated epidemic are not fully understood. Black MSM were enrolled in 6 US cities to evaluate a multi-component prevention intervention, with the current analysis focusing on the correlates of being newly diagnosed with HIV compared to being HIV-uninfected or previously diagnosed with HIV. HPTN 061 enrolled 1553 Black MSM whose median age was 40; 30% self-identified exclusively as gay or homosexual, 29% exclusively as bisexual, and 3% as transgender. About 1/6(th) (16.2%) were previously diagnosed with HIV (PD); of 1263 participants without a prior HIV diagnosis 7.6% were newly diagnosed (ND). Compared to PD, ND Black MSM were younger (p<0.001); less likely to be living with a primary partner (p<0.001); more likely to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.011) or chlamydia (p = 0.020). Compared to HIV-uninfected Black MSM, ND were more likely to report unprotected receptive anal intercourse (URAI) with a male partner in the last 6 months (p<0.001); and to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.004), and urethral (p = 0.025) or rectal chlamydia (p<0.001). They were less likely to report female (p = 0.002) or transgender partners (p = 0.018). Multivariate logistic regression analyses found that ND Black MSM were significantly more likely than HIV-uninfected peers to be unemployed; have STIs, and engage in URAI. Almost half the men in each group were poor, had depressive symptoms, and expressed internalized homophobia. ND HIV-infected Black MSM were more likely to be unemployed, have bacterial STIs and engage in URAI than other Black MSM. Culturally-tailored programs that address economic disenfranchisement, increase engagement in care, screen for STIs, in conjunction with safer sex prevention interventions, may help to decrease further transmission in this heavily affected community.
    PLoS ONE 01/2014; 9(1):e87298. · 3.73 Impact Factor
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    ABSTRACT: Background Although several interventions have shown reduced HIV incidence in clinical trials, the community-level effect of effective interventions on the epidemic when scaled up is unknown. We investigated whether a multicomponent, multilevel social and behavioural prevention strategy could reduce HIV incidence, increase HIV testing, reduce HIV risk behaviour, and change social and behavioural norms. Methods For this phase 3 cluster-randomised controlled trial, 34 communities in four sites in Africa and 14 communities in Thailand were randomly allocated in matched pairs to receive 36 months of community-based voluntary counselling and testing for HIV (intervention group) or standard counselling and testing alone (control group) between January, 2001, and December, 2011. The intervention was designed to make testing more accessible in communities, engage communities through outreach, and provide support services after testing. Randomisation was done by a computer-generated code and was not masked. Data were collected at baseline (n=14 567) and after intervention (n=56 683) by cross-sectional random surveys of community residents aged 18–32 years. The primary outcome was HIV incidence and was estimated with a cross-sectional multi-assay algorithm and antiretroviral drug screening assay. Thailand was excluded from incidence analyses because of low HIV prevalence. This trial is registered at ClinicalTrials.gov, number NCT00203749. Findings The estimated incidence of HIV in the intervention group was 1·52% versus 1·81% in the control group with an estimated reduction in HIV incidence of 13·9% (relative risk [RR] 0·86, 95% CI 0·73–1·02; p=0·082). HIV incidence was significantly reduced in women older than 24 years (RR=0·70, 0·54–0·90; p=0·0085), but not in other age or sex subgroups. Community-based voluntary counselling and testing increased testing rates by 25% overall (12–39; p=0·0003), by 45% (25–69; p<0·0001) in men and 15% (3–28; p=0·013) in women. No overall effect on sexual risk behaviour was recorded. Social norms regarding HIV testing were improved by 6% (95% CI 3–9) in communities in the intervention group. Interpretation These results are sufficiently robust, especially when taking into consideration the combined results of modest reductions in HIV incidence combined with increases in HIV testing and reductions in HIV risk behaviour, to recommend the Project Accept approach as an integral part of all interventions (including treatment as prevention) to reduce HIV transmission at the community level. Funding US National Institute of Mental Health, the Division of AIDS of the US National Institute of Allergy and Infectious Diseases, and the Office of AIDS Research of the US National Institutes of Health.
    The Lancet Global Health. 01/2014; 2(5):e267–e277.
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    ABSTRACT: Multi-assay algorithms (MAAs) can be used for cross-sectional HIV incidence estimation. We previously identified a robust MAA that includes the BED capture immunoassay (BED-CEIA), the BioRad-Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). MAAs were evaluated that included the BED capture immunoassay (BED-CEIA), the BioRad-Avidity assay, viral load, and HRM score, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. Performance characteristics based on the proportion of samples classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. Cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up._HIV diversity is a useful biomarker for HIV incidence estimation. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored plasma or serum samples, without the need for CD4 cell counts.
    Journal of clinical microbiology 10/2013; · 4.16 Impact Factor
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    ABSTRACT: In HPTN 061, 155 HIV-infected men reported no prior HIV diagnosis; 83 of those men had HIV viral loads <1,000 copies/mL at enrollment. Antiretroviral drug testing revealed that 65 (78.3%) of the 83 men were on antiretroviral treatment. Antiretroviral drug testing can help distinguish between newly-diagnosed and previously-diagnosed HIV infection.
    Clinical Infectious Diseases 10/2013; · 9.37 Impact Factor
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    ABSTRACT: Previous studies demonstrated that individuals with subtype D HIV infection who had been infected for two or more years were frequently misclassified as assay positive using cross-sectional incidence assays. Samples from 510 subjects (212 subtype A, 298 subtype D) who were infected for 2.2 to 14.5 years (median 5.4 years) and were not virally suppressed were tested using LAg-Avidity enzyme immunoassay (LAg-Avidity EIA), BioRad Avidity assay, and BED capture enzyme immunoassay (BED-CEIA). The performance of these three assays was evaluated using various assay cutoff values (LAg-Avidity EIA: <1.0 OD-n and <2.0 OD-n; BioRad Avidity assay: <40% avidity index (AI) and <80 AI %; BED-CEIA: <0.8 OD-n). The mean LAg-Avidity EIA result was higher for subtype A than D (4.54±0.95 vs. 3.86±1.26, p <0.001); the mean BioRad Avidity assay result was higher for subtype A than D (88.9%±12.5% vs. 75.1±30.5, p <0.001); and the mean BED-CEIA result was similar for the two subtypes (2.2±1.2 OD-n for subtype A, 2.2±1.3 OD-n for subtype D, p <0.9). The frequency of misclassification was higher for individuals with subtype D infection compared to those with subtype A infection, using either the LAg-Avidity EIA with a cutoff of <2.0 OD-n or the BioRad Avidity assay with cutoffs of <40% or <80% AI. No subtype-specific differences in assay performance were observed using the BED-CEIA. Sex and age were not significantly associated with misclassification by any assay. The LAg-Avidity EIA with a cutoff <1.0 OD-n had the lowest frequency of misclassification in this Ugandan population.
    AIDS research and human retroviruses 10/2013; · 2.18 Impact Factor
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    ABSTRACT: Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. HPTN 057 was a phase 1, open label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/ infant 4 mg/kg doses day 0, 3 and 5; maternal 900 mg doses/infant 6 mg/kg doses day 0, 3 and 5; maternal 600 mg doses/infant 6 mg/kg doses daily x7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid and breast milk tenofovir concentrations were determined by liquid chromatographic - tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. 122 mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 mg and 900 mg exceeded that in non-pregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74-97% of infants receiving daily dosing. A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in studies of TDF efficacy for HIV PMTCT and early infant treatment.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2013; · 4.65 Impact Factor
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    ABSTRACT: Background. Determinants of inter-subtype differences in HIV-1 clinical disease progression remain unknown.Methods. HIV-1 subtype was independently determined for five separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multi-region hybridization assay. Of these, replication capacities (RC) of 145 samples were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino-acid polymorphisms were examined for association with pol RC.Results. In multivariate analyses, subtype D pol had a 2.4 hazard ratio (HR) of progression to composite endpoint (CD4+ count<250 cells/mm(3), antiretroviral therapy initiation or death), compared to subtype A (p=0.001). Compared to subtype A pol (referent group), subtype D pol, pol RC>67% (median pol RC) had a significant hazard ratio of 4.6 (95% CI: 1.9 to 11.0, p=0.001) for progression to composite endpoint, while subtype D pol, pol RC≤67% infection had a non-significant 2.2 (95% CI: 1.0 to 4.9, p=0.051) hazard of progression to composite endpoint. Amino acid substitutions at protease positions 62 and 64, and reverse transcriptase position 272 were associated with significant differences in pol RC.Conclusion. HIV-1 pol gene inter-subtype and RC differences are associated with disease progression, and may be influenced by amino acid polymorphisms.
    The Journal of Infectious Diseases 08/2013; · 5.85 Impact Factor
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    ABSTRACT: The HIV Prevention Trials Network (HPTN) 052 enrolled serodiscordant couples. HIV-infected index participants reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45/96 (46.9%) participants with undetectable viral load (VL), 2/48 (4.2%) participants with low VL, and 1/65 (1.5%) participants with high VL (P<0.0001). ARV drugs were also detected in follow-up samples from participants who were not on study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.
    The Journal of Infectious Diseases 08/2013; · 5.85 Impact Factor
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    ABSTRACT: Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts. From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition. Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men ≤30 years old (95% CI: 3.6, 9.1%). Men ≤30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age ≤30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition. In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates.
    PLoS ONE 07/2013; 8(7):70413-. · 3.73 Impact Factor
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    ABSTRACT: Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
    The Journal of Infectious Diseases 06/2013; 207 Suppl 2:S70-7. · 5.85 Impact Factor
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    ABSTRACT: Background: Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Methods: Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Results: Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and in samples that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D infected individuals, samples misclassified by one assay were 3.5 times more likely to misclassify by the other assay. Conclusions: Differential misclassification by infecting subtype of long term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D co-circulate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D infected individuals limits the utility of using these assays in combination within this population.
    AIDS research and human retroviruses 05/2013; · 2.18 Impact Factor
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    ABSTRACT: The incidence of human immunodeficiency virus (HIV) is the rate at which new HIV infections occur in populations. The development of accurate, practical, and cost-effective approaches to estimation of HIV incidence is a priority among researchers in HIV surveillance because of limitations with existing methods. In this paper, we develop methods for estimating HIV incidence rates using multiple biomarkers in biological samples collected from a cross-sectional survey. An advantage of the method is that it does not require longitudinal follow-up of individuals. We use assays for BED, avidity, viral load, and CD4 cell count data from clade B samples collected in several US epidemiologic cohorts between 1987 and 2010. Considering issues of accuracy, cost, and implementation, we identify optimal multiassay algorithms for estimating incidence. We find that the multiple-biomarker approach to cross-sectional HIV incidence estimation corrects the significant deficiencies of currently available approaches and is a potentially powerful and practical tool for HIV surveillance.
    American journal of epidemiology 01/2013; · 5.59 Impact Factor
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    ABSTRACT: Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment. Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept. In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation.
    PLoS ONE 01/2013; 8(11):e78818. · 3.73 Impact Factor
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    ABSTRACT: In HIV-infected children, viral diversity tends to increase with age in the absence of antiretroviral treatment (ART). We measured HIV diversity in African children (ages 6-36 months) enrolled in a randomized clinical trial comparing two ART regimens (Cohort I of the P1060 trial). Children in this cohort were exposed to single dose nevirapine (sdNVP) at birth. HIV diversity was measured retrospectively using a high resolution melting (HRM) diversity assay. Samples were obtained from 139 children at the enrollment visit prior to ART initiation. Six regions of the HIV genome were analyzed: two in gag, one in pol, and three in env. A single numeric HRM score that reflects HIV diversity was generated for each region; composite HRM scores were also calculated (mean and median for all six regions). In multivariable median regression models using backwards selection that started with demographic and clinical variables, older age was associated with higher HRM scores (higher HIV diversity) in pol (P = 0.005) and with higher mean (P = 0.014) and median (P<0.001) HRM scores. In multivariable models adjusted for age, pre-treatment HIV viral load, pre-treatment CD4%, and randomized treatment regimen, higher HRM scores in pol were associated with shorter time to virologic suppression (P = 0.016) and longer time to study endpoints (virologic failure [VF], VF/death, and VF/off study treatment; P<0.001 for all measures). In this cohort of sdNVP-exposed, ART-naïve African children, higher levels of HIV diversity in the HIV pol region prior to ART initiation were associated with better treatment outcomes.
    PLoS ONE 01/2013; 8(11):e81213. · 3.73 Impact Factor

Publication Stats

4k Citations
843.11 Total Impact Points

Institutions

  • 2006–2014
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2013
    • Tan Tock Seng Hospital
      Tumasik, Singapore
  • 2011–2013
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2000–2013
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2007–2009
    • Monogram Biosciences
      San Francisco, California, United States
    • Centers for Disease Control and Prevention
      Atlanta, Michigan, United States
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 2003
    • University of Miami Miller School of Medicine
      • Division of Hospital Medicine
      Miami, FL, United States
  • 2001
    • Stanford University
      • Division of Infectious Diseases
      Stanford, CA, United States
    • University of California, Los Angeles
      • Department of Pediatrics
      Los Angeles, California, United States
  • 1998–1999
    • Case Western Reserve University
      • • Department of Pathology (University Hospitals Case Medical Center)
      • • Department of Oral Pathology
      Cleveland, OH, United States