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1.  QUANTITATIVE HUMAN PAPILLOMAVIRUS 16 AND 18 LEVELS IN INCIDENT INFECTIONS AND CERVICAL LESION DEVELOPMENT 
Journal of medical virology  2009;81(4):713-721.
Human papillomavirus (HPV) RNA levels may be a more sensitive early indicator of predisposition to carcinogenesis than DNA levels. We evaluated whether levels of HPV-16 and HPV-18 DNA and messenger RNA (mRNA) in newly detected infections are associated with cervical lesion development. Female university students were recruited from 1990-2004. Cervical samples for HPV DNA, HPV mRNA, and Papanicolaou testing were collected tri-annually, and women were referred for colposcopically-directed biopsy when indicated. Quantitative real-time polymerase chain reaction of L1 and E7 DNA and E7 mRNA was performed on samples from women with HPV-16 and HPV-18 infections that were incidently detected by consensus PCR. Adjusting for other HPV types, increasing E7 cervical HPV-16 mRNA levels at the time of incident HPV-16 DNA detection were associated with an increased risk of cervical intraepithelial neoplasia grade 2 to 3 (HR per 1 log10 increase in mRNA=6.36,95%CI=2.00-20.23). Increasing HPV-16 mRNA levels were also associated with an increased risk of cervical squamous intraepithelial lesions; the risk was highest at the incident positive visit and decreased over time. Neither HPV-16 E7 DNA levels nor HPV-18 E7 DNA nor mRNA levels were significantly associated with cervical lesion development. Report of >1 new partner in the past 8 months (relative to no new partners) was associated with increased HPV mRNA (viral level ratio [VLR]=10.05,95%CI=1.09-92.56) and increased HPV DNA (VLR=16.80,95%CI=1.46-193.01). In newly detected HPV-16 infections, increasing levels of E7 mRNA appear to be associated with an increased risk of developing cervical pre-cancer.
doi:10.1002/jmv.21450
PMCID: PMC3984467  PMID: 19235870
HPV; viral load; mRNA; cervical pre-cancer
2.  Standard Treatment Regimens for Nongonococcal Urethritis Have Similar but Declining Cure Rates: A Randomized Controlled Trial 
Cure rates for nongonococcal urethritis (NGU), were approximately 80% and there was no significant difference between azithromycin and doxycycline for clinical or microbiologic cure. Chlamydia trachomatis, Ureaplasma urealyticum biovar 2, and idiopathic NGU remained relatively sensitive to standard therapies, but Mycoplasma genitalium was not.
Background. Azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline.
Methods. From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks.
Results. Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%–85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%–82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred.
Conclusions. Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline. Mycoplasma genitalium treatment failure was extremely common.
Clinical Trials Registration. NCT00358462.
doi:10.1093/cid/cis1022
PMCID: PMC3588116  PMID: 23223595
urethritis; treatment; Mycoplasma genitalium; Chlamydia trachomatis; randomized trial
3.  An empiric risk scoring tool for identifying high-risk heterosexual HIV-1 serodiscordant couples for targeted HIV-1 prevention 
Background and objectives
Heterosexual HIV-1 serodiscordant couples are increasingly recognized as an important source of new HIV-1 infections in sub-Saharan Africa. A simple risk assessment tool could be useful for identifying couples at highest risk for HIV-1 transmission.
Methods
Using data from three prospective studies of HIV-1 serodiscordant couples from seven African countries and standard methods for development of clinical prediction rules, we derived and validated a risk scoring tool developed from multivariate modeling and composed of key predictors for HIV-1 risk that could be measured in standard research and clinical settings.
Results
The final risk score included age of the HIV-1 uninfected partner, married and/or cohabiting partnership, number of children, unprotected sex, uncircumcised male HIV-1 uninfected partner, and plasma HIV-1 RNA in the HIV-1 infected partner. The maximum risk score was 12, scores ≥5 were associated with an annual HIV-1 incidence of >3%, and couples with a score ≥6 accounted for only 28% of the population but 67% of HIV-1 transmissions. The area under the curve for predictive ability of the score was 0.74 (95% CI 0.70–0.78). Internal and external validation showed similar predictive ability of the risk score, even when plasma viral load was excluded from the risk score.
Conclusions
A discrete combination of clinical and behavioral characteristics defines highest-risk HIV-1 serodiscordant couples. Discriminating highest-risk couples for HIV-1 prevention programs and clinical trials using a validated risk score could improve research efficiency and maximize the impact of prevention strategies for reducing HIV-1 transmission.
doi:10.1097/QAI.0b013e31827e622d
PMCID: PMC3620695  PMID: 23187945
HIV-1 serodiscordant couples; HIV-1 acquisition; clinical prediction rule
4.  Estimating the Efficacy of Preexposure Prophylaxis for HIV Prevention Among Participants With a Threshold Level of Drug Concentration 
American Journal of Epidemiology  2013;177(3):256-263.
Assays for detecting levels of antiretroviral drugs in study participants are increasingly popular in preexposure prophylaxis (PrEP) trials, since they provide an objective measure of adherence. Current correlation analyses of drug concentration data are prone to bias. In this article, we formulate the causal estimand of prevention efficacy among drug compliers, those who would have had a threshold level of drug concentration had they been assigned to the drug arm of the trial. The identifiability of the causal estimand is facilitated by exploiting the exclusion restriction; that is, drug noncompliers do not acquire any prevention benefit. In addition, we develop an approach to sensitivity analysis that relaxes the exclusion restriction. Applications to published data from 2 PrEP trials, namely the Preexposure Prophylaxis Initiative (iPrEx) trial and the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial, suggest high efficacy estimates among drug compliers (in the iPrEx trial, odds ratio = 0.097 (95% confidence interval: 0.027, 0.352); in the CAPRISA 004 trial, odds ratio = 0.104 (95% confidence interval: 0.024, 0.447)). In summary, the proposed inferential method provides an unbiased assessment of PrEP efficacy among drug compliers, thus adding to the primary intention-to-treat analysis and correlation analyses of drug concentration data.
doi:10.1093/aje/kws324
PMCID: PMC3577049  PMID: 23302152
causal inference; compliance; exclusion restriction; potential outcome; principal stratification; two-phase sampling
5.  Use of a Multifaceted Approach to Analyze HIV Incidence in a Cohort Study of Women in the United States: HIV Prevention Trials Network 064 Study 
The Journal of Infectious Diseases  2012;207(2):223-231.
Background. Reliable methods for estimating the incidence of human immunodeficiency virus (HIV) infection are needed to monitor the epidemic, identify at-risk populations, and evaluate HIV prevention strategies. We used a multifaceted approach to estimate HIV incidence in the HIV Prevention Trials Network (HPTN) 064 study.
Methods. The HPTN 064 study enrolled 2067 HIV-seronegative women and 32 HIV-seropositive women with no prior HIV infection diagnosis. Women were followed for up to 12 months. HIV incidence estimates were based on (1) detection of acute HIV infection, (2) documentation of HIV seroconversion, and (3) detection of recent HIV infection, using a multiassay algorithm (MAA).
Results. Two women had acute HIV infection at enrollment, 4 seroconverted, and 2 were identified as recently infected at enrollment using the MAA. The annual HIV incidence estimate based on acute infection at enrollment (2.52% [95% confidence interval {CI}, .17%–9.33%], using a 14-day window period) was higher than the estimate based on seroconversion (0.24% [95% CI, .07%–.62%]; P = .027). Incidence estimates obtained using the MAA at enrollment and at the end of study were 0.25% (95% CI, .03%–.93%) and 0.13% (95% CI, .006%–.76%), respectively.
Conclusions. We detected a high frequency of acute infection at enrollment. Cross-sectional HIV incidence estimates obtained using the MAA were similar to the longitudinal estimate based on HIV seroconversion.
Clinical Trials Registration. NCT00995176.
doi:10.1093/infdis/jis658
PMCID: PMC3532822  PMID: 23129758
HIV-1; women; United States; incidence
6.  Partner Characteristics Predicting HIV-1 Set Point in Sexually Acquired HIV-1 Among African Seroconverters 
Abstract
Plasma HIV-1 RNA set point is an important predictor of HIV-1 disease progression. We hypothesized that inoculum size and HIV-1 exposure prior to HIV-1 transmission may modulate set point. We evaluated predictors of set point among 141 African HIV-1 seroconverters and their HIV-1-infected study partners. We compared characteristics of seroconverters and their HIV-1-infected partners and HIV-1 set point. Data were from a clinical trial of genital HSV-2 suppression with acyclovir to reduce HIV-1 transmission in HIV-1 serodiscordant couples with HIV-1 transmission linkage assigned through virus sequencing. Our analysis includes data from all transmissions including those with transmission linkage to the HIV-1-infected “source partner” and those that were not linked to their HIV-1-infected study partner. In multivariable analysis, higher plasma HIV-1 in source partners was associated with higher seroconverter set point (+0.44 log10 copies/ml per log10 source partner plasma HIV-1, p<0.001). In addition, bacterial vaginosis (BV) among female source partners near the time of infection was associated with higher set point in their male seroconverters (+0.49 log10, p=0.04). Source partner characteristics associated with lower set point included male circumcision (−0.63 log10, p=0.03) and assignment to acyclovir (−0.44 log10, p=0.02). The proportion of variation in set point explained by plasma HIV-1 RNA of the source partner, after controlling for other factors, was 0.06. Source partner plasma HIV-1 level is the most significant predictor of seroconverter set point, possibly reflecting characteristics of the transmitted virus. Acyclovir use, BV among women source partners, and circumcision among male source partners may alter the set point by affecting transmitted virus inoculum in the source partners' genital compartment.
doi:10.1089/aid.2012.0206
PMCID: PMC3537302  PMID: 23061422
7.  Prevalence and risk factors for oncogenic HPV infections in high-risk mid-adult women 
Sexually transmitted diseases  2012;39(11):848-856.
Background
The epidemiology of high-risk (hr) HPV infections in mid-adult women with new sex partners is undefined.
Methods
We analyzed baseline data from 518 25–65 year old female online daters. Women were mailed questionnaires and kits for self-collecting vaginal specimens for PCR-based hrHPV testing. Risk factors for infection were identified using Poisson regression models to obtain prevalence ratios (PRs).
Results
The prevalence of hrHPV infection was 35.9%. In multivariate analysis restricted to sexually active women, the likelihood of hrHPV infection was associated with abnormal Pap test history (PR=1.42, 95% CI:1.10–1.84), lifetime number of sex partners >14 (relative to 1–4; PR=2.13, 95% CI:1.13–4.02 for 15–24 partners and PR=1.91, 95% CI:1.00–3.64 for ≥25 partners), male partners with ≥1 concurrent partnership (PR=1.34, 95% CI:1.05–1.71) and male partners whom the subject met online (PR=1.39, 95% CI:1.08–1.79). Age was inversely associated with infection only in women who were sexually inactive (PR=0.67 per 5-year age difference, adjusted for Pap history and lifetime number of partners). Compared to sexually inactive women, the likelihood of infection increased with increasing risk level, (from low-risk to high-risk partners) (p<.0001 by trend test). In multivariate analysis, infection with multiple versus single hrHPV types was inversely associated with ever having been pregnant (PR=0.64, 95% CI:0.46–0.90) and recent consistent condom use (PR=0.56, 95% CI:0.32–0.97), and positively associated with genital wart history (PR=1.43, 95% CI:1.03–1.99).
Conclusions
Measures of both cumulative and recent sexual history were associated with prevalent hrHPV infection in this high-risk cohort of mid-adult women.
doi:10.1097/OLQ.0b013e3182641f1c
PMCID: PMC3476060  PMID: 23064533
HPV; human papilloma virus; mid-adult; prevalence; risk factors
8.  A unified procedure for meta-analytic evaluation of surrogate end points in randomized clinical trials 
Biostatistics (Oxford, England)  2012;13(4):609-624.
The meta-analytic approach to evaluating surrogate end points assesses the predictiveness of treatment effect on the surrogate toward treatment effect on the clinical end point based on multiple clinical trials. Definition and estimation of the correlation of treatment effects were developed in linear mixed models and later extended to binary or failure time outcomes on a case-by-case basis. In a general regression setting that covers nonnormal outcomes, we discuss in this paper several metrics that are useful in the meta-analytic evaluation of surrogacy. We propose a unified 3-step procedure to assess these metrics in settings with binary end points, time-to-event outcomes, or repeated measures. First, the joint distribution of estimated treatment effects is ascertained by an estimating equation approach; second, the restricted maximum likelihood method is used to estimate the means and the variance components of the random treatment effects; finally, confidence intervals are constructed by a parametric bootstrap procedure. The proposed method is evaluated by simulations and applications to 2 clinical trials.
doi:10.1093/biostatistics/kxs003
PMCID: PMC3616754  PMID: 22394448
Causal inference; Meta-analysis; Surrogacy
9.  Summary Measures of Adherence Using Pill Counts in Two HIV Prevention Trials: The Need for Standardisation in Reporting 
AIDS and Behavior  2013;17:3108-3119.
For trials of user-dependent HIV prevention products, accurate adherence measurements are essential to interpret and compare results across trials. We used pill count data from two recent HIV prevention trials of herpes simplex virus type 2 (HSV-2) suppression, to show that estimates of adherence vary substantially depending on assumptions that are made in analysing pill count data. We associate calculated adherence with biological markers of anti-HSV-2 activity. In both trials, calculated adherence varied considerably, depending on the summary measure used, and the handling of intervals with apparent ‘over-adherence’ (fewer pills returned than expected), and unreturned pills. Intervals of apparent over-adherence were associated with reduced antiviral effects on biological markers of herpes reactivation, indicating these are likely to represent periods of non-adherence. Our results demonstrate the clear need for standardisation in reporting of adherence data that are based on pill counts.
doi:10.1007/s10461-013-0542-9
PMCID: PMC3812335  PMID: 23801018
Adherence; HIV prevention; Pill counts
10.  Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine 
Journal of Clinical Virology  2011;53(3):239-243.
Background
The duration of protection conferred by prophylactic human papillomavirus (HPV) L1 virus-like particle vaccines is a critical determinant of their public health impact. A feature of vaccines that confer long-term immunity is their ability to induce immune memory.
Objectives
We evaluated antibody responses against HPV types 6, 11, 16 and 18 following administration of the quadrivalent HPV-6/11/16/18 vaccine to women who had previously received a monovalent HPV-16 vaccine.
Study design
As part of an extended follow-up study conducted between 2006 and 2009 in Seattle, Washington, we administered the quadrivalent HPV-6/11/16/18 vaccine to 52 women (19 vaccine and 33 placebo recipients) who had participated in a monovalent HPV-16 vaccine trial 8.5 years earlier. Serum samples were tested for anti-HPV antibodies using competitive Luminex immunoassay.
Results
Following administration of the first dose of the quadrivalent HPV-6/11/16/18 vaccine, the anti-HPV-16 geometric mean titer among monovalent HPV-16 vaccine recipients (GMT = 5024.0 milli-Merck units per milliliter [mMU/mL]; 95% confidence interval [CI]: 2710.1, 9313.6 mMU/mL) substantially exceeded that among the placebo recipients (GMT = 136.1; 95% CI: 78.5, 235.8 mMU/mL; p < 0.01) and their own highest anti-HPV-16 response observed during the original trial (GMT at month 7 of the original trial = 1552.7 mMU/mL; 95% CI: 1072.6, 2247.7 mMU/mL; p < 0.01).
Conclusions
The findings suggest that the administration of the three-dose regimen of the monovalent HPV-16 vaccine had produced memory lymphocytes, characterized by a heightened immune response following administration of the quadrivalent HPV-6/11/16/18 vaccine that effectively served as an antigen challenge.
doi:10.1016/j.jcv.2011.12.009
PMCID: PMC3279625  PMID: 22209292
Human papillomavirus type 16; Vaccines; Immune memory
11.  Plasma Viral Loads During Early HIV-1 Infection Are Similar in Subtype C– and Non-Subtype C–Infected African Seroconverters 
The Journal of Infectious Diseases  2013;207(7):1166-1170.
Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C–infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.
doi:10.1093/infdis/jit015
PMCID: PMC3583276  PMID: 23315322
HIV-1; group M subtype; plasma viral load; early infection; Africa
12.  Determinants of Per-Coital-Act HIV-1 Infectivity Among African HIV-1–Serodiscordant Couples 
The Journal of Infectious Diseases  2012;205(3):358-365.
(See the editorial commentary by Gray and Wawer on pages 351–2.)
Background. Knowledge of factors that affect per-act infectivity of human immunodeficiency virus type 1 (HIV-1) is important for designing HIV-1 prevention interventions and for the mathematical modeling of the spread of HIV-1.
Methods. We analyzed data from a prospective study of African HIV-1–serodiscordant couples. We assessed transmissions for linkage within the study partnership, based on HIV-1 sequencing. The primary exposure measure was the HIV-1–seropositive partners’ reports of number of sex acts and condom use with their study partner.
Results. Of 3297 couples experiencing 86 linked HIV-1 transmissions, the unadjusted per-act risks of unprotected male-to-female (MTF) and female-to-male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010–.0037) and 0.0010 (95% CI, .00060–.0017), respectively. After adjusting for plasma HIV-1 RNA of the HIV-1–infected partner and herpes simplex virus type 2 serostatus and age of the HIV-1–uninfected partner, we calculated the relative risk (RR) for MTF versus FTM transmission to be 1.03 (P = .93). Each log10 increase in plasma HIV-1 RNA increased the per-act risk of transmission by 2.9-fold (95% CI, 2.2–3.8). Self-reported condom use reduced the per-act risk by 78% (RR = 0.22 [95% CI, .11–.42]).
Conclusions. Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1–uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision.
doi:10.1093/infdis/jir747
PMCID: PMC3256946  PMID: 22241800
13.  Clinical and Virologic Response to Episodic Acyclovir for Genital Ulcers among HIV-1 Seronegative, HSV-2 Seropositive African Women: A Randomized, Placebo-Controlled Trial 
Sexually transmitted diseases  2012;39(1):21-24.
In a randomized trial among African women with recurrent genital herpes, episodic acyclovir therapy resulted in modestly greater likelihood of lesion healing (HR=1.48, p=0.098; mean 5.1 vs. 6.0 days) and cessation of HSV shedding (HR=1.88, p=0.008; mean 3.0 vs. 5.0 days) compared with placebo, similar to results from high-income countries. (ClinicalTrials.gov registration NCT00808405).
doi:10.1097/OLQ.0b013e31823b50c6
PMCID: PMC3244838  PMID: 22183840
herpes simplex virus; acyclovir; HSV shedding; women; Africa; genital herpes
14.  Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission 
PLoS ONE  2012;7(11):e51192.
Background
Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts ≤350 cells/µL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted.
Methods
Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts >350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: i) CD4 count <500 cells/µL, ii) viral load ≥10,000 or ≥50,000 copies/mL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions.
Results
Initiating treatment at viral load ≥50,000 copies/mL would require treating 19.8% of infected persons with CD4 counts >350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load ≥10,0000 copies/mL had a ratio of 1.5. In contrast, initiation at CD4 count <500 would require treating 41.8%, while averting 48.4% (ratio 1.1).
Conclusion
Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility.
doi:10.1371/journal.pone.0051192
PMCID: PMC3511400  PMID: 23250272
15.  Circumcision and acquisition of HPV infection in young men 
Sexually transmitted diseases  2011;38(11):1074-1081.
Background
The role of circumcision in male HPV acquisition is not clear.
Methods
Male university students (18–20 years of age) were recruited from 2003–2009 and followed tri-annually. Shaft/scrotum, glans, and urine samples were tested for 37 alpha HPV genotypes. Cox proportional hazards methods were used to evaluate the association between circumcision and HPV acquisition. Logistic regression was used to assess whether number of genital sites infected at incident HPV detection or site of incident detection varied by circumcision status.
Results
In 477 men, rates of acquiring clinically-relevant HPV types (high-risk types plus types 6 and 11) did not differ significantly by circumcision status (hazard ratio [HR] for uncircumcised relative to circumcised subjects: 0.9[95%CI:0.7–1.2]). However, compared to circumcised men, uncircumcised men were 10.1 (95%CI:2.9–35.6) times more likely to have the same HPV type detected in all 3 genital specimens than in a single genital specimen and were 2.7 (95%CI:1.6–4.5) times more likely to have an HPV-positive urine or glans specimen at first detection.
Conclusions
While the likelihood of HPV acquisition did not differ by circumcision status, uncircumcised men were more likely than circumcised men to have infections detected at multiple genital sites, which may have implications for HPV transmission.
doi:10.1097/OLQ.0b013e31822e60cb
PMCID: PMC3210112  PMID: 21992987
HPV; human papilloma virus; circumcision; epidemiology; risk factors
16.  Acyclovir Achieves a Lower Concentration in African HIV-Seronegative, Herpes Simplex Virus 2-Seropositive Women than in Non-African Populations 
Acyclovir pharmacokinetics was evaluated in 68 HIV-seronegative, herpes simplex virus 2 (HSV-2)-seropositive African women, who received a single oral 400-mg dose of acyclovir, with plasma acyclovir concentrations measured over 8 h. Geometric mean peak concentration and area under the concentration-time curve were 0.31 μg/ml and 1.59 h · μg/ml, respectively, 54% and 52% lower than values from non-Africans. Lower acyclovir concentrations may partly explain the reduced acyclovir suppression of HSV-2 genital ulcer recurrence in HPTN 039 African women participants.
doi:10.1128/AAC.06160-11
PMCID: PMC3346629  PMID: 22330926
18.  Prevalences of sexually transmitted infections in young adults and female sex workers in Peru: a national population-based survey 
The Lancet Infectious Diseases  2012;12(10):765-773.
Summary
Background
We assessed prevalences of seven sexually transmitted infections (STIs) in Peru, stratified by risk behaviours, to help to define care and prevention priorities.
Methods
In a 2002 household-based survey of the general population, we enrolled randomly selected 18–29-year-old residents of 24 cities with populations greater than 50 000 people. We then surveyed female sex workers (FSWs) in these cities. We gathered data for sexual behaviour; vaginal specimens or urine for nucleic acid amplification tests for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; and blood for serological tests for syphilis, HIV, and (in subsamples) herpes simplex virus 2 (HSV2) and human T-lymphotropic virus. This study is a registered component of the PREVEN trial, number ISRCTN43722548.
Findings
15 261 individuals from the general population and 4485 FSWs agreed to participate in our survey. Overall prevalence of infection with HSV2, weighted for city size, was 13·5% in men, 13·6% in women, and 60·6% in FSWs (all values in FSWs standardised to age composition of women in the general population). The prevalence of C trachomatis infection was 4·2% in men, 6·5% in women, and 16·4% in FSWs; of T vaginalis infection was 0·3% in men, 4·9% in women, and 7·9% in FSWs; and of syphilis was 0·5% in men, 0·4% in women, and 0·8% in FSWs. N gonorrhoeae infection had a prevalence of 0·1% in men and women, and of 1·6% in FSWs. Prevalence of HIV infection was 0·5% in men and FSWs, and 0·1% in women. Four (0·3%) of 1535 specimens were positive for human T-lymphotropic virus 1. In men, 65·0% of infections with HIV, 71·5% of N gonorrhoeae, and 41·4% of HSV2 and 60·9% of cases of syphilis were in the 13·3% who had sex with men or unprotected sex with FSWs in the past year. In women from the general population, 66·7% of infections with HIV and 16·7% of cases of syphilis were accounted for by the 4·4% who had been paid for sex by any of their past three partners.
Interpretation
Defining of high-risk groups could guide targeting of interventions for communicable diseases—including STIs—in the general Peruvian population.
Funding
Wellcome Trust-Burroughs Wellcome Fund Infectious Disease Initiative and US National Institutes of Health.
doi:10.1016/S1473-3099(12)70144-5
PMCID: PMC3459082  PMID: 22878023
19.  Antibody responses in oral fluid following administration of prophylactic human papillomavirus vaccines 
The Journal of Infectious Diseases  2009;200(9):1452-1455.
We sought to determine whether oral fluid can be used to assess serum human papillomavirus (HPV) antibody status by enrolling women who had received a prophylactic HPV-16 vaccine in a new follow-up study. After the prophylactic HPV-6/11/16/18 vaccine was licensed in the United States, we administered it to consenting participants. The sensitivity of oral fluid, treating serology as the gold standard, before and after administration of the quadrivalent vaccine was 49.6% (95% confidence interval [CI]: 42.0%–57.3%) and 100% (95% CI: 92.0%–100%), respectively. Oral fluid may have the potential to be used for monitoring of prophylactic HPV vaccines in the future.
doi:10.1086/606026
PMCID: PMC3392559  PMID: 19698077
Human papillomavirus; Prophylactic vaccines; Antibodies; Oral fluid
20.  Breast-Milk Infectivity in Human Immunodeficiency Virus Type 1–Infected Mothers 
The Journal of Infectious Diseases  2003;187(5):736-740.
Human immunodeficiency virus type 1 (HIV-1) is transmitted through blood, genital secretions, and breast milk. The probability of heterosexual transmission of HIV-1 per sex act is .0003–0015, but little is known regarding the risk of transmission per breast-milk exposure. We evaluated the probability of breast-milk transmission of HIV-1 per liter of breast milk ingested and per day of breast-feeding in a study of children born to HIV-1–infected mothers. The probability of breast-milk transmission of HIV-1 was .00064 per liter ingested and .00028 per day of breast-feeding. Breast-milk infectivity was significantly higher for mothers with more-advanced disease, as measured by prenatal HIV-1 RNA plasma levels and CD4 cell counts. The probability of HIV-1 infection per liter of breast milk ingested by an infant is similar in magnitude to the probability of heterosexual transmission of HIV-1 per unprotected sex act in adults.
doi:10.1086/374272
PMCID: PMC3382109  PMID: 12599046
21.  Quality of HIV care provided by non-physician clinicians and physicians in Mozambique: a retrospective cohort study 
AIDS (London, England)  2010;24(Suppl 1):S59-S66.
Objectives
To compare HIV care quality provided by non-physician clinicians (NPC) and physicians.
Design
Retrospective cohort study assessing the relationship between provider cadre and HIV care quality among non-pregnant adult patients initiating antiretroviral therapy (ART) in the national HIV care programme.
Methods
Computerized medical records from patients initiating ART between July 2004 and October 2007 at two HIV public HIV clinics in central Mozambique were used to develop multivariate analyses evaluating differences in process and care continuity measures for patients whose initial provider was a NPC or physician.
Results
A total of 5892 patients was included in the study, including 4093 (69.5%) with NPC and 1799 (30.5%) with physicians as initial providers. Those whose initial provider was a NPC were more likely to have a CD4 cell count 90–210 days [risk ratio (RR) 1.13, 1.04
Conclusion
NPC performance was similar to or better than that of physicians for the HIV care quality study measures. Our results highlight the important role of NPC in scaling up ART in Mozambique, and argue for using all relevant clinical resources to meet the large demands for care in countries with high HIV burdens.
doi:10.1097/01.aids.0000366083.75945.07
PMCID: PMC3372417  PMID: 20023441
antiretroviral therapy; Mozambique; non-physician clinicians; scale-up; task shifting
The Journal of Infectious Diseases  2011;203(10):1425-1433.
Background. Viral load may influence the course of human papillomavirus type 16 (HPV-16) infection.
Methods. This case-control study was nested within the 2-year Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study, in which women were followed semiannually for HPV and cervical intraepithelial neoplasia (CIN). Case patients (n = 62) were women diagnosed with CIN3 following HPV-16–positive detection at a follow-up visit. HPV-16–positive controls (n = 152) without CIN2 or CIN3 were matched to cases based on the follow-up visit in which viral load was measured. Real-time polymerase chain reaction was used for HPV-16 DNA quantification.
Results. The risk of CIN3 increased with increasing HPV-16 DNA load at the follow-up visit (odds ratio, 1.63; 95% confidence interval, 1.33–1.99 per 1 log10 unit increase); the association was not affected by whether HPV-16 was present at enrollment. When HPV-16 was present at both enrollment and follow-up, viral load remained high among cases (P = .77) but decreased substantially among controls (P = .004). Among women with HPV-16 found initially during follow-up, viral load in the first HPV-16–positive sample was associated with short-term persistence; load was higher in those with infection, compared with those without infection, 1 visit after the initial positivity (P = .001).
Conclusions. Viral load of newly detected infections and changes in viral load predict persistence and progression of HPV-16 infections.
doi:10.1093/infdis/jir049
PMCID: PMC3080901  PMID: 21415020
BACKGROUND
Characterizing short-term detection patterns of young women’s incident alpha-genus human papillomavirus (HPV) infections may further understanding of HPV transmission.
METHODS
Between 2000–2007, we followed 18–22 year old female university students with triannual HPV DNA and Papanicolau testing. Using Kaplan-Meier methods, we estimated: duration of detectable, type-specific incident infections; time to re-detection (among infections that became undetectable); and time to cervical lesion development after incident infection. We evaluated risk factors for short-term persistent versus transient infection with logistic regression.
RESULTS
303 incident type-specific infections were detected in 85 sexually active women. Median time to first negative test after incident infection was 9.4 (95%CI:7.8–11.2) months; 90.6% of infections became undetectable within two years. 19.4% of infections that became undetectable were re-detected within one year. Cervical lesions were common, and 60% were positive for multiple HPV types in concurrent cervical swabs. Incident HPV detection in the cervix only (versus the vulva/vagina only or both sites) was associated with short-term transience.
CONCLUSIONS
While most incident infections became undetectable within two years, re-detection was not uncommon. Cervical lesions were a common early manifestation of HPV infection.
IMPACT
It remains unclear whether potentially modifiable risk factors can be identified to reduce infection duration (and transmission likelihood).
doi:10.1158/1055-9965.EPI-10-1108
PMCID: PMC3078690  PMID: 21173170
human papillomavirus; incidence; duration; persistence; women; epidemiology
Lancet  2012;379(9821):1120-1128.
Summary
Background
Previous community-randomised trials of interventions to control sexually transmitted infections (STIs) have involved rural settings, were rarely multicomponent, and had varying results. We aimed to assess the effect of a multicomponent intervention on curable STIs in urban young adults and female sex workers (FSWs).
Methods
In this community-randomised trial, baseline STI screening was done between August, and November, 2002, in random household samples of young adults (aged 18–29 years) and in FSWs in Peruvian cities with more than 50 000 inhabitants. Geographically separate cities were selected, matched into pairs, and randomly allocated to intervention or control groups with an S-PLUS program. Follow-up surveys of random samples were done after 2 years and 3 years. The intervention comprised four modalities: strengthened STI syndromic management by pharmacy workers and clinicians; mobile-team outreach to FSWs for STI screening and pathogen-specific treatment; periodic presumptive treatment of FSWs for trichomoniasis; and condom promotion for FSWs and the general population. Individuals in control cities received standard care. The composite primary endpoint was infection of young adults with Chlamydia trachomatis, Trichomonas vaginalis, or Neisseria gonorrhoeae, or syphilis seroreactivity. Laboratory workers and the data analyst were masked, but fieldworkers, the Peruvian study team, and participants in the outcome surveys were not. All analyses were done by intention to treat. This trial is registered, ISRCTN43722548.
Findings
We did baseline surveys of 15 261 young adults in 24 Peruvian cities. Of those, 20 geographically separate cities were matched into pairs, in each of which one city was assigned to intervention and the other to standard of care. In the 2006 follow-up survey, data for the composite primary outcome were available for 12 930 young adults. We report a non-significant reduction in prevalence of STIs in young adults, adjusted for baseline prevalence, in intervention cities compared with control cities (relative risk 0·84, 95% CI 0·69–1·02; p=0·096). In subgroup analyses, significant reductions were noted in intervention cities in young adult women and FSWs.
Interpretation
Syndromic management of STIs, mobile-team outreach to FSWs, presumptive treatment for trichomoniasis in FSWs, and condom promotion might reduce the composite prevalence of any of the four curable STIs investigated in this trial.
Funding
Wellcome Trust and Burroughs Wellcome Fund, National Institutes of Health, Center for AIDS Research, CIPRA, and USAID-Peru.
doi:10.1016/S0140-6736(11)61846-1
PMCID: PMC3315635  PMID: 22341824
The design of studies evaluating the safety and efficacy of interventions for HIV prevention is challenging in the US context, where there is low generalized prevalence. HIV incidence is sufficiently high in the at-risk US population of men who have sex with men that prevention trials using HIV infection end points are feasible. In other US populations at higher risk of HIV exposure, clinical trials could be conducted to provide definitive evidence regarding the level of coverage that can be achieved by strategies for implementation of interventions that already have been established to be effective.
doi:10.1097/QAI.0b013e3181fbcb61
PMCID: PMC3298818  PMID: 21406984
prevention trial; trial design; HIV seroincidence; implementation

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