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1.  The association between the ratio of monocytes:lymphocytes and risk of tuberculosis(TB) amongst HIV infected postpartum women 
Recent human studies support historical animal studies that suggested an association between peripheral blood monocyte:lymphocyte(ML) ratio and tuberculosis(TB) disease. To evaluate generalizability of this finding, we modelled the association between peripartum ML ratio and incident TB disease within 18 months postpartum amongst 1202 HIV-infected women in South Africa, Tanzania, Uganda and Zimbabwe. The ML ratio was associated with increased risk of TB disease independently to combination antiretroviral-therapy(cART), WHO stage or CD4 count(HRadjusted = 1.22;95% CI 1.07–1.4;p=0.003 per 0.1 unit increase in ML ratio).
PMCID: PMC4229408  PMID: 25247435
Tuberculosis; HIV; pregnancy; monocytes; lymphocytes; ML ratio
2.  Clinicians’ perceptions and provision of hormonal contraceptives for HIV positive and at-risk women in Southern Africa: an original research article 
Contraception  2014;90(4):391-398.
To assess clinician provision of hormonal contraception for HIV positive and at-risk women in Southern Africa.
Study Design
We conducted a nationally representative survey of clinicians (n=1444) in HIV-prevalent settings in South Africa and Zimbabwe to evaluate evidence-based contraceptive care and clinician views of hormonal contraceptives for HIV positive and at-risk women. Multivariable logistic regression was used to analyze differences in contraceptive provision by professional training and practice setting.
Most providers offered oral contraceptives (85%), but only a small minority considered them appropriate for women at risk of HIV (27%) or HIV positive women (25%). A higher proportion of clinicians considered injections appropriate for women at risk of HIV (42%) or HIV positive women (46%). Very few considered emergency contraceptives appropriate (13%). Multivariable results showed that family planning training and clinic as compared to hospital practices, were associated with evidence-based attitudes about contraception for HIV positive or at-risk women, and greater provision. There were no differences, however, between physicians and nurses or by HIV training.
These findings emphasize the need to improve clinicians’ awareness of evidence-based guidelines for hormonal contraception for women at high risk of HIV and HIV-positive women. Evidence-based information that oral contraception and injections are appropriate is essential. Contraceptive education should be integrated into HIV training to reach at-risk populations.
Oral and injectable hormonal contraception are appropriate for HIV positive and at-risk women; women and clinicians need evidence-based information to ensure women have access to these effective contraceptive methods.
PMCID: PMC4437207  PMID: 24924260
Contraception; family planning; HIV; Southern Africa
3.  Differences in Clinical Manifestations of Acute and Early HIV-1 Infection between HIV-1 Subtypes in African Women 
Little is known about the differences in clinical manifestations between women with various HIV-1 subtypes during acute (AI) and early (EI) HIV infection. In a longitudinal cohort study, clinical signs and symptoms among Uganda and Zimbabwe women with AI and EI were compared with HIV-negative controls; symptoms were assessed quarterly for 15 to 24 months. Early HIV infection was defined as the first visit during which a woman tested HIV antibody positive. Women who were HIV negative serologically but DNA polymerase chain reaction positive were considered AI. In all, 26 women were classified AI and 192 EI, with 654 HIV-negative controls. Primary HIV infection (AI and EI) was associated with unexplained fever (P <.01), weight loss (P <.01), fatigue (P <.01), inguinal adenopathy (P <.01), and cervical friability (P =.01). More women with subtype C infection had unexplained fever, fatigue, and abnormal vaginal discharge compared to subtype A or D infection. Inguinal adenopathy occurred less often in women with subtype A infection than those with subtype C or D infection.
PMCID: PMC4511722  PMID: 24106054
HIV-1 subtype; clinical manifestations; STDs; acute HIV infection; women
4.  The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception 
mBio  2015;6(5):e00221-15.
Particular types of hormonal contraceptives (HCs) and genital tract infections have been independently associated with risk of HIV-1 acquisition. We examined whether immunity in women using injectable depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), or no HCs differs by the presence of cervicovaginal infections. Immune mediators were quantified in cervical swabs from 832 HIV-uninfected reproductive-age Ugandans and Zimbabweans. Bacterial infections and HIV were diagnosed by PCR, genital herpes serostatus by enzyme-linked immunosorbent assay (ELISA), altered microflora by Nugent score, and Trichomonas vaginalis and Candida albicans infection by wet mount. Generalized linear models utilizing Box-Cox-Power transformation examined associations between levels of mediators, infection status, and HCs. In no-HC users, T. vaginalis was associated with broadest spectrum of aberrant immunity (higher interleukin 1β [IL-1β], IL-8, macrophage inflammatory protein 3α [MIP-3α], β-defensin 2 [BD2], and IL-1 receptor antigen [IL-1RA]). In women with a normal Nugent score and no genital infection, compared to the no-HC group, COC users showed higher levels of IL-1β, IL-6, IL-8, and IL-1RA, while DMPA users showed higher levels of RANTES and lower levels of BD2, both associated with HIV seroconversion. These effects of COC were blunted in the presence of gonorrhea, chlamydia, trichomoniasis, candidiasis, and an abnormal Nugent score; however, RANTES was increased among COC users with herpes, chlamydia, and abnormal Nugent scores. The effect of DMPA was exacerbated by lower levels of IL-1RA in gonorrhea, chlamydia, or herpes, SLPI in gonorrhea, and IL-1β, MIP-3α, and IL-1RA/IL1β ratio in trichomoniasis. Thus, the effects of HC on cervical immunity depend on the genital tract microenvironment, and a weakened mucosal barrier against HIV may be a combined resultant of genital tract infections and HC use.
In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiome’s simultaneous interactions with hormones and HIV remain to be elucidated.
PMCID: PMC4556810  PMID: 26330510
5.  Differences in Clinical Manifestations of Acute and Early HIV-1 Infection between HIV-1 Subtypes in African Women 
Little is known about the differences in clinical manifestations between women with various HIV-1 subtypes during acute (AI) and early (EI) HIV infection. In a longitudinal cohort study, clinical signs and symptoms among Uganda and Zimbabwe women with AI and EI were compared with HIV-negative controls; symptoms were assessed quarterly for 15 to 24 months. Early HIV infection was defined as the first visit during which a woman tested HIV antibody positive. Women who were HIV negative serologically but DNA polymerase chain reaction positive were considered AI. In all, 26 women were classified AI and 192 EI, with 654 HIV-negative controls. Primary HIV infection (AI and EI) was associated with unexplained fever (P <.01), weight loss (P <.01), fatigue (P <.01), inguinal adenopathy (P <.01), and cervical friability (P =.01). More women with subtype C infection had unexplained fever, fatigue, and abnormal vaginal discharge compared to subtype A or D infection. Inguinal adenopathy occurred less often in women with subtype A infection than those with subtype C or D infection.
PMCID: PMC4511722  PMID: 24106054
HIV-1 subtype; clinical manifestations; STDs; acute HIV infection; women
6.  Fertility desires and condom use among HIV-positive women at an antiretroviral roll-out program in Zimbabwe 
As access to anti-retroviral therapy (ART) increases in sub-Saharan Africa, fertility and contraception patterns are likely to change. Two hundred HIV-positive women at an ART roll-out site in Zimbabwe responded to a questionnaire on fertility desires and condom use. Ten women (5%) reported planning a pregnancy in the next year, comprising 0% of women not yet eligible for ART, 8.22% of women on the waitlist for ART, and 4.17% of women on ART. Younger age, fewer living children, and higher quality of life were individually associated with intended pregnancy in the next year; however in multivariate analysis only the association with higher quality of life remained significant. Reported ever use of condoms was relatively low (46.5%) and condom use varied by neither ART status nor by fertility desires. In conclusion, our data demonstrates fertility desires among HIV-positive women in Zimbabwe correlate with higher perceived quality of life.
PMCID: PMC4431572  PMID: 21243916
Antiretroviral therapy; fertility desires; condom use; quality of life
7.  Efficacy and safety of an extended nevirapine regimen in infants of breastfeeding mothers with HIV-1 infection for prevention of HIV-1 transmission (HPTN 046): 18-month results of a randomized, double-blind, placebo-controlled trial 
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.
Randomized, placebo-controlled trial in four African countries. Infant diagnostic HIV testing was done 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.
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% CI 0.2-1.8%), compared to placebo: 2.4% (95% CI 1.3-2.6%), p=0.049; but not significantly lower thereafter. Eighteen month postnatal infection rates were low: 2.2% [95% CI 1.1-3.3%] versus 3.1% [95% CI 1.9-4.4%], 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 0.0-1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI 1.9-5.5%); and infants of mothers with CD4 >350/mm3 not receiving ART (4.8%, 95% CI 2.7-6.8%), (p=0.46). There were no differences in adverse events between study arms.
This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age six weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.
PMCID: PMC3945386  PMID: 24189151
nevirapine; infant HIV prophylaxis; PMTCT
8.  Integrating family planning and prevention of mother to child HIV transmission in Zimbabwe 
Contraception  2013;89(3):209-214.
Integrate enhanced family planning (FP) and prevention of mother-to-child HIV transmission (PMTCT) services in order to help HIV-positive Zimbabwean women achieve their desired family size and spacing as well as to maximize maternal and child health.
Study Design
HIV-positive pregnant women were enrolled into a standard-of-care (SOC, n=33) or intervention (n=65) cohort, based on study entry date, and followed for three months post-partum. The intervention cohort received education sessions aimed at increasing FP use and negotiation power. Both groups received care from nurses with enhanced FP training. Outcomes included FP use, FP knowledge, and HIV disclosure, and were assessed with Fisher’s exact, binomial, and t-tests.
The intervention cohort reported increased control over condom use (p=0.002), increased knowledge about IUDs (p=0.002), increased relationship power (p=0.01), and increased likelihood of disclosing their HIV status to a partner (p=0.04) and having that partner disclose to them (p=0.04), when compared to the SOC cohort. Long-acting reversible contraception (LARC) use in both groups increased from ~2% at baseline to >80% at three months post-partum (p<0.001).
FP and sexual negotiation skills and knowledge, as well as HIV disclosure, increased significantly in the intervention cohort. LARC uptake increased significantly in both the intervention and SOC cohorts, likely because both groups received care from nurses with enhanced FP training. Successful service integration models are needed to maximize health outcomes in resource-constrained environments; this intervention is such a model that should be replicable in other settings in sub-Saharan Africa and beyond.
PMCID: PMC3965605  PMID: 24332254
Contraception; HIV/AIDS; intervention; maternal child health; provider training; prevention education
9.  HIV Disease Progression in the First Year after Delivery among African Women followed in the HPTN 046 Clinical Trial 
Starting lifelong antiretroviral therapy (ART) in HIV-infected pregnant women may decrease HIV progression and transmission but adherence after delivery may be difficult, especially for asymptomatic women. We evaluated disease progression among HIV-infected women not on ART with CD4+ lymphocyte counts above 200 cells/uL at delivery.
We analysed risk of death, progression to AIDS (stage IV or CD4 < 200 cells/uL), or to CD4+ count < 350 one year after delivery among postpartum women enrolled to a prevention of breastfeeding transmission trial using Kaplan-Meier methods. In the primary analysis, women were censored if ART was initiated.
Among 1285 women who were < WHO stage IV at 6 weeks postpartum, 49 (4.3%) progressed to stage IV/CD4 < 200 cells/uL or death by one year. Progression to CD4 < 200 or death occurred among 16 (4.3%) of 441 women with CD4 count of 350–549 and 10 (1.6%) of 713 with CD4 counts > 550 at delivery. CD4 < 350 by 12 months postpartum occurred among 116 (37.0%) of 350 women with CD4 count 400–549 and 48 (7.4%) of 713 > 550 at delivery.
Progression to AIDS or CD4 count < 350 is uncommon through one year postpartum for women with CD4 counts over 550 at delivery, but occurred in over one third of those with CD4 counts under 550. ART should be continued after delivery or breastfeeding among women with CD4 counts < 550 if follow up and ARV adherence can be maintained.
PMCID: PMC3800257  PMID: 23846568
HIV; postpartum; disease progression
10.  Hormonal Contraceptive Use and Discontinuation among HIV-infected Women in Uganda and Zimbabwe 
Hormonal contraception (HC) use by HIV-infected women has been identified by the WHO as important strategy for reducing vertical HIV transmission. Little is known about factors associated with HC discontinuation among HIV-infected women.
We analyzed data from a prospective study of HC use among 231 HIV-infected oral contraceptive (OC) or injectable depot medroxyprogesterone acetate (DMPA) users in Uganda and Zimbabwe. We used Kaplan-Meier survival curves to estimate the median duration of OC and DMPA use and use of any highly effective contraceptive method. Cox proportional hazards models were used to investigate factors associated with HC discontinuation.
Median duration was 36 months (95% CI 14, 61) for OC use and 19 months (95% CI 14, 24) for DMPA use. Median duration of any highly effective method was 36 months (95% CI 26, N/A) for OC users and 22 months (95% CI 14, 38) for DMPA users. In multivariable analyses, living in Zimbabwe (HR 0.39; 95% CI 0.18, 0.83), no partner (HR 7.18; 95% CI 3.05, 16.88) and cervical infection (HR 1.99; 95% CI 0.90, 4.41) were associated with OC discontinuation. No partner (HR 2.00; 95% CI 1.12, 3.58), nausea (HR 1.84; 95% CI 1.02, 3.34) and excessive night sweats (HR 1.80; 95% CI 0.95, 3.40) were associated with DMPA discontinuation.
Long-term use of HC methods is acceptable to HIV-infected women. Women discontinue for a variety of reasons, primarily unrelated to HIV. Alternative methods and ongoing contraceptive counseling is essential to reduce unplanned pregnancies and vertical HIV transmission.
PMCID: PMC3700659  PMID: 23572011
vertical transmission; unplanned pregnancy; hormonal contraception; contraceptive discontinuation
11.  Impact of Maternal and Infant Antiretroviral Drug Regimens on Drug Resistance in HIV-Infected Breastfeeding Infants 
The Pediatric infectious disease journal  2013;32(4):10.1097/INF.0b013e31827f44ee.
The HPTN 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV-infection despite prophylaxis.
HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher’s exact tests were used to evaluate associations between categorical variables.
NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in seven (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8=75% in the NVP arm, 1/17=5.9% in the placebo arm, P=0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral (ARV) treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all four of those infants by 6 months of age (4/4=100%). In contrast, only three (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate ARV treatment developed NVP resistance (P=0.003).
Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.
PMCID: PMC3826537  PMID: 23249916
Nevirapine resistance; prevention of mother-to-child transmission; extended nevirapine; HIV
12.  Development of Methods for Cross-Sectional HIV Incidence Estimation in a Large, Community Randomized Trial 
PLoS ONE  2013;8(11):e78818.
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.
Methods and Findings
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.
PMCID: PMC3827276  PMID: 24236054
13.  Good Performance of Rapid Prostate-Specific Antigen Test for Detection of Semen Exposure in Women: Implications for Qualitative Research 
Sexually transmitted diseases  2009;36(8):501-506.
Prostate-specific antigen (PSA) is a valid biomarker of semen exposure in women and has been used to assess reliability of self-reported sexual behavior as well as serve as a proxy measure for condom efficacy. Quantitative PSA tests are expensive and require specialized equipment. A simple, rapid, and inexpensive test for PSA would facilitate semen biomarker evaluation in a variety of research settings. This study evaluated the performance of a rapid PSA test compared with a quantitative assay to identify semen in vaginal swab specimens.
We tested 581 vaginal swabs collected from 492 women participating in 2 separate research studies in Bangladesh and Zimbabwe. PSA in vaginal secretions was detected using the quantitative IMx (Abbott Laboratories) assay and the ABAcard p30 (Abacus Diagnostics) rapid immunochromatographic strip test.
The ABAcard test was 100% sensitive (95% confidence interval [CI], 98%–100%) and 96% specific (95% CI, 93%–97%) compared with the quantitative test in detecting >1.0 ng PSA/mL vaginal swab eluate. Rapid PSA results were semiquantitative and correlated well with PSA concentrations (κ = 0.88; 95% CI, 0.85–0.90).
Rapid PSA detection requires no instrumentation and can be performed easily and economically. Having rapid PSA results available immediately following interview provides opportunities to explore discrepancies between the objective marker of recent semen exposure and self-reported behaviors.
PMCID: PMC3790320  PMID: 19455082
14.  Willingness of Clinicians to Integrate Microbicides into HIV Prevention Practices in Southern Africa 
AIDS and behavior  2012;16(7):1821-1829.
The first vaginal microbicide was recently proven effective in clinical trials. We assessed the willingness of clinicians to integrate microbicides into HIV prevention practices in Southern Africa, where women face elevated HIV risks. We conducted in-depth interviews (n = 60) and nationally representative surveys (n = 1,444) in South Africa and Zimbabwe with nurses and physicians. Over half of clinicians (58%) were aware of microbicides, with physicians far more likely than nurses to be familiar. Clinicians, including those in rural areas, were generally willing to discuss microbicides, a female-initiated method less effective than the condom, particularly when condom use was unlikely (70%). Fewer would include microbicides while counseling adolescents (51%). Most clinicians (85%) thought their patients would use microbicides; greater clinician familiarity with microbicides was significant for support. Training for both nurses and physicians prior to introduction is critical, so they have sufficient knowledge and skills to offer a microbicide upon availability.
PMCID: PMC3745300  PMID: 22210482
Microbicides; HIV prevention for women; Clinicians; Zimbabwe; South Africa
15.  Male Circumcision for HIV Prevention: Clinical Practices and Attitudes among Healthcare Providers in South Africa and Zimbabwe 
Sexually Transmitted Diseases  2012;39(7):567-575.
This study aimed to document the clinical practices and attitudes of healthcare providers in South Africa and Zimbabwe on male circumcision for HIV prevention.
We conducted national surveys of physicians and nurses in both countries in 2008-2009 (N=1,444). Data on male circumcision for HIV prevention was analyzed; outcomes were patient counseling, provision of services, and desire for training. We used multivariable logistic regression to examine associations between these outcomes and clinician, practice and attitudinal variables.
Overall, 57% of clinicians reported counseling male patients on male circumcision, 17% were offering services (49% referrals), and 61% desired training. In the multivariable analyses, provision of services was more common in South Africa (P≤.001), but desire for training higher in Zimbabwe (P≤.01). Provision of services was highest among physicians (p≤.01) and in hospital settings (P≤.001). However, nurses had greater desire for training (P≤.05) as did younger clinicians (P≤.001). Clinicians in rural and clinic settings were just as likely to express training interest. Clinician attitudes that patients would be upset due to cultural beliefs and would increase risky behaviors were associated with less counseling and service provision (P≤.05).
Many clinicians in South Africa and Zimbabwe showed willingness to integrate new HIV prevention evidence into practice and to become trained to offer the procedure to patients. Results suggest that both countries should consider involving nurses in male circumcision for HIV prevention, including those in rural areas, and should help clinicians to address cultural concerns.
PMCID: PMC3377943  PMID: 22706221
Male circumcision; HIV prevention; Clinician practices; Zimbabwe; South Africa
16.  A nationally representative survey of healthcare provider counselling and provision of the female condom in South Africa and Zimbabwe 
BMJ Open  2013;3(3):e002208.
Female condoms are the only female-initiated HIV and pregnancy prevention technology currently available. We examined female condom counselling and provision among providers in South Africa and Zimbabwe, high HIV-prevalence countries.
A cross-sectional study using a nationally representative survey.
All facilities that provide family planning or HIV/sexually transmitted infection (STI) services.
National probability sample of 1444 nurses and physicians who provide family planning or HIV/STI services.
Primary and secondary outcome measures
Female condom practices with different female patients, including adolescents, married women, women using hormonal contraception and by HIV status. Using multivariable logistic analysis, we measured variations in condom counselling by provider characteristics.
Most providers reported offering female condoms (88%; 1239/1415), but perceived a need for novel female barrier methods for HIV/STI prevention (85%; 1191/1396). By patient type, providers reported less frequent female condom counselling of adolescents (55%; 775/1411), women using hormonal contraception (65%; 909/1409) and married women (66%; 931/1416), compared to unmarried (74%; 1043/1414) or HIV-positive women (82%; 1161/1415). Multivariable results showed providers in South Africa were less likely to counsel women on female condoms than in Zimbabwe (OR=0.48, 95% CI 0.35 to 0.68, p≤0.001). However, South African providers were more likely to counsel women on male condoms (OR=2.39, 95% CI 1.57 to 3.65, p≤0.001). Nurses counselled patients on female condoms more frequently than physicians (OR=5.41, 95% CI 3.26 to 8.98, p≤0.001). HIV training, family planning training, location (urban vs rural) and facility type (hospital vs clinic) were not associated with greater condom counselling.
Female condoms were integrated into provider counselling and care, although providers reported a need for new female-initiated multipurpose prevention technologies, suggesting female condoms do not meet all patient/provider needs or are not adequately well known or accessible. Providers should be included in HIV training efforts to raise awareness of new and existing products, and encouraged to educate all women.
PMCID: PMC3612751  PMID: 23512836
17.  Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial 
Lancet  2011;379(9812):221-228.
Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.
In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primaryefficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with, number NCT00074412.
Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1.1% (95% CI 0.3–1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3–3.6) of controls (difference 1.3%, 95% CI 0–2.6), equating to a 54% reduction in transmission (p=0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p=0.81) and combined HIV infection and mortality rates (2.3% vs 3.2%; p=0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.
Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.
US National Institutes of Health.
PMCID: PMC3539769  PMID: 22196945
18.  Diaphragm Used with Replens Gel and Risk of Bacterial Vaginosis: Results from a Randomized Controlled Trial 
Background. Bacterial vaginosis (BV) has been linked to female HIV acquisition and transmission. We investigated the effect of providing a latex diaphragm with Replens and condoms compared to condom only on BV prevalence among participants enrolled in an HIV prevention trial. Methods. We enrolled HIV-seronegative women and obtained a vaginal swab for diagnosis of BV using Nugent's criteria; women with BV (score 7–10) were compared to those with intermediate (score 4–6) and normal flora (score 0–3). During quarterly follow-up visits over 12–24 months a vaginal Gram stain was obtained. The primary outcome was serial point prevalence of BV during followup. Results. 528 participants were enrolled; 213 (40%) had BV at enrollment. Overall, BV prevalence declined after enrollment in women with BV at baseline (OR = 0.4, 95% CI 0.29–.56) but did not differ by intervention group. In the intention-to-treat analysis BV prevalence did not differ between the intervention and control groups for women who had BV (OR = 1.01, 95% CI 0.52–1.94) or for those who did not have BV (OR = 1.21, 95% CI 0.65–2.27) at enrollment. Only 2.1% of participants were treated for symptomatic BV and few women (5–16%) were reported using anything else but water to cleanse the vagina over the course of the trial. Conclusions. Provision of the diaphragm, Replens, and condoms did not change the risk of BV in comparison to the provision of condoms alone.
PMCID: PMC3485870  PMID: 23133307
19.  HIV-1 Protease Inhibitors and Clinical Malaria: a Secondary Analysis of the AIDS Clinical Trials Group A5208 Study 
HIV-1 protease inhibitors (PIs) have antimalarial activity in vitro and in murine models. The potential beneficial effect of HIV-1 PIs on malaria has not been studied in clinical settings. We used data from Adult AIDS Clinical Trials Group A5208 sites where malaria is endemic to compare the incidence of clinically diagnosed malaria among HIV-infected adult women randomized to either lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) or to nevirapine (NVP)-based ART. We calculated hazard ratios and 95% confidence intervals. We conducted a recurrent events analysis that included both first and second clinical malarial episodes and also conducted analyses to assess the sensitivity of results to outcome misclassification. Among the 445 women in this analysis, 137 (31%) received a clinical diagnosis of malaria at least once during follow-up. Of these 137, 72 (53%) were randomized to LPV/r-based ART. Assignment to the LPV/r treatment group (n = 226) was not consistent with a large decrease in the hazard of first clinical malarial episode (hazard ratio = 1.11 [0.79 to 1.56]). The results were similar in the recurrent events analysis. Sensitivity analyses indicated the results were robust to reasonable levels of outcome misclassification. In this study, the treatment with LPV/r compared to NVP had no apparent beneficial effect on the incidence of clinical malaria among HIV-infected adult women. Additional research concerning the effects of PI-based therapy on the incidence of malaria diagnosed by more specific criteria and among groups at a higher risk for severe disease is warranted.
PMCID: PMC3264273  PMID: 22123685
20.  Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial 
PLoS Medicine  2012;9(6):e1001236.
In a randomized control trial, Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment.
Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.
Methods and Findings
In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIV RNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.
Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm3.
Trial registration NCT00089505
Please see later in the article for the Editors' Summary
Editors' Summary
About 34 million people (mostly living in low- or middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that attack different parts of HIV—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. But, because ART was expensive, for people living in developing countries, HIV/AIDS remained a fatal illness. In 2006, the international community set a target of achieving universal access to ART by 2010 and, although this target has not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving one of the ART regimens recommended by the World Health Organization (WHO) in its 2010 guidelines.
Why Was This Study Done?
A widely used combination for the initial treatment of HIV-infected people (particularly women) in resource-limited settings is tenofovir and emtricitabine (both nucleotide reverse transcriptase inhibitors; reverse transcriptase is essential for HIV replication) and nevirapine (NVP, a non-nucleoside reverse transcriptase inhibitor). However, little is known about the efficacy of this NVP-based ART combination. Moreover, its efficacy and toxicity has not been compared with regimens containing lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral protease that is essential for HIV replication, is available in resource-limited settings but is usually reserved for second-line treatment. LPV/r-based ART is more expensive than NVP-based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited settings. Conversely, evidence of the clinical equivalence of NVP-based and LPV/r-based ART would provide support for NVP-based ART as an initial therapy. In this randomized equivalence trial, the researchers compare the efficacy and toxicity of NVP-based and LVP/r-based initial therapy for HIV infection among antiretroviral-naïve African women. In a randomized trial, patients are assigned different treatments by the play of chance and followed to compare the effects of these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
What Did the Researchers Do and Find?
The researchers followed 500 antiretroviral-naïve HIV-infected women with a low CD4 cell count living in seven African countries, half of whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded the time to virologic failure (the presence of virus in the blood above pre-specified levels) or death among the participants. Forty-two women in the NVP arm reached this primary endpoint (37 virologic failures and five deaths) compared to 50 women in the LPV/r arm (43 virologic failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria. During the initial assigned treatment, similar proportions of women in both treatment arms developed serious drug-related signs and symptoms and laboratory abnormalities. However, whereas 14% of the women in the NVP arm discontinued treatment because of adverse effects, none of the women in the LPV/r arm discontinued treatment. Finally, nearly half of the women tested in the NVP arm but only 15% of the women tested in the LVP/r arm had developed any drug resistance at the time of virologic failure.
What Do These Findings Mean?
These findings indicate that, among HIV-infected, treatment-naïve African women, initial NVP-based ART is as effective as LPV/r-based ART in terms of virologic failure and death although more women in the NVP arm discontinued treatment or developed new drug resistance than in the LPV/r arm. Several limitations of this study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed to single-dose NVP during childbirth to prevent mother-to-child transmission of HIV; in a parallel randomized trial, the researchers found that LPV/r-based ART was superior to NVP-based ART among women with prior exposure to single-dose NVP. Moreover, the duration of the current study means the long-term effects of the two treatments cannot be compared. Nevertheless, these findings support the WHO recommendation of NVP-based ART with careful early toxicity monitoring as an initial affordable and effective HIV treatment regiment in resource-limited settings, until access to better-tolerated and more potent regimens is possible.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about this trial, the OCTANE trial, is available
MedlinePlus provides detailed information about nevirapine and lopinavir/ritinovir (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
PMCID: PMC3373629  PMID: 22719231
21.  Hormonal contraceptive use and HIV disease progression among women in Uganda and Zimbabwe 
HIV-infected women need highly effective contraception to reduce unintended pregnancies and mother-to-child HIV transmission. Previous studies report conflicting results regarding the effect of hormonal contraception (HC) on HIV disease progression.
HIV-infected women in Uganda and Zimbabwe were recruited immediately after seroconversion; CD4 testing and clinical exams were conducted quarterly. The study endpoint was time to AIDS (two successive CD4 ≤200 cells/mm3 or WHO advanced stage 3 or stage 4 disease). We used marginal structural Cox survival models to estimate the effect of cumulative exposure to depot-medroxyprogesterone acetate (DMPA) and oral contraceptives (OC) on time to AIDS.
303 HIV-infected women contributed 1,408 person-years (py). 111 women (37%) developed AIDS. Cumulative probability of AIDS was 50% at 7 years and did not vary by country. AIDS incidence was 6.6, 9.3 and 8.8 per 100py for DMPA, OC and non-hormonal users. Neither DMPA (adjusted hazard ratio (AHR) = 0.90; 95% CI 0.76-1.08) nor OCs (AHR =1.07; 95% CI 0.89-1.29) were associated with HIV disease progression. Alternative exposure definitions of HC use during the year prior to AIDS or at time of HIV infection produced similar results. STI symptoms were associated with faster progression while young age at HIV infection (18-24 years) was associated with slower progression. Adding baseline CD4 level and setpoint viral load to models did not change the HC results but subtype D infection became associated with disease progression.
Hormonal contraceptive use was not associated with more rapid HIV disease progression but older age, STI symptoms and subtype D infection were.
PMCID: PMC3164299  PMID: 21358412
HIV; disease progression; hormonal contraception; family planning; women
22.  Increases in Human Papillomavirus Detection During Early HIV Infection Among Women in Zimbabwe 
The Journal of Infectious Diseases  2011;203(8):1182-1191.
Background. Individuals who acquire human immunodeficiency virus (HIV) may experience an immediate disruption of genital tract immunity, altering the ability to mount a local and effective immune response. This study examined the impact of early HIV infection on new detection of human papillomavirus (HPV).
Methods. One hundred fifty-five Zimbabwean women with observation periods before and after HIV acquisition and 486 HIV-uninfected women were selected from a cohort study evaluating hormonal contraceptive use and risk of HIV acquisition. Study visits occurred at 3-month intervals. Cervical swab samples available from up to 6 months before, at, and up to 6 months after the visit when HIV was first detected were typed for 37 HPV genotypes or subtypes.
Results. We observed ∼5-fold higher odds of multiple (≥2) new HPV detections only after HIV acquisition, relative to HIV-negative women after adjusting for sexual behavior and concurrent genital tract infections. We also observed ∼2.5-fold higher odds of single new HPV detections at visits before and after HIV acquisition, relative to HIV-uninfected women in multivariable models.
Conclusions. These findings suggest that HIV infection has an immediate impact on genital tract immunity, as evidenced by the high risk of multiple new HPV detections immediately after HIV acquisition.
PMCID: PMC3068021  PMID: 21451006
23.  The Frequency of Malaria Is Similar among Women Receiving either Lopinavir/Ritonavir or Nevirapine-based Antiretroviral Treatment 
PLoS ONE  2012;7(4):e34399.
HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population.
PMCID: PMC3317955  PMID: 22509297
24.  Differences in HIV Natural History among African and Non-African Seroconverters in Europe and Seroconverters in Sub-Saharan Africa 
PLoS ONE  2012;7(3):e32369.
It is unknown whether HIV treatment guidelines, based on resource-rich country cohorts, are applicable to African populations.
We estimated CD4 cell loss in ART-naïve, AIDS-free individuals using mixed models allowing for random intercept and slope, and time from seroconversion to clinical AIDS, death and antiretroviral therapy (ART) initiation by survival methods. Using CASCADE data from 20 European and 3 sub-Saharan African (SSA) cohorts of heterosexually-infected individuals, aged ≥15 years, infected ≥2000, we compared estimates between non-African Europeans, Africans in Europe, and Africans in SSA.
Of 1,959 (913 non-Africans, 302 Europeans - African origin, 744 SSA), two-thirds were female; median age at seroconversion was 31 years. Individuals in SSA progressed faster to clinical AIDS but not to death or non-TB AIDS. They also initiated ART later than Europeans and at lower CD4 cell counts. In adjusted models, Africans (especially from Europe) had lower CD4 counts at seroconversion and slower CD4 decline than non-African Europeans. Median (95% CI) CD4 count at seroconversion for a 15–29 year old woman was 607 (588–627) (non-African European), 469 (442–497) (European - African origin) and 570 (551–589) (SSA) cells/µL with respective CD4 decline during the first 4 years of 259 (228–289), 155 (110–200), and 199 (174–224) cells/µL (p<0.01).
Despite differences in CD4 cell count evolution, death and non-TB AIDS rates were similar across study groups. It is therefore prudent to apply current ART guidelines from resource-rich countries to African populations.
PMCID: PMC3295758  PMID: 22412867
25.  Investigating Potential Associations between Cervical Procedures and HIV Acquisition 
ISRN Obstetrics and Gynecology  2011;2011:789106.
Objective. Cervical human papillomavirus (HPV) infection has been associated with human immunodeficiency virus (HIV) acquisition in populations with a high prevalence of both infections. Procedures performed in the management of cervical dysplasia may facilitate HIV entry via mechanical injury. We sought to investigate the association between cervical procedures and incident HIV. Methods. Data on cervical cancer screening and procedures were collected in a cohort study evaluating the diaphragm for HIV prevention in 2040 women. In this secondary analysis, we investigated the association between cervical procedures and HIV acquisition. Results. Out of 2027 HIV-negative women at baseline, 199 underwent cervical procedures. Cumulative risk of HIV was 4.3% over 21 months of median followup (n = 88). Compared with women without cervical procedures, we observed no difference in HIV incidence after a cervical biopsy (RR 0.92, 95% CI 0.39–2.16), endocervical curettage (RR 0.29, 95% CI 0.07–1.22), or loop electrosurgical excision procedure (RR 1.00, 95% CI 0.30–3.30). Conclusions. In this cohort, cervical procedures were not associated with HIV incidence. This lack of association could be due to the small number of events.
PMCID: PMC3236408  PMID: 22191049

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