In addition to direct effects on virus infectivity, antibodies mediate antibody-dependent cellular cytotoxicity (ADCC), the killing of an antibody-coated virus-infected cell by cytotoxic effector ...cells. Although ADCC has been suggested to protect against HIV, the relationship between HIV-specific ADCC antibodies at the time of HIV exposure and infection outcome in humans remains to be assessed. We evaluated the ADCC activity of passively acquired antibodies in infants born to HIV-infected mothers. ADCC levels were higher in uninfected than infected infants, although not significantly. Increase in ADCC antibody activity in infected infants was associated with reduced mortality risk. Infant ADCC positively correlated with the magnitude of IgG1 binding, and IgG1 levels were associated with survival in infected infants. Infant IgG3-binding antibodies were not associated with infected infant survival. These data suggest a therapeutic benefit of pre-existing HIV-specific ADCC antibodies and support a role for eliciting ADCC-mediating IgG1 in HIV vaccines.
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•Passively transferred ADCC activity in HIV-infected infants is associated with survival•IgG1, and not IgG3, antibodies are associated with infected infant survival•Maternal ADCC antibody levels do not predict infected infant survival•De novo ADCC activity after infection does not correlate with pre-existing ADCC
Milligan et al. evaluate the role of pre-existing antibody-dependent cellular cytotoxicity (ADCC) in HIV infection. The levels of passively acquired ADCC antibodies and the magnitude of IgG1 binding were associated with decreased mortality risk in infected infants. This work supports a role for eliciting ADCC-mediating IgG1 in HIV vaccines.
Intimate partner violence (IPV) is a major public health problem and is the most common form of violence against women. Women with HIV in serodifferent relationships may be at an increased risk of ...IPV compared to women without HIV, hindering their ability to adhere to antiretroviral therapy, clinic appointments, and condom use during sex. This study assessed the prevalence and correlates of IPV in the past year among women with HIV in serodifferent relationships in Nairobi, Kenya. This cross-sectional study included women with HIV in serodifferent relationships who were at least 18 years old and provided written informed consent. Their experience of physical, sexual, or emotional violence in the past year by the current partner was assessed using 13 questions adapted from the World Health Organization survey on violence against women. Standardized instruments were used to assess sociodemographic and behavioral factors. Associations between intimate partner violence and other variables were evaluated using log binomial regression models. Of the 159 women enrolled, 47 (29.6%, 95% CI 22.9-37.2%) reported IPV in the past year. Of these, 32 (68.1%) reported emotional, 27 (57.4%) physical, and 27 (57.4%) sexual violence. In the multivariate model, pregnancy (adjusted prevalence ratio aPR 2.14, 95% CI 1.09-4.20), alcohol use (minimal drinking aPR 1.91, 95% CI 1.10-3.33; moderate/severe drinking aPR 1.17, 95% CI 0.53-2.59), male partner controlling behavior (aPR 2.09, 95% CI 1.24-3.51), and past physical violence (aPR 1.93, 95% CI 1.22-3.05) remained significantly associated with a higher prevalence of IPV in the past year. This study identified a high prevalence of IPV in the past year among women with HIV in serodifferent relationships. Pregnant women and women who had experienced prior violence had a higher prevalence of IPV. These data highlight the need to screen for IPV during clinic visits, and to offer evidence based interventions to support women in serodifferent relationships who have experienced IPV.
Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting ...assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.
We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel 40 mg, or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).
Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy.
ClinicalTrials.gov NCT00592124.
We evaluated diagnostic performance of oral swab analysis (OSA) for tuberculosis (TB) in a high HIV/TB burden setting in Kenya.
In this cross-sectional study, buccal swabs and sputum were collected ...from 100 participants with suspected TB in outpatient clinics in Kenya at enrollment and subsequent morning visits. Buccal swabs underwent IS6110-targeted qPCR analysis. Sputum was evaluated by Xpert MTB/RIF (Xpert) and culture. Diagnostic performance of OSA for TB diagnosis was evaluated relative to a combined reference of sputum Xpert and culture.
Among 100 participants, 54% were living with HIV (PLHIV). Twenty percent (20/100) of participants had confirmed TB (19/20 95% culture-positive, 17/20 85% Xpert-positive). Overall buccal swab sensitivity was 65.0% (95% CI 40.8-84.6%) vs. sputum Xpert/culture and 76.5% (95% CI 50.1-93.2%) vs. sputum Xpert alone. Specificity was 81.3% (95% CI 71.0-89.1%) and 81.9% (95% CI 72.0-89.5%) compared to sputum Xpert/culture and Xpert alone, respectively. Sensitivity among PLHIV (n = 54) with suspected TB was 83.3% (95% CI 35.9-99.6%) vs. sputum Xpert/culture and 100% (95% CI 47.8-100.0%) vs. sputum Xpert alone. Among participants with TB, mean OSA threshold quantitation cycle (Cq) value was lower (stronger signal) at subsequent morning compared to enrolment visit (33.4 SD ± 3.7 vs. 35.2 SD ± 2.9, p = 0.009).
In this pilot study, results confirm M. tuberculosis DNA is detectable in oral swabs including among PLHIV with fair diagnostic performance. Further work is needed to optimize OSA and evaluate its utility in diverse settings.
Disruptions of vaginal microbiota might increase women's susceptibility to HIV infection. Advances in molecular microbiology have enabled detailed examination of associations between vaginal bacteria ...and HIV acquisition. Therefore, this study aimed to evaluate the association between the concentrations of specific vaginal bacteria and increased risk of HIV acquisition in African women.
We did a nested case-control study of participants from eastern and southern Africa. Data from five cohorts of African women (female sex workers, pregnant and post-partum women, and women in serodiscordant relationships) were used to form a nested case-control analysis between women who acquired HIV infection versus those who remained seronegative. Deep sequence analysis of broad-range 16S rRNA gene PCR products was applied to a subset of 55 cases and 55 controls. From these data, 20 taxa were selected for bacterium-specific real-time PCR assays, which were examined in the full cohort as a four-category exposure (undetectable, first tertile, second tertile, and third tertile of concentrations). Conditional logistic regression was used to generate odds ratios (ORs) and 95% CIs. Regression models were stratified by cohort, and adjusted ORs (aORs) were generated from a multivariable model controlling for confounding variables. The Shannon Diversity Index was used to measure bacterial diversity. The primary analyses were the associations between bacterial concentrations and risk of HIV acquisition.
Between November, 2004, and August, 2014, we identified 87 women who acquired HIV infection (cases) and 262 controls who did not acquire HIV infection. Vaginal bacterial community diversity was higher in women who acquired HIV infection (median 1·3, IQR 0·4–2·3) than in seronegative controls (0·7, 0·1–1·5; p=0·03). Seven of the 20 taxa showed significant concentration-dependent associations with increased odds of HIV acquisition: Parvimonas species type 1 (first tertile aOR 1·67, 95% CI 0·61–4·57; second tertile 3·01, 1·13–7·99; third tertile 4·64, 1·73–12·46; p=0·005) and type 2 (first tertile 3·52, 1·63–7·61; second tertile 0·85, 0·36–2·02; third tertile 2·18, 1·01–4·72; p=0·004), Gemella asaccharolytica (first tertile 2·09, 1·01–4·36; second tertile 2·02, 0·98–4·17; third tertile 3·03, 1·46–6·30; p=0·010), Mycoplasma hominis (first tertile 1·46, 0·69–3·11; second tertile 1·40, 0·66–2·98; third tertile 2·76, 1·36–5·63; p=0·048), Leptotrichia/Sneathia (first tertile 2·04, 1·02–4·10; second tertile 1·45, 0·70–3·00; third tertile 2·59, 1·26–5·34; p=0·046), Eggerthella species type 1 (first tertile 1·79, 0·88–3·64; second tertile 2·62, 1·31–5·22; third tertile 1·53, 0·72–3·28; p=0·041), and vaginal Megasphaera species (first tertile 3·15, 1·45–6·81; second tertile 1·43, 0·65–3·14; third tertile 1·32, 0·57–3·05; p=0·038).
Differences in the vaginal microbial diversity and concentrations of key bacteria were associated with greater risk of HIV acquisition in women. Defining vaginal bacterial taxa associated with HIV risk could point to mechanisms that influence HIV susceptibility and provide important targets for future prevention research.
National Institute of Child Health and Human Development.
OBJECTIVE:To investigate the relationship between male involvement in prevention of mother-to-child HIV transmission services and infant HIV acquisition and mortality, a prospective cohort study was ...undertaken between 1999 and 2005 in Nairobi, Kenya.
METHODS:HIV-infected pregnant women were enrolled and followed with their infants for 1 year with infant HIV DNA testing at birth, 1, 3, 6, 9, and 12 months postpartum. Women were encouraged to invite male partners for prevention counseling and HIV testing.
RESULTS:Among 456 female participants, 140 partners (31%) attended the antenatal clinic. Eighty-two (19%) of 441 infants tested were HIV infected by 1 year of age. Adjusting for maternal viral load, vertical transmission risk was lower among women with partner attendance compared with those without adjusted hazard ratio (aHR) = 0.56, 95% confidence interval (CI)0.33 to 0.98; P = 0.042 and among women reporting versus not reporting previous partner HIV testing (aHR = 0.52, 95% CI0.32 to 0.84; P = 0.008). The combined risk of HIV acquisition or infant mortality was lower with male attendance (aHR = 0.55; 95% CI0.35 to 0.88; P = 0.012) and report of prior male HIV testing (aHR = 0.58; 95% CI0.34 to 0.88; P = 0.01) when adjusting for maternal viral load and breastfeeding.
CONCLUSIONS:Including men in antenatal prevention of mother-to-child HIV transmission services with HIV testing may improve infant health outcomes.
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial ...constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio HR = 0.71; 95% confidence interval CI 0.49-1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21-0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65-1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53-1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
OBJECTIVE:To develop and validate an HIV risk assessment tool to predict HIV acquisition among African women.
DESIGN:Data were analyzed from three randomized trials of biomedical HIV prevention ...interventions among African women (VOICE, HPTN 035 and FEM-PrEP).
METHODS:We implemented standard methods for the development of clinical prediction rules to generate a risk-scoring tool to predict HIV acquisition over the course of one year. Performance of the score was assessed through internal and external validation.
RESULTS:The final risk score resulting from multivariable modeling included age, married/living with a partner, partner provides financial or material support, partner has other partners, alcohol use, detection of a curable sexually transmitted infection, and herpes simplex virus-2 serostatus. Point values for each factor ranged from 0 to 2, with a maximum possible total score of 11. Scores ≥5 were associated with HIV incidence >5 per 100 person-years and identified 91% of incident HIV infections from among only 64% of women. The area under the curve (AUC) for predictive ability of the score was 0.71 (95% confidence interval CI 0.68, 0.74), indicating good predictive ability. Risk score performance was generally similar with internal cross-validation (AUC=0.69; 95% CI 0.66, 0.73), and external validation in HPTN 035 (AUC=0.70; 95% CI 0.65, 0.75) and FEM-PrEP (AUC=0.58; 95% CI 0.51, 0.65).
CONCLUSIONS:A discrete set of characteristics that can be easily assessed in clinical and research settings were predictive of HIV acquisition over one year. Use of a validated risk score could improve efficiency of recruitment into HIV prevention research and inform scale-up of HIV prevention strategies in women at highest risk.
Pregnant and postpartum women living with HIV (WLWH) need support for HIV and maternal child health (MCH) care, which could be provided using short message service (SMS). We compared 2-way ...(interactive) and 1-way SMS messaging to no SMS in a 3-arm randomized trial in 6 MCH clinics in Kenya. Messages were developed using the Health Belief Model and Social Cognitive Theory; HIV messages were integrated into an existing MCH SMS platform. Intervention participants received visit reminders and prespecified weekly SMS on antiretroviral therapy (ART) adherence and MCH, tailored to their characteristics and timing. Two-way participants could message nurses as needed. Clinic attendance, viral load (VL), and infant HIV results were abstracted from program records. Primary outcomes were viral nonsuppression (VL greater than or equal to1,000 c/ml), on-time clinic attendance, loss to follow-up from clinical care, and infant HIV-free survival. Among 824 pregnant women randomized between November 2015 and May 2017, median age was 27 years, gestational age was 24.3 weeks, and time since initiation of ART was 1.0 year. During follow-up to 2 years postpartum, 9.8% of 3,150 VL assessments and 19.6% of women were ever nonsuppressed, with no significant difference in 1-way versus control (11.2% versus 9.6%, adjusted risk ratio (aRR) 1.02 95% confidence interval (CI) 0.67 to 1.54, p = 0.94) or 2-way versus control (8.5% versus 9.6%, aRR 0.80 95% CI 0.52 to 1.23, p = 0.31). Median ART adherence and incident ART resistance did not significantly differ by arm. Overall, 88.9% (95% CI 76.5 to 95.7) of visits were on time, with no significant differences between arms (88.2% in control versus 88.6% in 1-way and 88.8% in 2-way). Incidence of infant HIV or death was 3.01/100 person-years (py), with no significant difference between arms; risk of infant HIV infection was 0.94%. Time to postpartum contraception was significantly shorter in the 2-way arm than control. Study limitations include limited ability to detect improvement due to high viral suppression and visit attendance and imperfect synchronization of SMS reminders to clinic visits. Integrated HIV/MCH messaging did not improve HIV outcomes but was associated with improved initiation of postpartum contraception. In programs where most women are virally suppressed, targeted SMS informed by VL data may improve effectiveness. Rigorous evaluation remains important to optimize mobile health (mHealth) interventions.
Preventing HIV-1 infection is a high global priority. This study assessed prevention strategies in young women in South Africa, Uganda, and Zimbabwe using oral or vaginal antiretroviral agents. No ...approach was found to be effective. The HIV-1 incidence was 5.7 per 100 person-years.
Daily oral preexposure prophylaxis with 300 mg of tenofovir disoproxil fumarate (TDF), alone or in combination with 200 mg of emtricitabine (FTC) (TDF-FTC Truvada, Gilead Sciences), reduces the risk of acquisition of human immunodeficiency virus type 1 (HIV-1) by 50% or more among persons with high adherence to the regimen, with demonstrated efficacy in men who have sex with men, heterosexuals, and injection-drug users.
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On the basis of these observations, in July 2012 the Food and Drug Administration approved daily treatment with Truvada for the prevention of HIV-1 acquisition, and the Centers for Disease Control and Prevention has issued . . .
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