Grace John-Stewart

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

Antenatal Couple Counseling Increases Uptake of Interventions to Prevent HIV-1 Transmission

To determine effect of partner involvement and couple counseling on uptake of interventions to prevent HIV-1 transmission, women attending a Nairobi antenatal clinic were encouraged to return with partners for voluntary HIV-1 counseling and testing (VCT) and offered individual or couple posttest counseling. Nevirapine was provided to HIV-1-seropositive women and condoms distributed to all participants. Among 2104 women accepting testing, 308 (15%) had partners participate in VCT, of whom 116 (38%) were couple counseled. Thirty-two (10%) of 314 HIV-1-seropositive women came with partners for VCT; these women were 3-fold more likely to return for nevirapine (P = 0.02) and to report administering nevirapine at delivery (P = 0.009). Nevirapine use was reported by 88% of HIV-infected women who were couple counseled, 67% whose partners came but were not couple counseled, and 45%whose partners did not present for VCT (P for trend = 0.006). HIV-1-seropositive women receiving couple counseling were 5-fold more likely to avoid breast-feeding (P = 0.03) compared with those counseled individually. Partner notification of HIV-1-positive results was reported by 138 women (64%) and was associated with 4-fold greater likelihood of condom use (P = 0.004). Partner participation in VCT and couple counseling increased uptake of nevirapine and formula feeding. Antenatal couple counseling may be a useful strategy to promote HIV-1 prevention interventions.

Longitudinal Analysis of Human Immunodeficiency Virus Type 1 RNA in Breast Milk and of Its Relationship to Infant Infection and Maternal Disease

Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding can occur throughout lactation. Defining both fluctuation in breast-milk virus level over time and how breast-milk virus correlates with mother-to-child transmission is important for establishing effective interventions. We quantified breast-milk HIV-1 RNA levels in serial samples collected from 275 women for up to 2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T cell count, and detection of HIV-1 DNA in maternal genital secretions were significantly associated with elevated breast-milk HIV-1 RNA. Within women who breast-fed, median virus load in colostrum/early milk was significantly higher than that in mature breast milk collected 14 days after delivery (P< or =.004). Breast-feeding mothers who transmitted HIV-1 to their infants had both significantly higher breast-milk viral RNA throughout lactation and more-consistent viral shedding, compared with mothers who did not transmit HIV-1. In breast-feeding women, a 2-fold-increased risk of transmission was associated with every 10-fold increase in breast-milk virus load (95% confidence interval, 1.3-3.0; P<.001). These results indicate that the risk of infant infection from breast-feeding is influenced by breast-milk virus load, which is highest early after delivery.

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

ABSTRACT Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies biz, 2G12, 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission.

Association of Levels of HIV-1—Infected Breast Milk Cells and Risk of Mother-to-Child Transmission

Understanding how the level of human immunodeficiency virus type 1 (HIV-1)-infected breast milk cells (BMCs) affects HIV transmission via breast-feeding can shed light on the mechanism of infection and aid in establishing effective interventions. The proportion of infected cells to total cells was measured in serial breast milk samples collected from 291 HIV-1-infected women in Nairobi, Kenya, by use of real-time DNA polymerase chain reaction amplification of BMCs. The number of infected BMCs per million cells was associated with levels of cell-free viral RNA in breast milk (R=.144; P=.032), levels of cell-free virus in blood plasma (R=.365; P<.001), and the detection of proviral DNA in cervical and vaginal secretions (P<.001 and P = .030, respectively). The number of infected BMCs per million cells was lower in colostrum or early milk than in mature milk (P<.001). Previous studies demonstrated that the concentration of BMCs varies throughout lactation, and we used these data to transform infected BMCs per million cells to infected BMCs per milliliter. The estimated concentration of infected BMCs per milliliter was higher in colostrum or early milk than in mature milk (P<.001). Each log10 increase in infected BMCs per milliliter was associated with a 3.19-fold-increased risk of transmission (P=.002), after adjustment for cell-free virus in plasma (hazard ratio [HR], 2.09; P=.03) and breast milk (HR, 1.01; P=1.00). This suggests that infected BMCs may play a more important role in transmission of HIV via breast-feeding than does cell-free virus.

Male antenatal attendance and HIV testing are associated with decreased infant HIV infection and increased HIV-free survival.

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% CI: 0.32 to 0.84; P = 0.008). The combined risk of HIV acquisition or infant mortality was lower with male attendance (aHR = 0.55; 95% CI: 0.35 to 0.88; P = 0.012) and report of prior male HIV testing (aHR = 0.58; 95% CI: 0.34 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.

Predictors of early mortality in a cohort of human immunodeficiency virus type 1-infected African children.

Background: Pediatric human immunodeficiency virus type 1 (HIV-1) infection follows a bimodal clinical course with rapid progression in 10–45% of children before the age of 2 years and slower progression in the remainder. A prospective observational study was undertaken to determine predictors of mortality in HIV-1-infected African infants during the first 2 years of life. Methods: Infants in a perinatal cohort identified to be HIV-1-infected by DNA PCR were followed monthly to 1 year, then quarterly to 2 years or death. Results: Among 62 HIV-1-infected infants, infection occurred by the age of 1 month in 56 (90%) infants, and 32 (52%) died at median age of 6.2 months. All infant deaths were caused by infectious diseases, most frequently pneumonia (75%) and diarrhea (41%). Univariate predictors of infant mortality included maternal CD4 count <200 cells/μl [hazard ratio (HR), 3.4; P = 0.008], maternal anemia (HR = 3.7; P = 0.005), delivery complications (HR = 2.7; P = 0.01), low birth weight (HR = 4.1; P = 0.001), weight, length and head circumference ≤5th percentile at age 1 month (HR = 3.7, P = 0.003; HR = 5.8, P < 0.001; and HR = 10.4, P < 0.001, respectively), formula-feeding (HR = 4.0; P = 0.01), infant CD4% ≤15% (HR = 5.5; P = 0.01), infant CD4 count <750 (HR = 9.7; P = 0.006) and maternal death (HR = 2.9, P = 0.05). In multivariate analysis, maternal CD4 count <200 (HR = 2.7; P = 0.03) and delivery complications (HR = 3.4; P = 0.005) were independently associated with infant mortality. Conclusions: Advanced maternal HIV disease, maternal anemia, delivery complications, early growth faltering, formula-feeding and low infant CD4 were predictors of early mortality in African HIV-1-infected infants. In resource-poor settings, these predictors may be useful for early identification and treatment of high risk infants.

Breast-milk infectivity in human immunodeficiency virus type 1-infected mothers.

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.

Male Perspectives on Incorporating Men into Antenatal HIV Counseling and Testing

Background Male partner involvement in antenatal voluntary HIV counseling and testing (VCT) has been shown to increase uptake of interventions to reduce the risk of HIV transmission in resource-limited settings. We aimed to identify methods for increasing male involvement in antenatal VCT and determine male correlates of accepting couple counseling in these settings. Methodology/Principal Findings We invited women presenting to a Nairobi antenatal clinic to return with their male partners for individual or couples VCT. Male attitudes towards VCT and correlates of accompanying female partners to antenatal clinic and receiving couple counseling were determined. Of 1,993 women who invited their partner, 313 (16%) returned with their partners to ANC. Men attending antenatal clinic were married (>99%), employed (98%), and unlikely to report prior HIV testing (14%). Wanting an HIV test (87%) or health information (11%) were the most commonly cited reasons for attending. Most (95%) men who came to antenatal clinic accepted HIV testing and 39% elected to receive counseling as a couple. Men who received counseling with partners were younger, had fewer children, and were less knowledgeable about prevention of mother-to-child HIV transmission (PMTCT) than those who received counseling individually (p<0.05). Only 27% of men stated they would prefer HIV testing at a site other than the ANC. There was agreement between male and female reports for sociodemographic characteristics; however, men were more likely to report HIV preventive behaviors and health communication within the partnership than their partners (p<0.05). Conclusions/Significance Offering VCT services to men at antenatal clinic with options for couple and individual counseling is an important opportunity and acceptable strategy for increasing male involvement in PMTCT and promoting male HIV testing.

Early response to highly active antiretroviral therapy in HIV-1-infected Kenyan children

Objectives:To describe the early response to World Health Organization (WHO)-recommended nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line highly active antiretroviral therapy (HAART) in HIV-1-infected Kenyan children unexposed to nevirapine. Design:Observational prospective cohort. Methods:HIV-1 RNA level, CD4 lymphocyte count, weight for age z score, and height for age z score were measured before the initiation of HAART and every 3 to 6 months thereafter. Children received no nutritional supplements. Results:Sixty-seven HIV-1-infected children were followed for a median of 9 months between August 2004 and November 2005. Forty-seven (70%) used zidovudine, lamivudine (3TC), and an NNRTI (nevirapine or efavirenz), whereas 25% used stavudine (d4T), 3TC, and an NNRTI. Nevirapine was used as the NNRTI by 46 (69%) children, and individual antiretroviral drug formulations were used by 63 (94%), with only 4 (6%) using a fixed-dose combination of d4T, 3TC, and nevirapine (Triomune; Cipla, Mumbai, India). In 52 children, the median height for age z score and weight for age z score rose from −2.54 to −2.17 (P < 0.001) and from −2.30 to −1.67 (P = 0.001), respectively, after 6 months of HAART. Hospitalization rates were significantly reduced after 6 months of HAART (17% vs. 58%; P < 0.001). The median absolute CD4 count increased from 326 to 536 cells/μL (P < 0.001), the median CD4 lymphocyte percentage rose from 5.8% before treatment to 15.4% (P < 0.001), and the median viral load fell from 5.9 to 2.2 log10 copies/mL after 6 months of HAART (P < 0.001). Among 43 infants, 47% and 67% achieved viral suppression to less than 100 copies/mL and 400 copies/mL, respectively, after 6 months of HAART. Conclusion:Good early clinical and virologic response to NNRTI-based HAART was observed in HIV-1-infected Kenyan children with advanced HIV-1 disease.