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Background: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study., Methods: Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We used these sequences to identify likely transmission pairs. After demographic weighting of the recipients in these pairs to match the overall HIV-positive population, we analysed the demographic characteristics of the sources to better understand transmission in the general population., Findings: We identified a total of 300 likely transmission pairs. 178 (59·4%) were male to female, with 130 (95% CI 110-150; 43·3%) from males aged 25-40 years. Overall, men transmitted 2·09-fold (2·06-2·29) more infections per capita than women, a ratio peaking at 5·87 (2·78-15·8) in the 35-39 years source age group. 40 (26-57; 13·2%) transmissions linked individuals from different communities in the trial. Of 288 sources with recorded information on drug resistance mutations, 52 (38-69; 18·1%) carried viruses resistant to first-line ART., Interpretation: HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and there is no outsized contribution to new infections from importation or drug resistance mutations. Men aged 25-39 years, underserved by current treatment and prevention services, should be prioritised for HIV testing and ART., Funding: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health., Competing Interests: Declaration of interests DJD, SHE, CF, EP-M, and OR report grant funding from NIH for this work. MSC reports other NIH grant funding. SHE reports NIH funding for meetings and travel. CF and OR report grant funding from the Bill & Melinda Gates Foundation for this work. HA reports honoraria from the Global Fund. MSC reports payments from Medscape and UpToDate for written material. WP reports consulting fees from WHO. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 pandemic has overwhelmed health systems with knock on effects on diagnosis, treatment, and care. To mitigate the impact, the government of Zimbabwe enforced a strict lockdown beginning 30 March 2020 which ran intermittently until early 2021. In this period, the Ministry of Health and Childcare strategically prioritized delivery of services leading to partial and full suspension of services considered non-essential, including HIV prevention. As a result, Voluntary Medical Male Circumcision (VMMC) services were disrupted leading to an 80% decline in circumcisions conducted in 2020. Given the efficacy of VMMC, we quantified the potential effects of VMMC service disruption on new HIV infections in Zimbabwe., Methods: We applied the GOALS model to evaluate the impact of COVID-19-related disruptions on reducing new HIV infections over 30-years. GOALS is an HIV simulation model that estimates number of new HIV infections based on sexual behaviours of population groups. The model is parameterized based on national surveys and HIV program data. We hypothesized three coverage scenarios by 2030: scenario I - pre-COVID trajectory: 80% VMMC coverage; Scenario II - marginal COVID-19 impact: 60% VMMC coverage, and scenario III - severe COVID-19 impact: 45% VMMC coverage. VMMC coverage between 2020 and 2030 was linearly interpolated to attain the estimated coverage and then held constant from 2030 to 2050, and discounted outcomes at 3%., Results: Compared to the baseline scenario I, in scenario II, we estimated that the disruption of VMMC services would generate an average of 200 (176-224) additional new infections per year and 7,200 new HIV infections over the next 30 years. For scenario III, we estimated an average of 413 (389-437) additional new HIV infections per year and 15,000 new HIV infections over the next 30 years. The disruption of VMMC services could generate additional future HIV treatment costs ranging from $27 million to $55 million dollars across scenarios II and III, respectively., Conclusion: COVID-19 disruptions destabilized delivery of VMMC services which could contribute to an additional 7,200 new infections over the next 30 years. Unless mitigated, these disruptions could derail the national goals of reducing new infections by 2030., (© 2023. The Author(s).)

Objectives: The aims of the study were (1) to compare targeted and routine HIV screening in a pediatric emergency department (PED) and (2) to compare provider documented HIV risk assessment with adolescent perception of HIV risk assessment conducted during the PED visit., Methods: This prospective study ran concurrent to a PED routine HIV screening pilot. Adolescents could be tested for HIV by the PED provider per usual care (targeted testing); if not tested, they were approached for the routine screening pilot. A subset of adolescents completed a questionnaire on HIV risk. χ 2 analysis compared adolescents with targeted testing and routine screening. HIV-tested patients were asked if HIV risk was assessed; κ analysis compared this with documentation in the provider note., Results: Over 4 months, 107 adolescents received targeted testing and 344 received routine screening. One 14-year-old patient tested positive by routine screening; this adolescent had 2 PED visits without targeted testing within 60 days. Compared with routine screening, adolescents with targeted testing were more likely female (82% vs 57%, P < 0.001), 16 years or older (71% vs 44%, P < 0.001), or had genitourinary/gynecologic concerns (48% vs 6%, P < 0.001). Adolescents with HIV risk factors were missed by targeted testing but received routine screening. Adolescents with documented HIV risk assessment were more likely to receive targeted testing. There was moderate agreement (κ = 0.61) between provider documentation and adolescent perception of HIV risk assessment., Conclusions: There are gaps in PED HIV risk assessment and testing, which may miss opportunities to diagnose adolescent HIV. Routine HIV screening addresses these gaps and expands adolescent HIV testing in the PED., Competing Interests: Disclosure: A.C.G. has received funding from Theratechnologies, Inc, for consulting. C.R.M. is the inventor or coinventor of several University of California, San Francisco-Benioff Children's Hospital Oakland patents/patent-pending applications that include nutritional supplements and biomarkers of cardiovascular disease, is an inventor of an Emory University School of Medicine patent application for a nutritional supplement, is a consultant for Pfizer, and has received research support from the US Food and Drug Administration and the National Institutes of Health. The other authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Managing HIV-associated cryptococcal meningitis (CM) can become challenging in the presence of concurrent unusual central nervous system infections., Case Presentation: A 58-year old HIV infected woman new ART starter, who was being treated effectively for cryptococcal meningitis, represented with worsening of neurological symptoms. Brain MRI revealed a multicystic lesion in the left temporal lobe. Anti-fungal treatment was escalated for a suspected cryptococcoma, but post-mortem CSF serological test confirmed racemose neurocysticercosis., Conclusion: Patients with HIV-associated CM are highly immunocompromised and may have multiple pathologies simultaneously. In endemic countries, neurocysticercosis should be considered in the differential diagnosis where there is central nervous system deterioration despite effective therapy for CM., (© 2021. The Author(s).)

Background: The Centers for Disease Control and Prevention (CDC) recommend universal human immunodeficiency virus (HIV) screening starting at 13 years, which has been implemented in many general U.S. emergency departments (EDs) but infrequently in pediatric EDs. We aimed to 1) implement a pilot of routine adolescent HIV screening in a pediatric ED and 2) determine the unique barriers to CDC-recommended screening in this region of high HIV prevalence., Methods: This was a prospective 4-month implementation of a routine HIV screening pilot in a convenience sample of adolescents 13 to 18 years at a single pediatric ED, based on study personnel availability. Serum-based fourth-generation HIV testing was run through a central laboratory. Parents were allowed to remain in the room for HIV counseling and testing. Data were collected regarding patient characteristics and HIV testing quality metrics. Comparisons were made using chi-square and Fisher's exact tests. Regression analysis was performed to assess for an association between parent presence at the time of enrollment and adolescent decision to participate in HIV screening., Results: Over 4 months, 344 of 806 adolescents approached consented to HIV screening (57% female, mean ± SD = 15.1 ± 1.6 years). Adolescents with HIV screening were more likely to be older than those who declined (p = 0.025). Other blood tests were collected with the HIV sample for 21% of adolescents; mean time to result was 105 minutes (interquartile range = 69 to 123) and 79% were discharged before the result was available. Having a parent present for enrollment was not associated with adolescent participation (adjusted odds ratio = 1.07, 95% CI = 0.67 to 1.70). Barriers to testing included: fear of needlestick, time to results, cost, and staff availability. One of 344 tests was positive in a young adolescent with Stage 1 HIV., Conclusions: Routine HIV screening in adolescents was able to be implemented in this pediatric ED and led to the identification of early infection in a young adolescent who would have otherwise been undetected at this stage of disease. Addressing the unique barriers to adolescent HIV screening is critical in high-prevalence regions and may lead to earlier diagnosis and treatment in this vulnerable population., (© 2020 by the Society for Academic Emergency Medicine.)

Background: The COVID-19 pandemic could lead to disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimated that more than two-thirds of the approximately 38 million people living with HIV resided in 2018. We aimed to predict the potential effects of such disruptions on HIV-related deaths and new infections in sub-Saharan Africa., Methods: In this modelling study, we used five well described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, an Imperial College London model, and Epidemiological MODeling software [EMOD]) to estimate the effect of various potential disruptions to HIV prevention, testing, and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months over 1 year from April 1, 2020. We considered scenarios in which disruptions affected 20%, 50%, and 100% of the population., Findings: A 6-month interruption of supply of antiretroviral therapy (ART) drugs across 50% of the population of people living with HIV who are on treatment would be expected to lead to a 1·63 times (median across models; range 1·39-1·87) increase in HIV-related deaths over a 1-year period compared with no disruption. In sub-Saharan Africa, this increase amounts to a median excess of HIV deaths, across all model estimates, of 296 000 (range 229 023-420 000) if such a high level of disruption occurred. Interruption of ART would increase mother-to-child transmission of HIV by approximately 1·6 times. Although an interruption in the supply of ART drugs would have the largest impact of any potential disruptions, effects of poorer clinical care due to overstretched health facilities, interruptions of supply of other drugs such as co-trimoxazole, and suspension of HIV testing would all have a substantial effect on population-level mortality (up to a 1·06 times increase in HIV-related deaths over a 1-year period due to disruptions affecting 50% of the population compared with no disruption). Interruption to condom supplies and peer education would make populations more susceptible to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sexual behaviour (up to 1·19 times increase in new HIV infections over a 1-year period if 50% of people are affected)., Interpretation: During the COVID-19 pandemic, the primary priority for governments, donors, suppliers, and communities should focus on maintaining uninterrupted supply of ART drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence., Funding: Bill & Melinda Gates Foundation., (© 2020 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

Background: Tenofovir disoproxil fumarate (TDF) use during pregnancy has been increasing, and studies linking bone toxicity with exposure to TDF have raised concern for its use in infants., Methods: Hand/wrist and spine radiographs were obtained at 3 days and 12 weeks of age in infants born to HIV-infected pregnant women enrolled in the HIV Prevention Trials Network 057 pharmacokinetic study of TDF conducted in Malawi and Brazil assigned to 3 TDF dosing cohorts. In cohort 1, mothers received 600 mg of TDF during labor. In cohort 2, infants received 4 mg/kg dose on days 0, 3 and 5. In cohort 3, a 900 mg maternal dose was given during labor, followed by a 6 mg/kg infant dose on days 0, 3 and 5 of life., Results: Across all 3 cohorts, 89 infants had radiographs performed at either time point, and 85 had radiographs performed at both time points. Metaphyseal lucency was present in 1 case in Brazil and 2 in Malawi. Fifteen percent of infants from Brazil and 9% of infants from Malawi presented bone age discrepancies. No other abnormalities were identified in Brazil, whereas in Malawi, there were 7 more cases of wrist osteopenia, 2 of spine osteopenia and 3 other abnormalities., Conclusion: Bone abnormalities were not uncommon in the overall cohort of HIV-exposed infants. Because of very limited study drug exposure at the time of birth, it is unlikely that TDF was associated with these findings. Untreated maternal HIV disease and/or maternal nutritional status could potentially be related to fetal bone development. This association should be explored in future cohort studies.

Integrated approaches provide better understanding of HIV/AIDS epidemics. We optimised a multiassay algorithm (MAA) and assessed HIV incidence, correlates of recent infections, viral diversity, plus transmission clusters among participants screened for Kisumu Incidence Cohort Study (KICoS1) (2007-2009). We performed BED-CEIA, Limiting antigen (LAg) avidity, Biorad avidity, and viral load (VL) tests on HIV-positive samples. Genotypic analyses focused on HIV-1 pol gene. Correlates of testing recent by MAA were assessed using logistic regression model. Overall, 133 (12%, 95% CI: 10.2-14.1) participants were HIV-positive, of whom 11 tested recent by MAA (BED-CEIA OD-n < 0.8 + LAg avidity OD-n < 1.5 + VL > 1000 copies/mL), giving an incidence of 1.46% (95% CI: 0.58-2.35) per year. This MAA-based incidence was similar to longitudinal KICoS1 incidence. Correlates of testing recent included sexually transmitted infection (STI) treatment history (OR = 3.94, 95% CI: 1.03-15.07) and syphilis seropositivity (OR = 10.15, 95% CI: 1.51-68.22). Overall, HIV-1 subtype A (63%), D (15%), C (3%), G (1%) and recombinants (18%), two monophyletic dyads and intrinsic viral mutations (V81I, V81I/V, V108I/V and K101Q) were observed. Viral diversity mirrored known patterns in this region, while resistance mutations reflected likely non-exposure to antiretroviral drugs. Management of STIs may help address ongoing HIV transmission in this region.

Objectives: Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi., Methods: The post-exposure prophylaxis of infants-Malawi trial (2004-2009) enrolled mothers/infants during labor or immediately post-partum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival-survival without HIV infection-was compared by maternal HAART status., Results: Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6-13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naïve with CD4 cell counts <250 cells/mm(3), and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naïve mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naïve mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36-0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality., Conclusions: HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. Clinical Trials Registration This study is registered at http://clinicaltrials.gov/ under trial number NCT00115648.

Objective: This study examined HIV superinfection in HIV-infected women postpartum, and its association with mother-to-child transmission (MTCT)., Design: Plasma samples were obtained from HIV-infected women who transmitted HIV to their infants after 6 weeks of age (transmitters, n = 91) and HIV-infected women who did not transmit HIV to their infants (nontransmitters, n = 91). These women were originally enrolled in a randomized trial for prevention of MTCT of HIV in Malawi (Post-Exposure Prophylaxis of Infants trial in Malawi)., Methods: Two HIV genomic regions (p24 and gp41) were analyzed by next-generation sequencing for HIV superinfection. HIV superinfection was established if the follow-up sample contained a new, phylogenetically distinct viral population. HIV superinfection and transmission risk were examined by multiple logistic regression, adjusted for Post-Exposure Prophylaxis of Infants study arm, baseline viral load, baseline CD4 cell count, time to resumption of sex, and breastfeeding duration., Results: Transmitters had lower baseline CD4 cell counts (P = 0.001) and higher viral loads (P < 0.0001) compared with nontransmitters. There were five cases of superinfection among transmitters (rate of superinfection = 4.7/100 person-years) compared with five cases among the nontransmitters (rate of superinfection = 4.4/100 person-years; P = 0.78). HIV superinfection was not associated with increased risk of postnatal MTCT of HIV after controlling for maternal age, baseline viral load, and CD4 cell count (adjusted odds ratio = 2.32, P = 0.30). Longer breastfeeding duration was independently associated with a lower risk of HIV superinfection after controlling for study arm and baseline viral load (P = 0.05)., Conclusion: There was a significant level of HIV superinfection in women postpartum, but this was not associated with an increased risk of MTCT via breastfeeding.

Use of HIV prevention methods may vary for women by types of sexual partners. In a microbicide safety and effectiveness trial (HPTN 035) differences in adherence to a microbicide study gel were compared between women with new versus ongoing partnerships over time. 1,757 women in the three HPTN 035 trial's arms completed the Follow-up Partner Status (FPS) questionnaire at their last study visit. Women married at baseline were asked if they had the same husband, new husband or new partner. Unmarried women were asked if they had changed partners or married. Self-reported gel adherence during the last sex act was compared at each quarterly visit between women with ongoing versus new partners. High gel adherence was compared with low gel adherence (85-100 vs. <85 % of last vaginal sex acts reported with gel use, respectively) in multivariable models to assess associations with partner change. Overall 7 % of women (n = 123) reported a new partner and 41 % (51) of those reported a new husband. Median gel adherence was reported to be 100 % in women with ongoing partners and 75 % for women with new partners (p < 0.001). In women reporting no gel use in their last sex act, only 12.5 % of the women with a new partner and none of those with an ongoing partner reported using condoms (p < 0.001). Fewer women with new partners reported using both the gel and condom during the last sex act as compared to women with ongoing partners (median 50 vs. 71.4 %, p < 0.001). After adjusting for age, site, education level, and sexual frequency, women with ongoing partners were more likely to report high gel adherence than those with new partners (AOR 2.5, 95 % CI 1.6, 3.9). This pattern persisted when gel use over time was compared between women with new versus ongoing partners. In the HPTN 035 trial, women with new partners had higher HIV incidence and reported less gel use and higher condom use. Specific counseling and support are needed to help women use potential HIV prevention methods, including microbicides, when they are changing partners.

Background: Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking., Methods: The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic-tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing., Results: One hundred twenty-two mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%-97% of infants receiving daily dosing., Conclusions: A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.

Background: In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission., Methods: Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks., Results: The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%-7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%-5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%-6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%-3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%-80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%-69%; P < .001)., Conclusions: Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.

Introduction: Continuous evaluation of child survival is needed in sub-Saharan Africa where HIV prevalence among women of reproductive age continues to be high. We examined mortality levels and trends over a period of ∼20 years among HIV-unexposed and -exposed children in Blantyre, Malawi., Methods: Data from 5 prospective cohort studies conducted at a single research site from 1989 to 2009 were analyzed. In these studies, children born to HIV-infected and -uninfected mothers were enrolled at birth and followed longitudinally for at least 2 years. Information on sociodemographic, HIV infection status, survival, and associated risk factors was collected in all studies. Mortality rates were estimated using birth-cohort analyses stratified by maternal and infant HIV status. Multivariate Cox regression models were used to determine risk factors associated with mortality., Results: The analysis included 8286 children. From 1989 to 1995, overall mortality rates (per 100 person-years) in these clinic-based cohorts remained comparable among HIV-uninfected children born to HIV-uninfected mothers (range 3.3-6.9) or to HIV-infected mothers (range 2.5-7.5). From 1989 to 2009, overall mortality remained high among all children born to HIV-infected mothers (range 6.3-19.3) and among children who themselves became infected (range 15.6-57.4, 1994-2009). Only lower birth weight was consistently and significantly (P < 0.05) associated with higher child mortality., Conclusions: HIV infection among mothers and children contributed to high levels of child mortality in the African setting in the pretreatment era. In addition to services that prevent mother-to-child transmission of HIV, other programs are needed to improve child survival by lowering HIV-unrelated mortality through innovative interventions that strengthen health infrastructure.

The self-assembling protein nanoparticle (SAPN) is an antigen-presenting system that has been shown to be suitable for use as a vaccine platform. The SAPN scaffold is based on the principles of icosahedral symmetry, beginning from a monomeric chain that self-assembles into an ordered oligomeric state. The monomeric chain contains two covalently linked α-helical coiled-coil domains, an N-terminal de novo-designed pentameric tryptophan zipper and a C-terminal de novo-designed trimeric leucine zipper, which assemble along the internal symmetry axes of an icosahedron. In this study, we incorporated the membrane proximal external region (MPER) of HIV-1 gp41 from HXB2 into the N-terminal pentamer, referred to as MPER-SAPN, attempting to reproduce the α-helical state of the 4E10 epitope while maintaining a structurally less-constrained 2F5 epitope. Sprague-Dawley rats were immunized with MPER-SAPNs, and their sera were analyzed for induced humoral anti-HIV-1 responses. We show that high membrane proximal external region-specific titers can be raised via the repetitive antigen display of MPER on the SAPN without the need for adjuvant. However, none of the sera displayed a detectable neutralizing activity against HIV-1. Thus, 4E10- and 2F5-like neutralizing antibodies could not be elicited by MPER conformationally restrained in the SAPN context., (© 2012 John Wiley & Sons A/S.)

Background: In the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial, infants received up to 14 weeks of extended nevirapine (NVP) or extended NVP with zidovudine (NVP + ZDV) to prevent postnatal HIV transmission. We examined emergence and persistence of NVP resistance in HIV-infected infants who received these regimens prior to HIV diagnosis., Methods: Infant plasma samples collected at 14 weeks of age were tested using the ViroSeq HIV Genotyping System and a sensitive point mutation assay, LigAmp (for K103N and Y181C). Samples collected at 6 and 12 months of age were analyzed using LigAmp., Results: At 14 weeks of age, NVP resistance was detected in samples from 82 (75.9%) of 108 HIV-infected infants. Although the frequency of NVP resistance detected by ViroSeq was lower in the extended NVP + ZDV arm than in the extended NVP arm, the difference was not statistically significant (38/55 = 69.1% vs. 44/53 = 83.0%, P = 0.12). Similar results were obtained using LigAmp. Using LigAmp, the proportion of infants who still had detectable NVP resistance at 6 and 12 months was similar among infants in the two study arms (at 6 months: 17/20 = 85.0% for extended NVP vs. 21/26 = 80.8% for extended NVP + ZDV, P = 1.00; at 12 months: 9/16 = 56.3% for extended NVP vs.10/13 = 76.9% for extended NVP + ZDV, P = 0.43)., Conclusion: Infants exposed to extended NVP or extended NVP + ZDV had high rates of NVP resistance at 14 weeks of age, and resistant variants frequently persisted for 6-12 months. Frequency and persistence of NVP resistance did not differ significantly among infants who received extended NVP only vs. extended NVP + ZDV prophylaxis.

Objectives: To determine normal hematologic and selected blood chemistry values among healthy, full-term, non-HIV-exposed infants in Uganda and Malawi, and to determine the proportion of healthy babies with an apparent laboratory toxicity based on Division of AIDS toxicity tables., Design: This was a cross-sectional laboratory study of infants from birth to 6 months of age., Methods: Blood samples were collected from a total of 561 infants and analyzed according to age categories similar to those in the 2004 Division of AIDS toxicity tables. Select chemistry and hematology parameters were determined and values compared with those in the toxicity tables., Results: In the first 56 days of life, there were few graded toxicities except for neutropenia in 2 of 10 (20%) Ugandan and 13 of 45 (29%) Malawian infants at birth. After 7 days, about 20% of the infants in Uganda and Malawi would have been classified as having a neutropenia whereas 47% and 53% of those more than 2 months of age in Uganda and Malawi respectively, would have been reported as having an abnormal hemoglobin. Chemistry findings were not different from US norms., Conclusions: These findings underscore the importance of establishing relevant local laboratory norms for infants.

Background: The risk of HIV-1 infection is high among breast-fed children in sub-Saharan Africa. Monitoring the nutritional status can provide useful information to determine the effect of HIV infection and breast-feeding on child growth and development. We longitudinally assessed the nutritional status and determined its association with HIV infection and breast-feeding among Malawian children., Methods: We analyzed data from 2 clinical trials to prevent mother-to-child transmission of HIV in Malawi. These trials were conducted during 2000-2003 before the current guidelines were implemented to breast-feed exclusively during the first 6 months and wean thereafter. The nutritional status of children was measured up to age 24 months, using z-scores. Age-specific differences in length-for-age (L/A), weight-for-age (W/A), and weight-for-length (W/L) were compared stratifying by gender and HIV infection status. Multivariable models examined the mean change in z-scores controlling for breast-feeding and other factors., Results: In this analysis, 1589 children were included. Boys had significantly lower L/A scores and became stunted (z-score -<2 standard deviations) earlier than girls. HIV-infected children had significantly lower mean L/A and W/A z-scores than HIV-uninfected children and became stunted and underweight at an earlier age. In multivariable analysis not being breast-fed and being HIV infected were significantly (P < 0.001) associated with decreases in mean L/A, W/A, and W/L z-scores., Conclusions: This study shows the impact of infant HIV infection on growth and supports the critical importance of breast-feeding. Mother-to-child transmission of HIV programs should endeavor to preserve breast-feeding and find alternative measures to prevent postnatal HIV transmission.

Background: In the Post-Exposure Prophylaxis of Infants (PEPI)-Malawi trial, most women received single-dose nevirapine (NVP) at delivery, and infants in the extended study arms received single-dose NVP along with 1 week of daily zidovudine (ZDV), followed by either extended daily NVP or extended daily NVP and ZDV up to 14 weeks of age. Although extended NVP prophylaxis reduces the risk of postnatal HIV transmission, it may increase the risk of NVP resistance among infants who are HIV-infected despite prophylaxis., Methods: We analyzed 88 infants in the PEPI-Malawi trial who were HIV-infected in utero and who received prophylaxis for a median of 6 weeks prior to HIV diagnosis. HIV genotyping was performed using the ViroSeq HIV Genotyping System., Results: At 14 weeks of age, the proportion of infants with NVP resistance was lower in the extended NVP and ZDV arm than in the extended NVP arm (28/45, 62.2% vs. 37/43, 86.0%; P = 0.015). None of the infants had ZDV resistance. Addition of extended ZDV to extended NVP was associated with reduced risk of NVP resistance at 14 weeks if prophylaxis was stopped by 6 weeks (54.5 vs. 85.7%, P = 0.007) but not if prophylaxis was continued beyond 6 weeks (83.3 vs. 87.5%, P = 1.00)., Conclusion: Addition of extended ZDV to extended NVP prophylaxis significantly reduced the risk of NVP resistance at 14 weeks in infants who were HIV-infected in utero, provided that HIV infection was diagnosed and the prophylaxis was stopped by 6 weeks of age.

Objective: To determine the factors associated with resumption of sexual activity and regular menses after childbirth among women infected with HIV-1., Methods: Information on sociodemographic, behavioral, and clinical factors was obtained from 2 HIV perinatal studies (NVAZ and PEPI trials) conducted in Malawi, 2000-2009. Factors associated with resumption of sexual activity and menses were analyzed using Cox proportional hazard models., Results: A total of 1838 women from the NVAZ study and 2982 women from the PEPI study were included in the analysis. Resumption of sexual activity was primarily associated with sociodemographic factors (e.g. in the PEPI study, marital status [adjusted hazard ratio (aHR) 0.56, P<0.001], use of contraceptive method [aHR 8.0, P<0.001], and breastfeeding [aHR 0.52, P<0.001]), whereas resumption of regular menses in the PEPI study was primarily associated with biological factors (e.g. plasma viral load [aHR 0.89, P<0.006], and breastfeeding [aHR 0.23, P<0.001)., Conclusion: HIV-infected women need adequate counseling to take into account their HIV infection status before resuming sexual activity after childbirth.

This study aimed to determine changes in fertility intentions of HIV-1 infected and uninfected reproductive age women in Blantyre, Malawi. Participants were asked about their fertility intentions at baseline and at 3-month visits for 1 year. Time-to-event statistical models were used to determine factors associated with changes in fertility intentions. Overall, 842 HIV uninfected and 844 HIV infected women were enrolled. The hazard of changing from wanting no more children at baseline to wanting more children at follow-up was 61% lower among HIV infected women compared to HIV uninfected women (P < 0.01) after adjusting for other factors, while HIV infected women were approximately 3 times more likely to change to wanting no more children. The overall pregnancy rate after 12 months was 14.9 per 100 person-years and did not differ among 102 HIV uninfected and 100 infected women who became pregnant. HIV infection is a significant predictor of fertility intentions over time.

Background: Perinatal HIV transmission could occur via microtransfused maternal blood during delivery. If so, detecting maternal cells in umbilical cord blood should correlate with infection risk., Objective: To develop sensitive assays for maternal DNA in infant's blood stored as dried blood spots (DBS) and examine the correlation between microtransfusion and perinatal HIV infection risk., Methods: Blood-in-blood serial dilutions were prepared as DBS. Extracted DNA was amplified for unique minor-population sequences using 24 allele-specific polymerase chain reaction assays. Using newborns born to HIV+ mothers, paired mother-infant samples were similarly examined to identify unique maternal sequences targeted by allele-specific polymerase chain reaction of DNA extracted from cord blood DBS. Cord-blood PCR-negative infants were categorized as uninfected or perinatally infected by HIV PCR on samples collected 4-8 weeks after birth., Results: Sequences from added cells were detected at less than 1: 1000 dilutions in 19 of 20 aliquots, and less than 1: 10 000 dilutions in seven of 20 aliquots; the median limit of detection (probit analysis) was one added genomic sequence in 9500 background sequences of amplifiable DNA. Maternal sequences were detected in cord-blood DBS of 50% of infected infants (N = 18) and 44% of uninfected infants (N = 43). Infection did not correlate with more frequent detection of maternal sequences., Conclusion: This semiquantitative assay reliably detected maternal DNA sequences in DBS at levels of less than 1: 1000 cells. Maternal sequences were frequently detected but did not correlate infection risk with detection or level of maternal DNA in umbilical cord blood. Therefore, we could not demonstrate that microtransfusions at parturition were responsible for perinatal HIV transmission.

Background: Data evaluating the biological events and determinants of early human immunodeficiency virus type 1 (HIV-1) infection are limited in sub-Saharan Africa. We examined plasma viral levels and trends during early and established HIV-1 infection among reproductive-age women who participated in a randomized trial to treat genital tract infection in Malawi. We also assessed the association of injectable hormonal contraceptive use with HIV-1 infection., Methods: We studied 3 groups of women who were infected or uninfected with HIV-1: seroconverters, seroprevalent women, and seronegative women. Questionnaires and blood samples were collected at baseline and every 3 months for 1 year. The virus set point in seroconverters and levels and trends of viral load over time were determined. The associations of injectable hormonal contraceptive use with HIV-1 infection and viral load were assessed using conditional logistic regression and mixed-effect models, respectively., Results: In the original clinical trial, 844 women infected with HIV-1 and 842 women not infected with HIV-1 were enrolled. Of 31 women who experienced seroconversion during 12 months, 27 were matched with 54 seroprevalent and 54 seronegative women. The estimated median plasma virus set point was 4.45 log(10) copies/mL (interquartile range, 4.32-5.14 log(10) copies/mL). Injectable hormonal contraceptive use was significantly associated with HIV-1 seroconversion (adjusted odds ratio, 10.42; P = .03) but not with established HIV-1 infection. Among the seroconverters, a statistically significant interaction was found between the linear association of viral load and time of injectable hormonal contraceptive use (regression coefficient, -0.14; P = .02)., Conclusion: Knowledge of virus set point and trends of viral load in HIV-1 seroincident and seroprevalent asymptomatic women could assist in antiretroviral treatment management.

We compared the ability of the LigAmp assay and an ASPCR assay to detect and quantify K103N-containing HIV variants in samples from 63 women who received single-dose nevirapine in a clinical trial. Samples were first analyzed with the ViroSeq HIV Genotyping system, and ViroSeq PCR products were used as templates for the LigAmp and ASPCR assays. A cutoff of 0.5% K103N for detection of K103N was used for both assays. Results for the percentage K103N were similar for the two assays (R(2) = 0.92). Forty-six samples (73.0%) were positive for K103N by both assays and 13 samples (20.6%) were negative by both assays. Four samples (6.3%) were positive by ASPCR only. No samples were positive by LigAmp only. Eight discordant samples were analyzed in more detail. Sequence polymorphisms near oligonucleotide binding sites provided a possible explanation for the discordance in four of eight samples. The percentage K103N was also determined by analyzing 40 HIV clones from each of these eight samples, using a combined amplification/sequencing method (AmpliSeq). The percentage K103N determined by clonal analysis was consistent with the LigAmp result for five of eight samples, and was consistent with the ASPCR result for three of eight samples. Among 320 clones analyzed, we identified eight different codons at position 103 (mean = 3.8 codons/sample), which encoded six different amino acids, illustrating the extensive genetic diversity in HIV. Further studies are needed to compare performance of assays for detection and quantification of HIV drug resistance mutations in clinical samples.

Objective: To study temporal changes in HIV-1 seroreversion (change in reactivity of HIV serology from positive to negative) in uninfected infants born to HIV-1-infected mothers., Methods: Secondary analysis of data from 3 cohort studies conducted in Malawi among infants born 1989 through 1991 (International Collaborative AIDS Research [ICAR]), 1993 through 1996 (HIV Network for Prevention Trials [HIVNET]), and 2000 through 2003 (nevirapine/zidovudine [NVAZ]). The proportion of children HIV seroreverting at ages 15, 18, and 21 months and the relative odds for seroreversion comparing infants born before 1997 to those born after 1999 were calculated., Results: Included in this analysis were 635 infants from ICAR, 459 from HIVNET, and 1020 from NVAZ. During the study, there was a consistent trend of decrease in proportion of children seroreverting over time: highest during 1989 through 1991, intermediate during 1993 through 1996, and lowest during 2000 through 2003. Additionally, there was a strong association between seroreversion and year of birth (before 1997 vs. after 1999): adjusted relative odds 5.1 at 15 months, 8.2 at 18 months, and 11.2 at 21 months., Conclusions: Age of seroreversion in HIV-1-exposed uninfected infants increased over time. Persistence of maternal HIV-1 antibodies could have implications on timing of infant HIV-1 diagnosis using serological diagnostic methods.

K103N is frequently detected in HIV-infected women after single dose (SD) nevirapine (NVP). K103N-containing variants were detected more frequently by the ViroSeq HIV-1 Genotyping System in women with subtype C (69.2%) than subtypes A (19.4%, p < 0.0001) or D (36.1%, p < 0.0001). K103N-containing variants were also detected more frequently and at higher levels in women with subtype C by the LigAmp assay. In this report, we analyzed samples collected prior to or within hours after SD NVP administration from antiretroviral drug-naive African women with subtypes A, C, and D. Only 1/254 samples had an NVP resistance mutation detected with the ViroSeq system, and only 4/236 samples had K103N detected at < 0.5% with the LigAmp assay [2/110 (1.8%) with subtype A, 1/46 (2.2%) with subtype C, and 1/80 (1.3%) with subtype D] (p = 0.92). We did not detect significant differences in the pre-NVP frequency of NVP resistance mutations or the pre-NVP levels of K103N-containing variants in women with subtypes A, C, and D that explain the dramatic subtype-based differences in emergence of HIV-1 variants with these mutations after SD NVP exposure.

Objective: The objective of this study was to determine the incidence of HIV-1., Goal: The goal of this study was to inform HIV prevention and vaccine trials by conducting a multisite study in Malawi and Zimbabwe., Study Design: Women of reproductive age were enrolled in a prospective study. They received 5 intensive HIV counseling and condom promotion sessions over 2 months. Subsequently, HIV-negative women completed quarterly follow-up visits. HIV incidence rates and predictors of HIV acquisition were assessed., Results: A total of 2016 HIV-negative women were enrolled in the condom promotion and counseling phase of the study. Of these, 1679 were tested for HIV during follow up and 113 women seroconverted, resulting in an overall HIV incidence rate of 4.7 per 100 women-years (95% confidence interval = 3.8-5.6). Incidence rates were similar across sites. The major predictors of HIV acquisition were young age, presence of sexually transmitted infections, being unmarried, and higher educational level., Conclusion: The incidence of HIV continues to be high among women in both Malawi and Zimbabwe despite counseling and condom promotion.

Introduction: We used a sensitive point mutation assay, LigAmp, to detect and quantify K103N-containing variants in African women who received single-dose nevirapine (NVP) to prevent mother-to-child HIV-1 transmission., Methods: Plasma for testing was collected 6 to 8 weeks postpartum from 301 women (144 subtype A, 63 subtype C, and 94 subtype D)., Results: The portion of women with 0.5% or more K103N-containing variants was lowest for subtype A (60/144, 41.7%) and highest for subtype C (44/63, 69.8%; P < 0.0001). K103N was rarely detected in pre-NVP samples. In a multivariate model, K103N detection was associated with HIV-1 subtype (C > A), after adjusting for log10 delivery viral load, the number of days between NVP dosing and sample collection, age, and parity. Among women with K103N detected: (1) the median %K103N was lower for subtype A (2.2%) than C (11.7%, P = 0.0001) or D (5.5%, P = 0.04), and (2) in a multivariate linear model, higher log10 (%K103N) was associated with HIV subtype (C > A, P = 0.0001; D > A, P = 0.01; and C vs D, no difference), but not other factors., Conclusions: After administration of single-dose NVP, K103N was detected more frequently and at higher levels in women with subtypes C and D than A. Further studies are needed to evaluate the clinical significance of NVP-resistant variants in this setting.

Replication capacity and transmission of human immunodeficiency virus (HIV)-1 in antiretroviral drug-naive Malawian women who had subtype C infection were investigated. Infant children of these women received either 1 dose of nevirapine or 1 dose of nevirapine plus 1 week of daily doses of zidovudine. PhenoSense HIV was used to determine replication capacity in 49 women whose infants were infected with HIV-1 and in 47 women whose infants were uninfected by 6-8 weeks of age. Mean replication capacity was higher in transmitters than in nontransmitters (P=.01). In a multivariate model, higher replication capacity was associated with transmission (odds ratio, 1.45 for each 10% increase in replication capacity [95% confidence interval, 1.11-1.90]; P = .0063), after adjustment for maternal HIV-1 load and other factors.

Objective: This study analyzed mother-to-child HIV transmission rates by sex and exposure time for babies born to HIV-infected, untreated African women., Methods: Data were analyzed from 2 independent studies done in Malawi during the 1990s. Infections were established by polymerase chain reaction on blood samples. Odds ratios (ORs) for transmission were examined by period at risk: in utero (infected in umbilical cord blood), perinatal (infected in 1st postnatal blood > or =4 weeks), and postnatal (later postnatal infection)., Results: Among 1394 singleton births, girls were more likely to become infected than boys. For in utero transmission, the OR was 1.4 (95% CI: 0.9 to 2.2). For transmission during early life (umbilical cord blood not available) the OR was 2.7 (95% CI: 1.5 to 4.9). However, transmission risks in the perinatal and postnatal infection periods did not differ in boys and girls. Among 303 tested twin-birth pairs, girls were at higher risk than boys for in utero (OR: 2.6; 95% CI: 1.2 to 5.8) and perinatal (OR: 1.9; 95% CI: 1.0 to 3.7) infection. Recognized mother-to-child transmission risk factors did not explain the higher risk of infection in girls., Conclusions: Girls were at higher risk of early (in utero and perinatal) HIV infection than boys. It is proposed that minor histocompatibility reactions between maternal lymphocytes and infant Y chromosome-derived antigens reduce the risk of HIV transmission in boys.

The administration of single-dose nevirapine to women in labor and their infants can prevent HIV-1 mother-to-child transmission. We examined nevirapine resistance in infants who were HIV-1 infected despite single-dose nevirapine prophylaxis, including 18 Ugandan infants (HIVNET 012 trial, nine subtype A and nine subtype D) and 23 Malawian infants (NVAZ trial, all subtype C). Nevirapine resistance was more frequent in infants with subtype C than with subtypes A and D (87 versus 50%, P = 0.016).

Objective: In the Human Immunodeficiency Virus (HIV) Network for Prevention Trials (HIVNET) 012 trial in Uganda, 6-8 weeks after single-dose nevirapine (SD-NVP), NVP resistance mutations were detected at a higher rate in women with HIV-1 subtype D than in women with subtype A. Here, we evaluate the rate of NVP resistance mutations in women with subtype C., Methods: NVP resistance mutations were detected using the ViroSeq HIV-1 Genotyping System., Results: The portion of women with any NVP resistance mutation was higher in those with subtype C (45/65 [69.2%] in the NVP and zidovudine trial, Malawi) than in those in the HIVNET 012 trial with either subtype A (28/144 [19.4%]; P<.0001) or subtype D (35/97 [36.1%]; P<.0001). In a multivariate model, subtype (C vs. A: odds ratio [OR], 8.73 [95% confidence interval {CI}, 4.29-17.76]; C vs. D: OR, 3.38 [95% CI, 1.65-6.93]) and viral load at delivery (OR, 2.35 [95% CI, 1.62-3.40]) independently predicted NVP resistance mutations, but maternal age, parity, and time between SD-NVP and the 6-8-week visit did not., Conclusions: The rate of NVP resistance mutations after SD-NVP was significantly higher in women with HIV-1 subtype C than in women with subtype A or D. Studies are needed to assess the clinical significance of this finding.

Defining viral dynamics in natural infection is prognostic of disease progression and could prove to be important for vaccine trial design as viremia may be a likely secondary end point in phase III HIV efficacy trials. There are limited data available on the early course of plasma viral load in subtype C HIV-1 infection in Africa. Plasma viral load and CD4+ T cell counts were monitored in 51 recently infected subjects for 9 months. Individuals were recruited from four southern African countries: Zambia, Malawi, Zimbabwe, and South Africa and the median estimated time from seroconversion was 8.9 months (interquartile range, 5.7-14 months). All were infected with subtype C HIV-1 and median viral loads, measured using branched DNA, ranged from 3.82-4.02 log10 RNA copies/ml from 2-24 months after seroconversion. Viral loads significantly correlated with CD4+ cell counts (r=-0.5, p<0.0001; range, 376-364 cells/mm3) and mathematical modeling defined a median set point of 4.08 log10 (12 143 RNA copies/ml), which was attained approximately 17 months after seroconversion. Comparative measurements using three different viral load platforms (bDNA, Amplicor, and NucliSens) confirmed that viremia in subtype C HIV-1-infected individuals within the first 2 years of infection did not significantly differ from that found in early subtype B infection. In conclusion, the course of plasma viremia, as described in this study, will allow a useful baseline comparator for understanding disease progression in an African setting and may be useful in the design of HIV-1 vaccine trials in southern Africa.

We assessed the safety of short-term antiretroviral prophylaxis to prevent mother-to-child transmission (MTCT) of HIV by monitoring haematological changes in children up to the age of 18 months. Babies of HIV-infected women were randomised at birth to receive a single dose of nevirapine (NVP) alone or with zidovudine (ZDV) twice daily for a week. Based on the time of presentation to the labour ward, mothers of these babies might or might not have received intrapartum NVP. Complete blood counts were performed at birth and at 1.5, 3, 6, 9, 12, 15 and 18 months. Babies' HIV status was determined by HIV-1 RNA testing. A total of 1755 babies were included in the study. Age-specific mean haemoglobin levels and prevalence of anaemia (haemoglobin < 10 g/dL) were not significantly different in cases where only the babies received a single dose of NVP and cases where NVP was given to mother/infant pairs or additional ZDV to the baby. Among HIV-infected children compared with uninfected children, the age-specific frequency of anaemia was significantly greater, anaemia started earlier and recovery to normal levels was slower and prolonged. A reversible granulocytopenia was observed in all children between 1.5 and 3 months of age. HIV infection significantly increased the children's risk of death. Antiretroviral prophylaxis appeared to protect against anaemia and child death. Short regimens of antiretrovirals to prevent MTCT of HIV are not associated with long-term adverse haematological changes.

Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.

An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

We examined birth order and delivery route as risk factors for mother-to-child transmission of human immunodeficiency virus (HIV)-1 in 315 twin pairs born in Malawi during 1994-1998. No antiretroviral drugs were administered to these subjects. Infections were detected by polymerase chain reaction and were stratified as having occurred either in utero, perinatally, or postnatally. Risk of in utero infection for 630 infants (39 infections) did not differ by birth order (first born, 6.3%; second born, 6.0%). Similarly, in 260 vaginally delivered infants evaluated for perinatal infection (45 infections), risk did not differ by birth order (first born, 15.9%; second born, 18.7%); risk of perinatal infection was significantly lower in cesarean-delivered infants (odds ratio, 0.19 [95% confidence interval, 0.02-0.78]). There was no effect on postnatal transmission rates. Thus, in contrast to the authors of earlier studies, we did not find birth order to be an important risk factor for infection in twins. These findings indicate that birth-canal exposure is not a major contributor to a newborn's risk of HIV-1 infection.

Vitamin A is essential for immunity and growth. A controlled clinical that involved 697 human immunodeficiency virus (HIV)-infected pregnant women was conducted to determine whether vitamin A prevents anemia, low birth weight, growth failure, HIV transmission, and mortality. Women received daily doses of iron and folate, either alone or combined with vitamin A (3 mg retinol equivalent), from 18-28 weeks' gestation until delivery. In the vitamin A and control groups, respectively, the mean (+/-SE) birth weights were 2895+/-31 g and 2805+/-32 g (P=.05), the proportions of low-birth-weight infants were 14.0% and 21.1% (P=.03), the proportions of anemic infants at 6 weeks postpartum were 23.4% and 40.6% (P<.001), and the respective cumulative proportions of infants who were HIV infected at 6 weeks and 24 months of age were 26.6% and 27.8% (P=.76) and 27.7% and 32.8% (P=.21). Receipt of vitamin A improved birth weight and neonatal growth and reduced anemia, but it did not affect perinatal HIV transmission.

Host genetic factors may influence the course of human immunodeficiency virus (HIV) infection. In Blantyre, Malawi, polymerase chain reaction was used to identify twin pairs who were concordantly HIV-1-infected in utero or perinatally and then to examine strain divergence or virus levels in identical and fraternal twin pairs. Among 315 twin pairs, both infants in 14 fraternal and 5 identical pairs were found to be infected at the same visit. Among 10 pairs, HIV-1 sequences were determined for both infants at >or=1 time point. HIV levels had a common profile in both fraternal and identical twin pairs. Identical twins were not always infected by the same quasi species, indicating that their mothers had multiple quasi species capable of infecting their infants. Subsequent viral divergence appears to depend on quasi-species stability rather than on genetically controlled host immune responses. Thus, given infection, factors intrinsic to HIV-1 are more important than host genetics in viral evolution.

Objective: To measure hepatic and hematological parameters among neonates randomized to receive ultra-short antiretroviral regimens., Design: As part of an on-going clinical trial in Malawi, infants born to women who received (early presenters) or did not receive (late presenters) standard intrapartum nevirapine (NVP) dosing were randomized to receive orally either single dose NVP alone or NVP plus zidovudine (twice daily for 1 week). An additional group of untreated infants (born to HIV-uninfected women) was enrolled as a control., Methods: Laboratory measurements were performed at birth and repeated at 6 weeks of age. Serum alanine aminotransferase (ALT) was measured on approximately 200 infants consecutively enrolled and randomized at the start of the trial. Complete blood count (CBC) was performed on approximately 800 infants at birth and 600 infants at 6 weeks of age. ALT and CBC were also determined on approximately 200 control infants., Results: At birth there were no differences in ALT values between the groups of children. At 6 weeks of age, ALT levels were significantly higher among the treated groups compared with control group (geometric mean of 11.5 U/l for controls and 16.2-19.1 U/l for treated groups; P < 0.0001). Hematological parameters did not differ between groups at birth. At 6 weeks of age, levels of hemoglobin, hematocrit, granulocytes, and platelets were significantly (P < 0.0001) lower among antiviral drug-treated groups compared with controls. These changes were consistent with grade 1 (mild) toxicity, and were more noticeable among HIV-infected infants., Conclusions: Hepatic and hematologic abnormalities associated with short-term neonatal antiretrovirals among African children are minimal.