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Author(s): Osorio, Luiz Eduardo; Boechat, Maria Ines; Mirochnick, Mark; Kumwenda, Newton; Kreitchmann, Regis; Emel, Lynda; Pinto, Jorge; Joao, Esau; Santos, Breno; Swenson, Molly; George, Kathleen; Sato, Paul; Mofenson, Lynne; Nielsen-Saines, Karin; HIV Prevention Trials Network (HPTN) 057 Protocol Team | Abstract: BackgroundTenofovir 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.MethodsHand/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.ResultsAcross 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.ConclusionBone 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.

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.

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 naive with CD4 cell counts

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

We measured longitudinal levels of vitamin D in unsupplemented Malawian infants at 0 (birth), 2, 12, 15, 18 and 24 months of age. Matched maternal plasma and breast milk vitamin D(2) and D(3) levels were also measured at delivery and 2 months postpartum. Vitamin D was measured using isotope-dilution liquid chromatography tandem-mass spectrometry. Vitamin D(3) levels in children were 36% of adult levels at birth, 60% of adult levels at age 2 months, and at par with adult levels by 12 months of age. This adult-equivalent level is subsequently maintained through age 24 months and consisted of a 98% molar ratio of vitamin D(3). Vitamin D levels in breast milk were below the limit of detection, 0.1 ng/ml. Breast milk of unsupplemented Malawian mothers is a poor source of vitamin D.

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 approximately 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.

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

First-line antiretroviral treatment regimens in resource-limited settings used in breastfeeding mothers often include stavudine (d4T). Limited data describing d4T concentrations in breast milk are available. We analyzed d4T concentrations in 52 mother-infant pairs using ultra-performance liquid chromatography-tandem mass spectrometry (lower limit of quantification: 5 ng/mL in plasma, 20 ng/mL in breast milk). Median (interquartile range) d4T concentrations were 86 (36-191) ng/mL in maternal plasma, 151 (48-259) ng/mL in whole milk, 190 (58-296) ng/mL in skim milk, and5 (5 to5) ng/mL in infant plasma. Although d4T is concentrated in breast milk relative to maternal plasma, the infant d4T dose received from breast milk is very small and not clinically significant.

Optimizing the survival of HIV-uninfected infants born to HIV-infected mothers (ie, HIV-exposed infants) is a major challenge in sub-Saharan Africa, where prevalence of HIV infection remains high among reproductive-age women [1]. The detrimental effects of early weaning to prevent HIV transmission have been shown in multiple studies from Malawi, Uganda, and Botswana [2–5]. In these studies, the risk of severe gastroenteritis and mortality associated with gastroenteritis were higher among HIV-exposed but uninfected infants who were weaned early (at 4–6 months of age), compared with those who breastfed (BF) for longer periods. Additional adverse effects of nonbreastfeeding (NBF) or early weaning among HIV-uninfected African children include acute malnutrition, such as marasmus and kwashiorkor [5], and growth faltering [6, 7]. Infants who stopped BF also did not show increases in HIV-free survival (ie, both remaining alive and free of HIV infection) [8, 9]. How to balance the risks and benefits of BF of HIV-uninfected children of HIV-infected mothers in resource-constrained settings of sub-Saharan Africa where BF alternatives are not safe has been extensively discussed [10–12]. The recent World Health Organization (WHO) recommendations on infant feeding and HIV emphasize infant HIV-free survival [13]. Despite the evidence that NBF increases infant morbidity and mortality in resource-constrained settings, our understanding of the timing of these adverse events is limited. For clinical management and program planning, it will be valuable to know immediate and long-term effects of weaning whenever this practice is initiated. We hypothesize that cessation of BF to prevent transmission of HIV leads to early acute morbidity that occurs during the process of weaning or immediately after weaning. However, infant mortality associated with weaning is a late effect and occurs after the weaning process is completed. The aim of this study was to determine, among HIV-exposed, uninfected Malawian infants, morbidity rates in short follow-up intervals (∼3 months) that encompass weaning and to assess cumulative rates of mortality over time. These infants were originally enrolled in the extended antiretroviral Post-exposure Prophylaxis of Infants in Malawi (PEPI-Malawi) trial.

The expanding services of antiretroviral treatment (ART) in sub-Saharan Africa provide unique opportunities to reduce HIV/AIDS-related morbidity and mortality. In these settings, HIV prevalence among antenatal women remains high and treating eligible pregnant or breastfeeding women with antiretrovirals can substantially reduce transmission of HIV from the mother to her infant. However, identification of women eligible for treatment and ensuring access to ART services is challenging. In this analysis, we used data from a large clinical trial (the PEPI-Malawi study, 2004–09) to prevent mother-to-child transmission of HIV through extended antiretroviral prophylaxis of infants to examine barriers for wider coverage with highly active antiretroviral treatment (HAART) of postpartum women. Maternal HAART was not part of the original PEPI-Malawi clinical trial but became available through a government programme during the course of the study. Therefore, eligible women (CD4 cell count

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.

BACKGROUND: The association between postnatal human immunodeficiency virus type 1 (HIV-1) transmission and maternal highly active antiretroviral therapy (HAART) after infant extended antiretroviral prophylaxis was assessed. METHODS: A follow-up study was conducted for the Post-Exposure Prophylaxis of Infants trial in Blantyre Malawi (PEPI-Malawi). In PEPI-Malawi breast-feeding infants of HIV-infected women were randomized at birth to receive a either control regimen (single-dose nevirapine plus 1 week of zidovudine); the control regimen plus nevirapine to age 14 weeks; or the control regimen plus nevirapine and zidovudine to age 14 weeks. Infant HIV infection maternal CD4 cell count and HAART use were determined. Maternal HAART use was categorized as HAART eligible but untreated (CD4 cell count of

article i nfo 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

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 (P0.01) 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.

The objective was 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. 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. 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. 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. (authors)

BACKGROUND The present study was undertaken to determine the risk and timing of late postnatal transmission (LPT) of human immunodeficiency virus type 1 (HIV-1). METHODS Breast-fed infants previously enrolled in 2 trials of antiretroviral prophylaxis were monitored in Malawi. Kaplan-Meier and proportional hazard models assessed cumulative incidence and association of factors with LPT. RESULTS Overall, 98 infants were HIV infected, and 1158 were uninfected. The cumulative risk of LPT at age 24 months was 9.68% (95% confidence interval, 7.80%-11.56%). The interval hazards at 1.5-6, 6-12, 12-18, and 18-24 months were 1.22%, 4.05%, 3.48%, and 1.27%, respectively. CONCLUSIONS The risk of LPT beyond 6 months is substantial. Weaning at 6 months could prevent >85% of LPT.

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.Plasma for testing was collected 6 to 8 weeks postpartum from 301 women (144 subtype A, 63 subtype C, and 94 subtype D).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%; P0.0001). K103N was rarely detected in pre-NVP samples. In a multivariate model, K103N detection was associated with HIV-1 subtype (CA), 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 (CA, P = 0.0001; DA, P = 0.01; and C vs D, no difference), but not other factors.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.

The HIVNET 012 trial in Uganda showed that mother-to-child transmission (MTCT) of HIV-1 can be prevented by providing pregnant women and their infants with a single dose (SD) of the antiretroviral drug nevirapine (NVP). Safety and efficacy of 1- or 2-dose NVP prophylaxis for prevention of MTCT have been documented in other studies. We have shown that NVP resistance emerges in some women after SD NVP prophylaxis and that the portion of women with NVP resistance is influenced by HIV-1 subtype. At 6 to 8 weeks after SD NVP NVP resistance was more common in women with subtype C (69.2%) than in women with subtype D (36.1% P < 0.0001) or subtype A (19.4% P < 0.0001).4 Selection of NVP-resistant HIV-1 variants in women after NVP dosing could theoretically lower the efficacy of NVP prophylaxis for prevention of HIV transmission by breast-feeding in the first few weeks after birth. In the HIVNET 012 trial most women were infected with HIV-1 subtype A or D. Risk of MTCT was slightly (but not statistically) higher in women with subtype D. In this report we combined data from the HIVNET 012 and NVAZ trials to compare the risk of MTCT in women with subtype C to the risk of MTCT in women with subtypes A and D in the setting of SD NVP prophylaxis. (excerpt)

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.

This study analyzed mother-to-child HIV transmission rates by sex and exposure time for babies born to HIV-infected untreated African women. 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 = 4 weeks) and postnatal (later postnatal infection). 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. 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. (authors)

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

Innovative, low-cost, and acceptable measures are needed to reduce sexually transmitted infections (STIs) including HIV. Use of a topical microbicide wipe for penile cleaning before and after sex might be effective in preventing STIs. However, evaluation of this simple method has not been done. Two studies were conducted in Malawi to determine the safety, acceptability, and potential efficacy of a benzalkonium chloride topical penile microbicide wipe. The first study was a phase 1 dose-escalating clinical trial among low-risk circumcised or uncircumcised HIV-negative men. The second study was a pilot before-after efficacy study among uncircumcised HIV-negative or -positive men. In the first study 24 circumcised and 27 uncircumcised men were enrolled. During the entire study period, 18 adverse events (AEs) were reported, and 3 AEs were confirmed by physical examination. Acceptability concerns did not increase with dose escalation, and adherence to use of the wipe ranged from 89%-95%. In the second study, 27 men were enrolled. Gram stain and culture tests showed significant reductions in frequency of several organisms after use of the wipe, including STI-associated bacteria. This penile wipe is safe, acceptable, and can decrease the frequency of penile colonization with microorganisms. The clinical relevance remains to be determined in larger clinical trials.

The epidemiology and microbiology of subclinical mastitis, a risk factor for perinatal HIV transmission, have not been well characterized. In all, 250 HIV-infected women were followed from two weeks to 12 months postpartum in Blantyre, Malawi, and subclinical mastitis was assessed by breast milk leukocyte counts. The point prevalence of subclinical mastitis at 2, 4, 6, 10, and 14 weeks, and 6, 9, and 12 months was 12.2%, 7.8%, 6.8%, 3.7%, 10.6%, 5.1%, 4.9%, and 1.9%, respectively ( P = 0.002), and 27.2% of women had at least one episode of subclinical mastitis. There was no significant relationship between maternal plasma HIV load or parity and subclinical mastitis. Staphylococcus aureus was isolated in 30% of women with subclinical mastitis, and the proportion of women with positive cultures decreased during follow-up ( P = 0.02). Subclinical mastitis is prevalent among breastfeeding mothers and further studies are needed to characterize the differences between infectious and non-infectious subclinical mastitis.

The acute phase response and inflammation are associated with lower plasma retinol concentrations, but their effect on breast milk retinol concentrations is unclear. We measured plasma retinol concentrations, acute phase proteins, and breast milk retinol concentrations in 237 breast-feeding women at 2 wk postpartum in Blantyre, Malawi; 16.5% of the women had plasma retinol0.70 micromol/L and 14.8% had breast milk retinol1.05 micromol/L. Among women with and without inflammation [alpha(1)-acid glycoprotein (AGP)1 g/L and/or C-reactive protein (CRP)5 mg/L], geometric mean (95% CI) plasma retinol was 0.89 (0.84, 0.94) and 1.05 (1.01, 1.17) mumol/L, respectively (P0.0001). Among women with and without inflammation, geometric mean (95% CI) breast milk retinol was 2.12 (1.89, 2.36) and 2.05 (1.75, 2.39) micromol/L, respectively (P = 0.74). In multiple linear regression models adjusting for age, parity, education, BMI, and days postpartum, plasma retinol concentrations were associated with plasma AGP and CRP concentrations (P0.0001 and P = 0.01, respectively), whereas breast milk retinol concentrations were unaffected by plasma AGP and CRP concentrations (P = 0.22 and P = 0.86, respectively). These findings suggest that breast milk retinol concentrations are not affected by systemic inflammation.

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.

The objectives were to evaluate the safety of 100 mg nonoxynol-9 (N-9) gel a vaginal microbicide on the genital mucosa of women from Malawi and Zimbabwe in preparation for a phase III efficacy study. HIV-uninfected women (180) were enrolled and randomized to either N-9 or placebo gel and instructed to insert gel into the vagina twice daily for 14 days. Follow up examinations were conducted at 7 and 14 days. The number of adverse events in the N-9 gel group was higher than in the placebo group (40% versus 13%; P < 0.01). Reported number of any genital symptoms was significantly higher in the N-9 group (38% N-9 13% placebo; P = 0.01). The number of total epithelial disruptions was higher in the N-9 group (20% versus 3%; P < 0.01); however the number of genital ulcers and abrasions in the N-9 group was low (2% and 3% respectively) and not different from that in the placebo group (1% and 2% respectively). N-9 gel 100 mg caused a significant increase in the rate of genital symptoms and epithelial disruptions compared with placebo. The clinical significance of these epithelial disruptions is unknown. Although these findings alone were not sufficient to cancel the planned phase III study when considered together with the negative results from the COL-1492 effectiveness trial of 52.5 mg N-9 gel the decision was made to cancel the planned phase III trial of 100 mg N-9 gel. (authors)

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.

Objective. To compare the effectiveness of methods for assessing the quality of pediatric outpatient health provider performance in developing countries. Design. Exit interviews, record reviews, and provider interview results were compared with those of direct observation of pediatric patient care. Thirty health care providers in 14 facilities in Lilongwe District, Malawi were interviewed and observed, treating 436 children in August 1994. Caretakers for 426 of the patients were interviewed, and 362 pediatric outpatient entries in the health center patient register were located and reviewed. Main measures. Kappa statistics measuring the level of agreement on the same sample were used for three methods (record reviews, provider interviews, and exit interviews) in comparison with the fourth method, direct observation. Results. All three methods had strengths and weaknesses. Exit interviews with caretakers provided reliable responses for many history-taking tasks, easily discernible physical exam tasks, and many counseling tasks. Record review took little time, but provided limited information: however, the results were reliable for treatments. Provider interviews had much lower reliability, but were usable for assessing more rare events (treating severely ill children). Conclusions. Although exit interviews and direct observation provide the ‘best’ data, they are most resource-intensive. Depending on the purpose of the assessment, various combinations of methods might be more effective.

Background: HIV-1 surveys in defined populations identify underlying risks and trends useful to mount interventions. Goal: The goal of the study was to determine HIV-1 prevalence and risk factors among men working at a Malawian sugar estate. Study Design: Three independent surveys were conducted in 1994, 1997, and 1998. Procedures included obtaining informed consent, interviewing, and drawing blood for HIV and syphilis testing. Analyses determined prevalence of HIV and associated risk factors. Results: HIV prevalence was 24.3% in 1994 (n = 1691), 22.8% in 1997 (n = 615), and 20.9% in 1998 (n = 1354; P < 0.03). From 1994 to 1998, the percentage of subjects with a history of sexually transmitted disease (STD) decreased from 43.6% to 29.5% (P < 0.0001), accompanied by a substantial rise in STDs confirmed by physical examination (from 7.5% to 16.8%; P < 0.0001) and by laboratory testing for syphilis (from 6.5% to 10.4%; P < 0.0001). The percentage with multiple sex partners declined (from 62.0% to 35.2%; P < 0.0001), and condom use rose (from 10.9% to 18.9%; P < 0.0001). STDs were significantly associated with prevalent HIV infection each year. Conclusions: The prevalence of HIV has remained relatively stable and high in this cohort.

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

INTRODUCTION Although studies suggest that vitamin A or its metabolites influence the synthesis of erythropoietin in vitro and in animal models, it is unclear whether vitamin A supplementation increases plasma erythropoietin concentrations in humans. OBJECTIVE To determine whether daily vitamin A supplementation increases plasma erythropoietin concentrations in pregnant women with a high prevalence of anaemia. METHODS A randomized, double-blind, controlled clinical trial was conducted to examine the effect of daily vitamin A (3000 microg retinol equivalent), iron (30 mg), and folate (400 microg) versus iron (30 mg) and folate (400 microg) (control) on haemoglobin and plasma erythropoietin concentrations in 203 pregnant women in Malawi, Africa. RESULTS Mean gestational age at enrollment was 23 wk, at which time 50% of the women were anaemic (haemoglobin

HIV-infected and uninfected children who survived their first year of life were prospectively followed in Malawi to assess levels of mortality and related risk factors during the second and third years of life.Children with known HIV status from an earlier perinatal intervention trial were enrolled. These children [HIV-infected (Group A); HIV-uninfected but born to HIV-seropositive mothers (Group B); and children born to HIV-seronegative mothers (Group C)] were followed every 3 months until age 36 months. Mortality data were collected at each visit. Immunologic data (CD4+ percent) were collected at or immediately after enrollment.Overall 702 children were enrolled and 83 children died during follow-up. The mortality rate per 1000 person years of observation was 339.3 among Group A children, 46.3 among Group B children and 35.7 among Group C children. Among HIV-infected children the cumulative proportion surviving to age 24 months was 70% and those surviving to age 36 months was 55%. By age 32 months none of the severely immunosuppressed (CD4%15%) children had survived. The mortality differentials between HIV-infected and uninfected children persisted after adjusting for several risk factors. The major causes of death among infected children (n = 52) were wasting and respiratory conditions.Although all HIV-infected children had received childhood immunizations, mortality was high. Management of these children should include aggressive antimicrobial treatment, and evaluation of prophylactic regimens should be considered.

Breast milk transmission of HIV-1 continues to present enormous challenges for prevention of infant HIV-1 infection. Breast milk confers a variety of benefits to infants but can also be a vehicle for HIV- 1 transmission. Determining the amount of risk due to breast-feeding duration of risk and cofactors for risk is useful for designing efficient interventions to decrease the incidence of infant HIV-1 infection. In this issue of the Journal Taha et al. evaluated late postnatal transmission in cohorts of Malawian mother-infant pairs who participated in 2 previously published clinical trials of antiretrovirals to prevent mother-to-child transmission (the nevirapine-zidovudine studies). Overall 1256 infants without HIV-1 infection at 1.5 months were monitored for 24 months to determine the risk of late postnatal transmission. The risk of HIV-1 acquisition in this group was 9.7% and the vast majority (87.4%) of late infections occurred after 6 months of age. The study was large yielded a fairly precise risk estimate and included a 2-year follow-up which enabled comparison of risk estimates for serial intervals of ~6 months. Interestingly the 1.5-6-month age interval was the one with the lowest risk of HIV-1 transmission (1.22%). Finally utilizing the cohorts size and long follow-up period the authors were also able to identify several significant correlates of late postnatal transmission. (excerpt)

To examine rates of HIV-1 and sexually transmitted disease (STD) among pregnant and postpartum women in urban Malawi, Africa.Serial cross-sectional surveys and a prospective study.Three major surveys were conducted in 1990, 1993 and 1994/1995. Consecutive first-visit antenatal women and women giving birth at the Queen Elizabeth Central Hospital were tested for HIV and STD after counseling and obtaining informed consent. Unlinked, anonymous HIV testing was also conducted on smaller samples of antenatal women in the same hospital to provide annual prevalence data. HIV-seronegative postpartum women from the 1990 and 1993 surveys were enrolled in a prospective study to determine HIV incidence.HIV seroprevalence rose from 2.0% in 1985 to 32.8% in 1996, a 16-fold increase. The highest age-specific HIV prevalence was in the following age-groups: 20-24 years during 1990, 25-29 years during 1993, and 30-34 years during 1996. Among 1173 women followed for a median of 30.9 months, HIV incidence was 5.98 per 100 person-years in women aged20 years and declined steadily in older women. The prevalence of STD significantly declined among both HIV-positive and negative women. This decline in STD prevalence, however, was not accompanied by increased condom use over time.Among urban childbearing women in Malawi, incidence of HIV is highest among young women while, currently, prevalence is highest among older women. Recent declines in STD prevalence suggest that HIV prevention programs are having an impact either through improved STD diagnosis and treatment or reduced risk behaviors. Sequential cross-sectional STD prevalence measures may be useful in monitoring effectiveness of STD and HIV prevention activities.Prevalence rates of HIV-1 and other sexually transmitted diseases (STDs) among pregnant and postpartum women were investigated in sequential, cross-sectional studies (1990, 1993, and 1994-95) conducted at Queen Elizabeth Central Hospital in Blantyre, Malawi. Annual anonymous, unlinked testing revealed a linear increase in HIV-1 prevalence among antenatal patients from 2.0% in 1985 to 32.8% in 1996. Analysis of demographic attributes of women enrolled in the 1990 and 1993 surveys of consecutive, first-visit antenatal women (n = 6603 and 2161, respectively) and the 1994-95 study of all women giving birth at the hospital during a 6-month period (n = 6964) indicated that HIV-infected women were most likely to be young, with fewer pregnancies, and be more educated. The highest age-specific HIV prevalence shifted from 20-24 years in 1990 to 30-34 years in 1996, indicating an aging cohort of women who became infected at a younger age. Reported lifetime use of condoms increased from 5.6% in 1990 to 17.5% in 1993, then declined to 4.9% in 1995; condom use was consistently higher among HIV-positive than HIV-negative women. The prevalence of all STDs (syphilis, trichomoniasis, gonorrhea, and genital warts and ulcers) declined significantly during 1990-96, with the most consistent decreases recorded among HIV-positive women. In a follow-up study of 1173 HIV-seronegative, postpartum women evaluated for 2302 person-years (average duration, 30.9 months), 97 seroconverted (4.21/100 person-years). The seroconversion rate declined steadily from 21.26/100 person-years in 1990 to 1.11/100 person-years in 1994-95. These findings are consistent with those from other sub-Saharan African countries, indicating a rapid increase in HIV prevalence followed by stabilization within about 10 years of the onset of the epidemic. The large decline in STD prevalence in the antenatal population suggests that Malawi's national AIDS prevention program is having an impact, either through improved STD diagnosis and treatment or reduced risk behaviors.

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).

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.

A total of 51 women with urinary schistosomiasis haematobium were examined in order to identify diagnostic indicators for female genital schistosomiasis (FGS). Patients were selected at random from the outpatient department of the Mangochi District Hospital, Malawi. The medical histories were recorded according to a pre-designed questionnaire and the women were subjected to a thorough gynaecological examination including colposcopy and photographic documentation of lesions. Microscopy of genital biopsies revealed that 33 of the 51 women had S. haematobium ova in cervix, vagina and/or vulva in addition to the presence of ova in urine. The most sensitive diagnostic procedure was beside microscopic examination of a wet cervix biopsy crushed between two glass slides, which revealed 25 of the 33 genital infections. There was a significant correlation between the size of genital lesions and the number of ova counted per mm2 of crushed tissue. Women with FGS had significantly more tumours in the vulva than women with schistosomiasis limited to the urinary tract. Most of the observed genital pathology could easily be identified by the naked eye, but colposcopic examination yielded valuable additional information like the demonstration of neovascularisation around cervical sandy patches. Few of the symptoms previously regarded as indicators for FGS could be linked to the presence of schistosome ova in genital tissue. Husbands of infertile women with FGS had children with other women significantly more often than husbands of women who only had urinary schistosomiasis. This, together with the finding that the majority of the divorced women had FGS, indicates that the manifestation of this disease may have implications for the marital and sexual life of the affected women.

Schistosomiasis of the lower female reproductive tract manifests itself in a broad spectrum of clinical features. However, clinical and histopathological findings have never been studied in a synoptic manner. Based on the assumption that any type of pathology present in the female reproductive tract is the expression of a complex pathophysiological reaction towards eggs sequestered in the genital tissues, we decided to analyze colposcopic and histopathological findings in a comprehensive manner. Thirty-three women in Malawi with urinary and genital schistosomiasis were examined parasitologically and gynecologically. A thorough colposcopic examination with photodocumentation was performed and biopsies were taken from the cervix, the vagina and/or the vulva for histological sectioning and immunohistochemistry. The predominant colposcopic findings were sandy patches on the cervical surface similar to those seen in the bladder and polypous/papillomatous tumors with irregular surface on the vaginal wall and in the vulvar area. The histopathological sections of sandy-patch-like lesions demonstrated only a small cellular reaction around S. haematobium eggs in various stages of disintegration. In contrast, in the case of polyps the histology revealed a more pronounced immunological reaction characterized by a heavy cellular infiltrate. One case of invasive squamous cell carcinoma of the cervix was diagnosed. We conclude that colposcopy is a useful tool in the detection of FGS related pathology in the lower female reproductive tract and that the synoptic assessment of surface and of corresponding histological sections helped to understand the pathophysiology of S. haematobium associated disease in genital tissue.

Little is known whether and to what extent antiparasitic treatment cures female genital schistosomiasis (FGS). Using a standard protocol, of twenty-one women with FGS nine were re-examined at two to nine weeks after they had been treated with praziquantel at a single dose of 40 mg/kg. Symptoms related to pathology of the urinary tract and to a lesser extent of genital pathology subsided in most patients. Schistosoma haematobium ova were no longer detectable in urine of any of the patients post-treatment. Efficiency of chemotherapy against adult worms was confirmed by the disappearance of circulating anodic antigen (CAA) in serum. Sandy patches showed resolution in two of four cases after chemotherapy. Papillomata due to schistosomiasis alone improved, but persisted in mixed infection with human papilloma virus (HPV) or when HPV was the only underlying cause. In one patient ulcera could not be related with certainty to schistosomiasis at admission, but resolved after treatment with parziquantel. Leukoplakia (two cases) was not influenced by chemotherapy, or even increased during follow-up, regardless of whether ova had been detected or not. Although the follow-up period was rather short, time intervals were not standardized, and a relatively small number of patients was investigated, it could be shown that genital pathology due to sequestered S. haematobium ova is, at least partially, reversible already two to nine weeks after killing the adult worms by praziquantel. This is paralleled by a normalization of inflammatory immune responses detectable in histological sections and vaginal lavage.

Data on paediatric reference laboratory values are limited for sub-Saharan Africa.To describe the distribution of haematological and chemical pathology values among healthy infants from Malawi and Uganda.A cross-sectional study was conducted among healthy infants, 0-6 months old, born to HIV-uninfected mothers recruited from two settings in Blantyre, Malawi and Kampala, Uganda. Chemical pathology and haematology parameters were determined using standard methods on blood samples. Descriptive analyses by age-group were performed based on 2004 Division of AIDS Toxicity Table age categories. Mean values and interquartile ranges were compared by site and age-group.A total of 541 infants were included altogether, 294 from Malawi and 247 from Uganda. Overall, the mean laboratory values were comparable between the two sites. Mean alkaline phosphatase levels were lower among infants aged ≤21 days while aspartate aminotransferase, creatinine, total bilirubin and gamma-glutamyl transferase were higher in those aged 0-7 days than in older infants. Mean haematocrit, haemoglobin and neutrophil counts were higher in the younger age-groups (35 days) and overall were lower than US norms. Red and white blood cell counts tended to decrease after birth but increased after ∼2 months of age. Mean basophil counts were higher in Malawi than in Uganda in infants aged 0-1 and 2-7 days; mean counts for eosinophils (for age groups 8-21 or older) and platelets (for all age groups) were higher in Ugandan than in Malawian infants. Absolute lymphocyte counts increased with infant age.The chemical pathology and haematological values in healthy infants born to HIV-uninfected mothers were comparable in Malawi and Uganda and can serve as useful reference values in these settings.

The use of antiretroviral (ARV) drugs for HIV-1 treatment and prevention of mother-to-child transmission (MTCT) of HIV in low- and middle-income countries has expanded dramatically since 2003.1 Some African countries with high HIV prevalence and suboptimal coverage of prevention of MTCT programs are now considering universal ARV treatment (ART) for HIV-infected pregnant women.2 Globally, there are conflicting findings on the impact of combination ART on low birth weight (LBW) and preterm (PT) birth. Studies in Europe and the United States showed a relatively high rate of PT births among infants of HIV-infected mothers on highly active antiretroviral therapy (HAART)3-5 and some indication of very LBW among babies born to protease inhibitor users.6 Others studies from Europe, the Caribbean, Latin America and the United States, reported no association with birth weight (BW), gestational age (GA), or risk of stillbirths,7,8 or an increased risk of PT and LBW birth without ART.9 More broadly, the extent to which HIV contributes to adverse birth outcomes compared to established non-HIV-related risk factors, such as demographic, environmental and behavioral factors10 has been speculated but not well defined.11 A study from Rwanda, prior to ART, looking at intrauterine growth indicated that maternal HIV was significantly associated with LBW but not with PT birth12 while another report from the same study suggested infant HIV status is a more valuable predictor of BW.13 Existing information on maternal ART and adverse birth outcomes has been derived from observational studies conducted mainly in developed countries. In most African countries, information on BW is generated from small studies or national estimates which are not stratified by maternal HIV status. Similarly, there are no national data on GA. One published study in Botswana showed lower BW in HIV-uninfected infants exposed to HAART in-utero compared to those exposed to zidovudine alone; these lower birth weights were corrected in the first 6 months of life.14 The same trial concluded protease inhibitors were associated with increased PT delivery but not with excess hospitalization or mortality.15 Trend data on mean BW and GA among infants of ART-naive, HIV-infected women could be instrumental in providing baseline estimates when monitoring birth outcomes associated with ART exposure. These data could also assist in establishing local and regional surveillance databases to study the effects of ART on these outcomes, as coverage and access continue to expand. In Malawi, several MTCT observational and interventional studies were conducted at a single site in Blantyre over the past 20 years.16 This provides a unique opportunity to document BW and GA over time in cohorts of HIV-infected women and their HIV-exposed children. These studies predated use of ART during pregnancy for prevention of MTCT of HIV in Malawi. In this paper, we examine trends in mean BW and GA, and the proportion of LBW and PT births in cohorts of infants born to HIV-infected, ART-naive women screened and enrolled in multiple MTCT studies in Blantyre, Malawi. We also assess risk factors associated with these pregnancy outcomes.

Background. The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)‐infected lactating women with CD41 cell counts ,350 cells/lL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis. Methods. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests. Results. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P 5 .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P 5 .003). Conclusions. postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.

BACKGROUND: This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009. METHODS: Infants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection death and HIV infection or death using Kaplan-Meier analysis. RESULTS: This analysis includes 3126 infants uninfected at birth as follows: 1004 control 1071 ExtNVP and 1051 ExtNVP/ZDV. By 9 months HIV infection rates were 5.0% in ExtNVP 6.0% in ExtNVP/ZDV and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm. CONCLUSIONS: Daily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.

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

ContextUnderstanding the risk of human immunodeficiency virus (HIV) transmission through breastfeeding is essential for advising HIV-infected mothers and formulating public health policy recommendations.ObjectiveTo measure the frequency, timing, and risk factors of HIV transmission through breast milk.DesignProspective cohort study conducted between 1994 and 1997, with follow-up of infants through 24 months of age.SettingPostnatal clinic of tertiary care hospital, Blantyre, Malawi.ParticipantsA total of 672 infants (HIV-negative at birth) born to HIV-infected women who had not received antiretroviral drugs during or after pregnancy.Main Outcome MeasureIncidence of HIV in breastfed infants by age and maternal and infant risk factors for HIV transmission, using proportional hazard models to derive risk ratios (RRs) and 95% confidence intervals (CIs).ResultsForty-seven children became HIV-infected while breastfeeding but none after breastfeeding had stopped. The cumulative infection rate while breastfeeding, from month 1 to the end of months 5, 11, 17, and 23, was 3.5%, 7.0%, 8.9%, and 10.3%, respectively. Incidence per month was 0.7% during age 1 to 5 months, 0.6% during age 6 to 11 months, and 0.3% during age 12 to 17 months (P=.01 for trend). The only factors significantly associated with low risk of postnatal HIV transmission in a multivariate model were high maternal parity (RR, 0.23; 95% CI, 0.09-0.56) and older maternal age (RR, 0.44; 95% CI, 0.23-0.84).ConclusionsOur data suggest that the risk of HIV infection is highest in the early months of breastfeeding, which should be considered in formulating breastfeeding policy recommendations.

BACKGROUND: We assessed gastroenteritis (GE) burden in 2 randomized trials conducted in Malawi to reduce postnatal HIV transmission before and after World Health Organization recommendations regarding exclusive breastfeeding for HIV-exposed infants were adopted. The 2 trials were the nevirapine/AZT (NVAZ 2000-2003 with prolonged breastfeeding) and the Postexposure Prophylaxis to the Infant (PEPI 2004-2007 with breastfeeding cessation by 6 months). METHODS: From NVAZ and PEPI trials data GE frequency through age 12 months among HIV-negative exposed infants was evaluated. Overall and GE-related cumulative mortality rates were estimated using Kaplan-Meier curves. RESULTS: The frequency of at least one GE-related hospitalization was greater in PEPI vs. NVAZ after age 6 months (respectively 2.9% vs. 0.1% at 7-9 months and 1.6% vs. 0.2% at 10-12 months P < 0.001). Cumulative GE-related mortality was significantly higher in PEPI than in NVAZ after age 6 months; at ages 9 and 12 months GE-related mortality was 19 and 24 per 1000 infants in PEPI vs. 7 and 12 per 1000 infants in NVAZ (P = 0.0002). CONCLUSIONS: Early weaning was associated with increased risk of severe GE and GE-related mortality among HIV-exposed infants. Strategies are urgently needed which allow longer breastfeeding while reducing the risk of HIV breast milk transmission in resource-limited settings.

Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings.Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth.Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug.Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. (ClinicalTrials.gov number, NCT00115648.)

The aim of this study was to determine HIV-1 incidence among women of reproductive age in Malawi. A prospective study design was followed. HIV-1 uninfected women were followed up for nine visits during a period of 12 months. At baseline, women received HIV-1 counselling and testing. At each visit, venous blood was collected for HIV-1 testing. Incidence rate for HIV-1 was estimated using person-years of follow up (PYFU). Risk factors for HIV acquisition were assessed using Cox proportional hazard models. A total of 842 HIV-1 negative women were enrolled in the study. Of these, 787 had subsequent HIV testing and 31 were found HIV-1 infected; an overall incidence rate of 4.51 (95% confidence interval: 2.96–6.06) per 100 PYFU was obtained. Young age, using hormonal injectable contraceptives and bacterial vaginosis were the main predictors of HIV acquisition. The incidence of HIV continues to be high among women in Malawi, and young women appear to be at higher risk.

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.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.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).Knowledge of virus set point and trends of viral load in HIV-1 seroincident and seroprevalent asymptomatic women could assist in antiretroviral treatment management.