Growth and Resorption of Chronic Subdural Hematomas: Gardner, Weir, and the Osmotic Hypothesis Revisited.

BACKGROUND: To explain why some chronic subdural hematomas (CSDHs) grow and/or resorb, a physically decreasing outer membrane (OM) surface area (SA) to CSDH volume (V) ratio has been reexplored, and a critical CSDH size inferred (OM SA ≈ V). Gardner showed that since CSDH protein exceeded cerebrospinal fluid (CSF) protein, CSF→CSDH osmosis occurred across a semipermeable inner membrane (n = 1). By contrast, Zollinger and Gross demonstrated that serum→CSDH osmosis could also occur across the OM (n = 1). Notably, Weir refuted Zollinger and Gross by finding equal CSDH and serum total protein (n = 20); however, Weir did not refute Gardner. Although all extant mechanisms, especially rehemorrhages, explain CSDH growth, only OM SA ≥ V simultaneously permits resorption. We aimed to reevaluate the osmotic hypothesis. METHODS: Paired serum and CSDH samples were measured in a prospective cohort. RESULTS: Results were consecutively obtained in 116 patients (87 men; mean age, 73 ± 13 years). Serum osmolality and CSDH osmolality were similar (285.70 ± 7.99 vs. 283.85 ± 7.52 mmol/kg, respectively; P = 0.11) and significantly correlated (r = 0.75, P < 0.0001). Serum total protein significantly exceeded CSDH total protein (66.6 ± 6.8 vs. 43.68 ± 20.24 g/L, P < 0.0001) as did serum albumin (35.62 ± 4.46 vs. 30.85 ± 8.5 g/L, P < 0.0001) and serum total globulins (31.5 ± 6 vs. 18.6 ± 11.4 g/L, P < 0.0001). Serum and CSDH proteins were not correlated (total protein: r = 0.003; albumin: r = 0.08; globulins: r = 0.21). CONCLUSIONS: Only crystalloids equilibrated. CSDH colloids were significantly decreased. CSDH dilution or colloidal flocculation is implied. CSDH dilution (by CSF→CSDH inner membrane [IM] osmosis or OM transudation/exudation) could favor CSDH growth, as would repeated OM hemorrhages. Contrariwise, isolated colloidal flocculation could favor CSDH shrinkage by OM CSDH→serum osmosis. The latter may result in OM SA ≥ V favorable for ultimate resolution. Our results refute Weir and Zollinger and Gross, but not Gardner. Osmotic gradients simultaneously exist for both CSDH growth and resorption. Each equilibrium could depend on each gradient relative to each IM/OM semipermeability.

The aetiology of diarrhoea, pneumonia and respiratory colonization of HIV-exposed infants randomized to breast- or formula-feeding.

BACKGROUND: Diarrhoea and pneumonia are common causes of childhood death in sub-Saharan Africa but there are few studies describing specific pathogens. OBJECTIVES: The study aimed to describe the pathogens associated with diarrhoea, pneumonia and oropharyngeal colonization in children born to HIV-infected women (HIV-exposed infants). METHODS: The Mashi Study randomized 1200 HIV-infected women and their infants to breastfeed for 6 months with ZDV prophylaxis or formula-feed with 4 weeks of ZDV. Children were tested for HIV by PCR at 1, 4, 7, 9 and 12 months and by ELISA at 18 months. Pre-defined subsets of children were sampled during episodes of diarrhoea (n = 300) and pneumonia (n = 85). Stool was tested for bacterial pathogens, rotavirus and parasites. Children with pneumonia underwent bacterial blood culture, and testing of nasopharyngeal aspirates for viral pathogens by PCR. Oropharyngeal swabs were collected from a consecutive subset of 561 infants at the routine 3-month visit for bacterial culture. RESULTS: The median age (range) at sampling was 181 days for diarrhoea (0-730) and 140 days for pneumonia (2-551). Pathogens were identified in 55 (18%) children with diarrhoea and 32 (38%) with pneumonia. No differences in pathogens by child HIV status (HIV-infected vs HIV-uninfected) or feeding strategy were identified. Campylobacter was the most common diarrhoeal pathogen (7%). Adenovirus (22%) and other viruses (19%) were the primary pathogens isolated during pneumonias. More formula-fed infants had oropharyngeal colonization by pathogenic Gram-negative bacteria (16.8% vs 6.2%, P = 0.003), which was associated with a non-significant increased risk of pneumonia (OR 2.2, 95% CI 0.8-5.7). CONCLUSION: A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.

Predictors of early breastfeeding cessation among HIV-infected women in Botswana.

OBJECTIVE: Infants born to HIV-infected women receiving antiretroviral treatment (ART) can be breastfed through at least 6 months with very low risk of HIV acquisition. We aimed to identify demographic and cultural factors that may influence mothers' willingness to breastfeed for the recommended duration. METHODS: We evaluated factors associated with early cessation of breastfeeding (i.e. before 5 months post-partum) in a randomized clinical trial evaluating different ART regimens used for prevention of mother-to-child transmission during breastfeeding in Botswana. Univariate and multivariable Cox regressions were used to describe predictors of early exclusive BF cessation. RESULTS: Among 677 women who started breastfeeding, the median time to breastfeeding cessation was 178 days (IQR 150-181) and 25.1% weaned early. In multivariable analysis, urban location (aHR = 1.86 95%CI 1.27-2.73; P = 0.002), salaried employment or being a student (aHR = 2.78 95% CI 1.63-4.75; P < 0.001) and infant hospitalisation before weaning (aHR = 2.04 95% CI 1.21-3.45; P = 0.008) were independently and significantly associated with early BF cessation. CONCLUSIONS: Improved support for breastfeeding among employed mothers, especially in urban settings, may allow HIV-infected women who are receiving ART prophylaxis to breastfeed longer.

HIV transmission and 24-month survival in a randomized trial of HAART to prevent MTCT during pregnancy and breastfeeding in Botswana.

OBJECTIVES: HAART for prevention of mother-to-child HIV transmission (MTCT) may impact long-term survival of women and children. DESIGN: Randomized clinical trial. METHODS: HIV-infected pregnant women with CD4+ cell count at least 200 cells/µl were randomly assigned to abacavir, zidovudine, lamivudine (arm A) or lopinavir­ritonavir, zidovudine­lamivudine (arm B) from week 26 to 34 gestation through planned weaning by 6 months postpartum. Women with baseline CD4+ cell count less than 200 cells/µl received nevirapine­zidovudine­lamivudine indefinitely (Obs arm), as did randomized women later qualifying for treatment. RESULTS: Among 560 randomized and 170 observational women enrolled, there were 14 deaths (1.9%) ­ one antenatally (Obs), three from delivery to 6 months postpartum (1 arm A, 2 Obs), and 10 from 6 to 24 months postpartum (5 arm A, 3 arm B, 2 Obs). Time to death or CD4+ cell count below 200 cells/µl was shorter in arm A vs. B (P = 0.03). Of the 709 live-born children, 97% breastfed for a median of 5.8 months. Of 37 (5.2%) deaths by 24 months, nine were before breastfeeding initiated (3 arm A, 2 arm B, 4 Obs); six while breastfeeding (1 arm A, 2 arm B, 3 Obs); and 22 after weaning (9 arm A, 11 arm B, 2 Obs). Only eight children (1.1%) were HIV-infected at 24 months (6 arm A, 1 arm B, 1 Obs), all before 6 months. CONCLUSION: Low MTCT was maintained through extended follow-up in all arms. Disease progression appeared slower after discontinuing protease inhibitor-based HAART, but a concerning number of maternal deaths occurred after stopping either regimen. Strategies to improve maternal and child survival in the postintervention period are required.

No clinically significant drug-resistance mutations in HIV-1 subtype C-infected women after discontinuation of NRTI-based or PI-based HAART for PMTCT in Botswana.

Risk of developing drug resistance after stopping antiretroviral regimens to prevent mother-to-child HIV-1 transmission is unknown. The Mma Bana Study randomized treatment-naive pregnant women with CD4 ≥200 cells per cubic millimeter to receive either abacavir/zidovudine/lamivudine [triple nucleoside reverse transcriptase inhibitor (NRTI) arm] or lopinavir/ritonavir/zidovudine/lamivudine [protease inhibitor (PI) arm]. Drugs were discontinued after 6 months of breastfeeding. One month after discontinuation, 29 NRTI arm samples and 25 PI arm samples were successfully genotyped. No clinically significant antiretroviral resistance mutations were detected. Eight minor resistance mutations were found among 11 (20%) women (3 from NRTI arm and 8 from PI arm), occurring at similar frequencies to those reported in HIV-1 subtype C treatment-naive cohorts.

Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana.

BACKGROUND: Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available. METHODS: Women in the Mma Bana Study initiated HAART from 18 to 34 weeks of gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC) and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum. RESULTS: Sampling occurred a median of 14 h (range 11-17) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 µg/ml versus 5.51 µg/ml; P = 0.02), antepartum levels with standard LPV dosing were therapeutic for all women (> 1.0 µg/ml). Very low LPV levels (< 0.25 µg/ml) were detected in breast milk. Median ABC levels in breast milk were 85% of those in plasma (0.057 µg/ml versus 0.067 µg/ml). Breast milk concentrations of NVP and 3TC were 27% and 74% of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk. CONCLUSIONS: Standard LPV dosing achieved therapeutic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.

Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy.

BACKGROUND: Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. METHODS: HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. RESULTS: Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. CONCLUSIONS: PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.

Increased risk of severe infant anemia after exposure to maternal HAART, Botswana.

BACKGROUND: Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission but may increase the risk for infant anemia. METHODS: The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). RESULTS: A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. CONCLUSIONS: Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.

HIV-1 subtype C-infected individuals maintaining high viral load as potential targets for the "test-and-treat" approach to reduce HIV transmission.

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1-4.2 log(10)) and cART-initiating cohorts (5.1-5.3 log(10)) by about one log(10). The proportion of individuals with high (> or = 50,000 (4.7 log(10)) copies/ml) HIV-1 RNA levels ranged from 24%-28% in the general HIV-positive population cohorts to 65%-83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%-50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load > or = 50,000 (4.7 log(10)) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%-82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified "test-and-treat" strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.

Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4(+) cell counts in Gaborone, Botswana.

BACKGROUND: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy. METHODS: From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana. RESULTS: We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4(+) cell counts, of whom 62 (16%) had a CD4(+) cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy. CONCLUSIONS: We observed low rates of CD4(+) cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4(+) cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.

Microbicides development programme: engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania.

BACKGROUND: HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. METHODS: A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives. RESULTS: Key recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. CONCLUSION: Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64716212.

Risk factors for early and late transmission of HIV via breast-feeding among infants born to HIV-infected women in a randomized clinical trial in Botswana.

Risk factors for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breast-feeding were evaluated in a randomized trial. HIV-infected women and their infants received zidovudine as well as single-dose nevirapine or placebo. Infants were randomized to formula-feed (FF) or breast-feed (BF) in combination with zidovudine prophylaxis. Of 1116 at-risk infants, 6 (1.1%) in the FF group and 7 (1.3%) in the BF group were infected between birth and 1 month (P=.99). Maternal receipt of nevirapine did not predict early MTCT in the BF group (P=.45). Of 547 infants in the BF group at risk for late MTCT, 24 (4.4%) were infected. Maternal HIV-1 RNA levels in plasma (P<.001) and breast milk (P<.001) predicted late MTCT. These findings support the safety of 1 month of breast-feeding in combination with maternal and infant antiretroviral prophylaxis. Trial registration. ClinicalTrials.gov identifiers: NCT00197691 and NCT00197652.

Adult combination antiretroviral therapy in sub-Saharan Africa: lessons from Botswana and future challenges.

Numerous national public initiatives offering first-line combination antiretroviral therapy (cART) for HIV infection have commenced in sub-Saharan Africa since 2002. Presently, 2.1 million of an estimated seven million Africans in need of cART are receiving treatment. Analyses from the region report favorable clinical/treatment outcomes and impressive declines in AIDS-related mortality among HIV-1-infected adults and children receiving cART. While immunologic recovery, virologic suppression and cART adherence rates are on par with resource-rich settings, loss to follow-up and high mortality rates, especially within the first 6 months of treatment, remain a significant problem. Over the next decade, cART coverage rates are expected to improve across the region, with attendant increases in healthcare utilization for HIV- and non-HIV-related complications and the need for expanded laboratory and clinical services. Planned and in-progress trials will evaluate the use of cART to prevent primary HIV-1 infection with so-called 'test and treat' expansions of coverage and treatment. Education and training programs as well as patient-retention strategies will need to be strengthened as national cART programs are expanded and more people require lifelong monitoring and care.

Infant morbidity, mortality, and breast milk immunologic profiles among breast-feeding HIV-infected and HIV-uninfected women in Botswana.

BACKGROUND: Infants of human immunodeficiency virus (HIV)-infected women have high mortality, but the immunologic integrity and protection afforded by the breast milk of HIV-infected women is unknown. METHODS: We determined morbidity and mortality by 24 months among breast-fed infants of 588 HIV-infected and 137 HIV-uninfected women followed-up in a clinical trial in Botswana. A matched case-control study compared clinical, behavioral, and breast milk immunologic parameters among 120 HIV-infected women by infant outcome. Breast milk factors were also compared between HIV-infected and HIV-uninfected women. RESULTS: Twenty-four-month mortality was 29.5% among HIV-infected infants, 6.7% among HIV-exposed uninfected infants, and 1.6% among HIV-unexposed infants. No differences were detected in breast milk immunologic profiles of HIV-infected women whose infants were either ill or well. Discontinuation of breast-feeding was the strongest predictor of illness (P<.001). Levels in breast milk of pathogen-specific immunoglobulin (Ig) G and IgA to Haemophilus influenzae, Campylobacter jejuni, Helicobacter pylori, Streptococcus pneumoniae, and innate immune factors were not lower among HIV-infected women than among HIV-uninfected women. CONCLUSIONS: Mortality was higher among HIV-infected and HIV-exposed infants than among HIV-unexposed infants. However, the immunologic profiles of breast milk among HIV-infected women were intact, and discontinuation of breast-feeding was the primary risk for infant morbidity. Thus, the breast milk of HIV-infected women may confer protection against common infant pathogens. TRIAL REGISTRATION: (ClinicalTrials.Gov) identifiers: NCT00197691 and NCT00197652.

Response to antiretroviral therapy after a single, peripartum dose of nevirapine.

BACKGROUND: A single dose of nevirapine during labor reduces perinatal transmission of human immunodeficiency virus type 1 (HIV-1) but often leads to viral nevirapine resistance mutations in mothers and infants. METHODS: We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana involving the prevention of the transmission of HIV-1 from mother to child. All women were treated with antenatal zidovudine. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment, estimated within groups by the Kaplan-Meier method. RESULTS: Of 218 women who started antiretroviral treatment, 112 had received a single dose of nevirapine and 106 had received placebo. By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P=0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P<0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P=0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P<0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment. CONCLUSIONS: Women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine. However, this applied only when nevirapine-based antiretroviral therapy was initiated within 6 months after receipt of a single, peripartum dose of nevirapine. (ClinicalTrials.gov number, NCT00197587 [ClinicalTrials.gov].).

Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

CONTEXT: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. OBJECTIVE: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. DESIGN, SETTING, AND PATIENTS: A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. INTERVENTION: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). MAIN OUTCOME MEASURES: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. RESULTS: The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). CONCLUSIONS: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00197587.