Determining the lower limit of detection required for HCV viral load assay for test of cure following direct-acting antiviral-based treatment regimens: Evidence from a global data set.

Achieving global elimination of hepatitis C virus requires a substantial scale-up of testing. Point-of-care HCV viral load assays are available as an alternative to laboratory-based assays to promote access in hard to reach or marginalized populations. The diagnostic performance and lower limit of detection are important attributes of these new assays for both diagnosis and test of cure. Therefore, our objective was to determine an acceptable LLoD for detectable HCV viraemia as a test for cure, 12 weeks post-treatment (SVR12). We assembled a global data set of patients with detectable viraemia at SVR12 from observational databases from 9 countries (Egypt, the United States, United Kingdom, Georgia, Ukraine, Myanmar, Cambodia, Pakistan, Mozambique) and two pharmaceutical-sponsored clinical trial registries. We examined the distribution of HCV viral load at SVR12 and presented the 90th, 95th, 97th and 99th percentiles. We used logistic regression to assess characteristics associated with low-level virological treatment failure (defined as <1000 IU/mL). There were 5973 cases of detectable viraemia at SVR12 from the combined data set. Median detectable HCV RNA at SVR12 was 287,986 IU/mL. The level of detection for the 95th percentile was 227 IU/mL (95% CI 170-276). Females and those with minimal fibrosis were more likely to experience low-level viraemia at SVR12 compared to men (adjusted odds ratio AOR = 1.60 95% confidence interval [CI] 1.30-1.97 and those with cirrhosis (AOR = 1.49 95% CI 1.15-1.93). In conclusion, an assay with a level of detection of 1000 IU/mL or greater may miss a proportion of those with low-level treatment failure.

Treatment outcomes and costs of a simplified antiviral treatment strategy for hepatitis C among monoinfected and HIV and/or hepatitis B virus-co-infected patients in Myanmar.

Access to hepatitis C virus (HCV) testing and treatment is limited in Myanmar. We assessed an integrated HIV and viral hepatitis testing and HCV treatment strategy. Sofosbuvir/velpatasvir (SOF/VEL) ± weight-based ribavirin for 12 weeks was provided at three treatment sites in Myanmar and sustained virologic response (SVR) assessed at 12 weeks after treatment. Participants co-infected with HBV were treated concurrently with tenofovir. Cost estimates in 2018 USD were made at Yangon and Mandalay using standard micro-costing methods. 803 participants initiated SOF/VEL; 4.8% were lost to follow-up. SVR was achieved in 680/803 (84.6%) by intention-to-treat analysis. SVR amongst people who inject drugs (PWID) was 79.7% (381/497), but 92.5% among PWID on opioid substitution therapy (OST) (74/80), and 97.4% among non-PWID (298/306). Utilizing data from 492 participants, of whom 93% achieved SVR, the estimated average cost of treatment per patient initiated was $1030 (of which 54% were medication costs), with a production cost per successful outcome (SVR) of $1109 and real-world estimate of $1250. High SVR rates were achieved for non-PWID and PWID on OST. However, the estimated average cost of the intervention (under the assumption of no genotype testing and reduced real-world effectiveness) of $1250/patient is unaffordable for a national elimination strategy. Reductions in the cost of antivirals and linkage to social and behavioural health services including substance use disorder treatment to increase retention and adherence to treatment are critical to HCV elimination in this population.

The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV-infected Malawian mothers and associations with maternal and infant biomarkers.

We evaluated effects of antiretroviral (ARV) therapy and lipid-based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV-infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post-partum and blood during pregnancy (≤30 weeks gestation) were collected from 535 mothers/infant-pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post-partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80-90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1-19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = -.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11-.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal α-1-acid glycoprotein and C-reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation.

Co-trimoxazole Prophylaxis, Asymptomatic Malaria Parasitemia, and Infectious Morbidity in Human Immunodeficiency Virus-Exposed, Uninfected Infants in Malawi: The BAN Study.

Background: Human immunodeficiency virus (HIV)-exposed infants are disproportionately at risk of morbidity and mortality compared with their HIV-unexposed counterparts. The role of co-trimoxazole preventive therapy (CPT) in reducing leading causes of infectious morbidity is unclear. Methods: We used data from the Breastfeeding, Antiretrovirals and Nutrition (BAN) clinical trial (conducted 2004-2010, Malawi) to assess the association of (1) CPT and (2) asymptomatic malaria parasitemia with respiratory and diarrheal morbidity in infants. In June 2006, all HIV-exposed infants in BAN began receiving CPT (240 mg) from 6 to 36 weeks of age, or until weaning occurred and HIV infection was ruled out. All HIV-exposed, uninfected infants (HEIs) at 8 weeks of age (n = 1984) were included when CPT was the exposure. A subset of HEIs (n = 471) were tested for malarial parasitemia using dried blood spots from 12, 24, and 36 weeks of age. Cox proportional hazards models for recurrent gap-time data were used to examine the association of time-varying exposures on morbidity. Results: CPT was associated with a 36% reduction in respiratory morbidity (hazard ratio [HR], 0.64 [95% confidence interval {CI}, .60-.69]) and a 41% reduction in diarrheal morbidity (HR, 0.59 [95% CI, .54-.65]). Having asymptomatic malaria parasitemia was associated with a 40% increase in respiratory morbidity (HR, 1.40 [95% CI, 1.13-1.74]) and a 50% increase in diarrheal morbidity (HR, 1.50 [95% CI, 1.09-2.06]), after adjusting for CPT. Conclusions: CPT may have an important role to play in reducing the leading global causes of morbidity and mortality in the growing population of HEIs in malaria-endemic resource-limited settings.

Impact of daily cotrimoxazole on clinical malaria and asymptomatic parasitemias in HIV-exposed, uninfected infants.

BACKGROUND: Cotrimoxazole preventive therapy (CPT) is recommended for all human immunodeficiency virus (HIV)-exposed infants to avoid opportunistic infections. Cotrimoxazole has antimalarial effects and appears to reduce clinical malaria infections, but the impact on asymptomatic malaria infections is unknown. METHODS: We conducted an observational cohort study using data and dried blood spots (DBSs) from the Breastfeeding, Antiretrovirals and Nutrition study to evaluate the impact of CPT on malaria infection during peak malaria season in Lilongwe, Malawi. We compared malaria incidence 1 year before and after CPT implementation (292 and 682 CPT-unexposed and CPT-exposed infants, respectively), including only infants who remained HIV negative by 36 weeks of age. Malaria was defined as clinical, asymptomatic (using DBSs at 12, 24, and 36 weeks), or a composite outcome of clinical or asymptomatic. Linear and binomial regression with generalized estimating equations were used to estimate the association between CPT and malaria. Differences in characteristics of parasitemias and drug resistance polymorphisms by CPT status were also assessed in the asymptomatic infections. RESULTS: CPT was associated with a 70% (95% confidence interval, 53%-81%) relative reduction in the risk of asymptomatic infection between 6 and 36 weeks of age. CPT appeared to provide temporary protection against clinical malaria and more sustained protection against asymptomatic infections, with no difference in parasitemia characteristics. CONCLUSIONS: CPT appears to reduce overall malaria infections, with more prolonged impacts on asymptomatic infections. Asymptomatic infections are potentially important reservoirs for malaria transmission. Therefore, CPT prophylaxis may have important individual and public health benefits.

Plasma Micronutrient Concentrations Are Altered by Antiretroviral Therapy and Lipid-Based Nutrient Supplements in Lactating HIV-Infected Malawian Women.

BACKGROUND: Little is known about the influence of antiretroviral therapy with or without micronutrient supplementation on the micronutrient concentrations of HIV-infected lactating women in resource-constrained settings. OBJECTIVE: We examined associations of highly active antiretroviral therapy (HAART) and lipid-based nutrient supplements (LNS) with concentrations of selected micronutrients in HIV-infected Malawian women at 24 wk postpartum. METHODS: Plasma micronutrient concentrations were measured in a subsample (n = 690) of Breastfeeding, Antiretrovirals, and Nutrition (BAN) study participants who were randomly assigned at delivery to receive HAART, LNS, HAART+LNS, or no HAART/no LNS (control). HAART consisted of protease inhibitor-based triple therapy. LNS (140 g/d) met energy and micronutrient requirements of lactation. Multivariable linear regression tested the association of HAART and LNS, plus their interaction, with micronutrient concentrations, controlling for season, baseline viral load, and baseline CD4 count. RESULTS: We found significant HAART by LNS interactions for folate (P = 0.051), vitamin B-12 (P < 0.001), and transferrin receptors (TfRs) (P = 0.085). HAART was associated with lower folate (with LNS: -27%, P < 0.001; without LNS: -12%, P = 0.040) and higher TfR concentrations (with LNS: +14%, P = 0.004; without LNS: +28%, P < 0.001), indicating iron deficiency. LNS increased folate (with HAART: +17%, P = 0.037; without HAART: +39%, P < 0.001) and decreased TfR concentrations (with HAART only: -12%, P = 0.023). HAART was associated with lower vitamin B-12 concentrations only when LNS was present (-18%, P = 0.001), whereas LNS increased vitamin B-12 only when no HAART was present (+27%, P < 0.001). HAART, but not LNS, was associated with higher retinol-binding protein (RBP; +10%, P = 0.007). We detected no association of HAART or LNS with selenium, ferritin, or hemoglobin. CONCLUSION: The association of HAART with lower folate, iron deficiency, and higher RBP plus the attenuation of LNS effects on folate and vitamin B-12 when combined with HAART has implications for the health of lactating HIV-infected women taking HAART in prevention of mother-to-child transmission programs. This trial was registered at clinicaltrials.gov as NCT00164736.

Hepatitis B virus infection among HIV-infected pregnant women in Malawi and transmission to infants.

BACKGROUND & AIMS: The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants. METHODS: Plasma from 2048 HIV-infected, Malawian women and their infants were tested for markers of HBV infection. Study participants were provided standard-of-care health services, which included administration of pentavalent vaccine to infants at 6, 10, and 14 weeks of age. RESULTS: One-hundred and three women (5%) were HBsAg-positive; 70 of these HBsAg-positive women were also HBV-DNA-positive. Sixteen women (0.8%) were HBV-DNA-positive but HBsAg-negative. Five of 51 infants (9.8%) born to HBsAg-positive and/or HBV-DNA-positive women were HBV-DNA-positive by 48 weeks of age.HBV DNA concentrations of two infants of mothers who received extended lamivudine-containing anti-HIV prophylaxis were <4 log10 IU/ml compared to ⩾ 8 log10 IU/ml in three infants of mothers who did not. CONCLUSIONS: HBV DNA was detected in nearly 10% of infants born to HBV/HIV-coinfected women. Antenatal testing for HIV and HBV, if instituted, can facilitate implementation of prophylactic measures against infant infection by both viruses.

Changes in soluble transferrin receptor and hemoglobin concentrations in Malawian mothers are associated with those values in their exclusively breastfed, HIV-exposed infants.

Infant iron status at birth is influenced by maternal iron status during pregnancy; however, there are limited data on the extent to which maternal iron status is associated with infant iron status during exclusive breastfeeding. We evaluated how maternal and infant hemoglobin and iron status [soluble transferrin receptors (TfR) and ferritin] were related during exclusive breastfeeding in HIV-infected women and their infants. The Breastfeeding, Antiretrovirals, and Nutrition Study was a randomized controlled trial in Lilongwe, Malawi, in which HIV-infected women were assigned with a 2 × 3 factorial design to a lipid-based nutrient supplement (LNS), or no LNS, and maternal, infant, or no antiretroviral drug, and followed for 24 wk. Longitudinal models were used to relate postpartum maternal hemoglobin (n = 1926) to concurrently measured infant hemoglobin, adjusting for initial infant hemoglobin values. In a subsample, change in infant iron status (hemoglobin, log ferritin, log TfR) between 2 (n = 352) or 6 wk (n = 167) and 24 wk (n = 519) was regressed on corresponding change in the maternal indicator, adjusting for 2 or 6 wk values. A 1 g/L higher maternal hemoglobin at 12, 18, and 24 wk was associated with a 0.06 g/L (P = 0.01), 0.10 g/L (P < 0.001), and 0.06 g/L (P = 0.01), respectively, higher infant hemoglobin. In the subsample, a reduction in maternal log TfR and an increase in hemoglobin from initial measurement to 24 wk were associated with the same pattern in infant values (log TfR ß = -0.18 mg/L, P < 0.001; hemoglobin ß = 0.13 g/L, P = 0.01). Given the observed influence of maternal and initial infant values, optimizing maternal iron status in pregnancy and postpartum is important to protect infant iron status. This trial was registered at clinicaltrials.gov as NCT00164736.

Acceptability, feasibility and appropriateness of intensified health education, SMS/phone tracing and transport reimbursement for uptake of voluntary medical male circumcision in a sexually transmitted infections clinic in Malawi: a mixed methods study.

Introduction: Uptake of voluntary medical male circumcision (VMMC) remains a challenge in many settings. Innovative implementation strategies are required to scale-up VMMC uptake. Methodology: RITe was a multi-faceted intervention comprising transport reimbursement (R), intensified health education (IHE) and SMS/Telephone tracing (Te), which increased the uptake of VMMC among uncircumcised men with sexually transmitted infections (STIs) in Malawi. Using a concurrent exploratory mixed-method approach, we assessed the intervention's acceptability, feasibility and appropriateness among men with STIs and healthcare workers (HCWs) at Bwaila District Hospital. Participants completed Likert scale surveys and participated in-depth interviews (IDIs) and focus group discussions (FGDs). We calculated percentages of responses to survey items and summarized common themes using thematic analysis. Median scores and interquartile ranges (IQR) were calculated for acceptability, feasibility and appropriateness of each strategy at baseline and end-line and compared using the Wilcoxon signed rank test. Results: A total of 300 surveys, 17 IDIs and 4 FGDs were conducted with men and HCWs between baseline and end-line. The mean age for men in the survey was 29 years (SD ±8) and most were married/cohabiting (59.3%). Mean age for HCWs was 38.5 years (SD ±7), and most were female (59.1%). For acceptability, participants agreed that RITe was welcome, approvable, and likable. Despite participants agreeing that RITe was a good idea, culture and religion influenced appropriateness, particularly at baseline, which improved at end-line for Te and R. For feasibility, HCWs agreed that RITe was easy to implement, but expressed concerns that R (end-line median = 4, IQR: 2, 4) and Te (end-line median = 4, IQR: 4, 4), were resource intensive, hence unsustainable. Interviews corroborated the survey results. Participants reported that IHE provided important information, Te was a good reminder and R was attractive, but they reported barriers to R and Te such as electricity, limited access to phones and distrust in the government. Conclusions: The RITe intervention was acceptable, feasible and appropriate. However, culture/religion and structural barriers affected perceptions of appropriateness and feasibility, respectively. Continued awareness raising on VMMC and addressing setting-specific structural factors are required to overcome barriers that impede demand-creation interventions for VMMC. Study registration: ClinicalTrials.gov identifier: NCT04677374. Registered on December 18, 2020.

Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial.

BACKGROUND: In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per µL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736. FINDINGS: 676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternal-antiretroviral (4%, 3-6; p=0·0273) or the infant-nevirapine (4%, 2-5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1·1 [95% CI 1·0-1·2] vs 0·7 [0·7-0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group). INTERPRETATION: In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity. FUNDING: US Centers for Disease Control and Prevention.

Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.

BACKGROUND: We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi. METHODS: We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test. RESULTS: Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. CONCLUSIONS: The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)

Lipid-based nutrient supplements are feasible as a breastmilk replacement for HIV-exposed infants from 24 to 48 weeks of age.

The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study randomized HIV-infected mothers and their infants to receive either maternal lipid-based nutrient supplements (LNS) during lactation or no LNS and then to 1 of 3 antiretroviral drug (ARV) arms (maternal, infant, or no drugs). Assigned interventions were provided from 0 to 28 wk and all infants (n = 1619) were given LNS during (24-28 wk) and following (28-48 wk) weaning. This paper assesses the feasibility of infant LNS as a breastmilk replacement and uses longitudinal random effects models to examine associations of interventions, morbidity, and season with weight-for-age (WAZ), length-for-age (LAZ), and BMI-for-age (BMIZ) Z-scores from 24 to 48 wk. Infant LNS adherence was high (94.1% ate it daily). From 24 to 48 wk, mean WAZ (-0.42 to -0.76 SD; P < 0.001) and LAZ (-0.93 to -1.56 SD; P < 0.001) steadily declined, whereas BMIZ remained >0 throughout. A higher LAZ was associated with assignment to the maternal LNS arm (ß=0.19; P < 0.05). Lower WAZ and BMIZ were associated with seasonal food insecurity (ß=-0.08 and -0.09, respectively; both P < 0.001), fever (ß=-0.07 and -0.13; both P < 0.001), diarrhea (ß=-0.19 and -0.23; both P < 0.001), and assignment to the infant ARV arm (ß=-0.17 and -0.17; both P < 0.05). The magnitude of the season and morbidity effects was small and BAN infants had higher weights and lengths than their counterparts in the general population. High LNS adherence and the modest impact of morbidity on growth indicate that LNS is a feasible breastmilk replacement for HIV-exposed infants weaned early, but controlled trials are needed to quantify the effects of LNS on growth in this population.

Maternal weight loss during exclusive breastfeeding is associated with reduced weight and length gain in daughters of HIV-infected Malawian women.

Maternal weight loss during exclusive breastfeeding may influence the growth of exclusively breast-fed infants through impaired quality or quantity of breast milk. This study evaluated how maternal weight loss from 2 to 24 wk postpartum was related to infant weight and length gain in 1309 lactating HIV-infected mothers and their exclusively breast-fed infants. Malawian mother-infant pairs in the Breastfeeding, Antiretrovirals, and Nutrition Study were randomized with a 2 × 3 factorial design to a 2-arm nutritional intervention with a lipid-based nutrient supplement (LNS), meeting nutritional needs of lactation, or no LNS and a 3-arm antiretroviral (ARV) intervention (maternal, infant, or no ARV regimen). Linear regression models were used to relate maternal weight loss (weight loss vs. no weight loss) to infant weight and length gain from birth to 24 mo, stratifying by gender and controlling for maternal BMI at 2 wk (mean ± SD: 23.2 ± 3.0 kg/m(2)) and interacting maternal BMI with weight loss. In adjusted models, compared with daughters of women who did not lose weight, length and weight gain were lower in daughters whose mothers had a lower BMI at 2 wk postpartum coupled with the weight loss. For example, among mothers with an initial BMI of 18 kg/m(2), daughters of those who lost weight gained less weight [ß = -0.29 kg (95% CI: -0.53, -0.06)] and length [ß = -0.88 cm (95% CI: -1.52, -0.23)] from birth to 24 wk than daughters of those who gained weight. Though effects were only observed in girls, suggesting possible gender differences in suckling and feeding behavior, these findings indicate that maternal weight loss with low energy reserves represents a risk factor for poor infant growth outcomes.

Use of lipid-based nutrient supplements by HIV-infected Malawian women during lactation has no effect on infant growth from 0 to 24 weeks.

The Breastfeeding, Antiretrovirals, and Nutrition Study evaluated the effect of daily consumption of lipid-based nutrient supplements (LNS) by 2121 lactating, HIV-infected mothers on the growth of their exclusively breast-fed, HIV-uninfected infants from 0 to 24 wk. The study had a 2 × 3 factorial design. Malawian mothers with CD4(+) ≥250 cells/mm(3), hemoglobin ≥70 g/L, and BMI ≥17 kg/m(2) were randomized within 36 h of delivery to receive either no LNS or 140 g/d of LNS to meet lactation energy and protein needs, and mother-infant pairs were assigned to maternal antiretroviral drugs (ARV), infant ARV, or no ARV. Sex-stratified, longitudinal, random effects models were used to estimate the effect of the 6 study arms on infant weight, length, and BMI. Logistic regression models were used to calculate the odds of growth faltering [decline in weight-for-age Z-score (WAZ) or length-for-age Z-score (LAZ) >0.67] using the control arm as the reference. Although some differences between study arms emerged with increasing infant age in boys, there were no consistent effects of the maternal supplement across the 3 growth outcomes in longitudinal models. At the ages where differences were observed, the effects on weight and BMI were quite small (≤200 g and ≤0.4 kg/m(2)) and unlikely to be of clinical importance. Overall, 21 and 34% of infants faltered in WAZ and LAZ, respectively. Maternal supplementation did not reduce the odds of infant weight or length faltering from 0 to 24 wk in any arm. These results indicate that blanket supplementation of HIV-infected lactating women may have little impact on infant growth.

Treatment outcomes and costs of a simplified antiretroviral treatment strategy for hepatitis C among Hepatitis C Virus and Human Immuno deficiency Virus co-infected patients in Ukraine.

Background and Aim: To demonstrate the use of a standard dose of ledipasvir (LDV) and sofosbuvir (SOF), with or without ribavirin, to treat hepatitis C and hepatitis C/HIV co-infection in Ukraine. Methods: Eligible HCV viraemic adults from two clinics in Kyiv were treated with LDV/SOF with or without weight-based ribavirin for 12 weeks. Clinical assessments were performed at screening and at week 24, and as needed; treatment was dispensed every 4 weeks. The primary outcome was sustained virologic response (SVR) 12 weeks after treatment, with analysis by intention to treat. Cost per patient was estimated in USD (2018) over the 24-week period. Results: Of 868 patients included in the study and initiated on therapy, 482 (55.5%) were co-infected with HIV. The common genotypes were 1 (74.1%) and 3 (22%). Overall, SVR was achieved in 831 of the 868 patients (95.7%). SVR in patients with hepatitis C alone and hepatitis C/HIV co-infection was 98.4% and 93.6%, respectively. Adverse events were infrequent and usually mild. Using generic medication, cost per patient was estimated at US$680. Conclusion: A standard dose of LDV and SOF, with ribavirin as per protocol, resulted in good outcomes for patients with both hepatitis C alone and co-infected with hepatitis C/HIV. Program costs in Ukraine were modest using generic medication.

Predictors of Perinatal HIV Transmission Among Women Without Prior Antiretroviral Therapy in a Resource-Limited Setting: The Breastfeeding, Antiretrovirals and Nutrition Study.

BACKGROUND: To investigate potential risk factors for perinatal (intrauterine and intrapartum) mother-to-child transmission (MTCT) of HIV in women unexposed to antiretroviral therapy (ART) during pregnancy. METHODS: We compared factors according to perinatal MTCT outcome among 2275 ART-naive (until the onset of labor) HIV-infected women in the Breastfeeding, Antiretrovirals and Nutrition study (2004-2010) in Lilongwe, Malawi. Factors included HIV viral load during pregnancy, food security, demographic characteristics, hematologic and blood chemistry measures, medical history and physical factors. Associations with perinatal MTCT and interactions with maternal viral load were assessed using simple and multivariable logistic regression. RESULTS: There were 119 (115 intrauterine and 4 intrapartum) cases of perinatal MTCT, only one to a mother with <1000 HIV copies/mL. Maternal viral loads >10,000 copies/mL were common (63.1%). Lower maternal viral load (<1000 copies/mL and 1000.1-10,000 copies/mL) was associated with reduced odds of perinatal MTCT [adjusted odds ratio (aOR), 0.1; 95% confidence interval (CI): 0.01-0.4 and aOR, 0.2; 95% CI: 0.1-0.4, respectively), compared with maternal viral load >10,000 copies/mL. Low CD4+ T cell count (≤350 cells/µL) was only associated with perinatal MTCT in unadjusted models. Food shortage (aOR, 1.8; 95% CI: 1.2-2.6), sexually transmitted infection (STI) (past year; aOR, 1.9; 95% CI: 1.0-3.7), histories of herpes zoster (aOR, 3.0; 95% CI: 1.6-5.6) and tuberculosis (aOR, 2.5; 95% CI: 1.1-5.7) were associated with increased odds of perinatal MTCT. CONCLUSIONS: These findings confirm that lowering maternal HIV viral load is most important in preventing perinatal MTCT and support efforts to address food shortage, STI and tuberculosis prevention, while informing programs to improve ART coverage in pregnancy.

Antiretroviral Drug Concentrations in Breastmilk, Maternal HIV Viral Load, and HIV Transmission to the Infant: Results From the BAN Study.

BACKGROUND: Concentration of antiretroviral (ARV) drug found in plasma, and amounts of drug excreted into breastmilk, may affect HIV viral load and potentially perinatal HIV transmission. METHODS: In this cohort study with 2-phase sampling, we included mothers randomized to postpartum maternal ARVs or daily infant nevirapine during 28 weeks of breastfeeding in the Breastfeeding, Antiretrovirals, and Nutrition study. Among these, we included all mothers who transmitted HIV to their infants between 2 and 28 weeks and 15% of mothers who did not (n = 27 and 227, respectively). Spearman correlation coefficients (r) were used to assess the correlation between maternal plasma and breastmilk ARV concentration. Associations between the median effective drug concentration (EC50) and detectable maternal viral load (plasma: >40 copies per milliliter, breastmilk: >56 copies per milliliter) were assessed using mixed-effects models. Cox models were used to estimate the association between maternal or infant plasma drug concentration and breastmilk HIV transmission from 2 to 28 weeks. RESULTS: All ARV compounds exhibited substantial correlations between maternal plasma and breastmilk concentrations (r: 0.85-0.98, P-value <0.0001). Having plasma drug concentration above the EC50 was associated with lower odds of having detectable HIV RNA [maternal plasma odds ratio (OR) 0.64, 95% confidence interval (CI): 0.45 to 0.91; breastmilk OR 0.22, 95% CI: 0.14 to 0.35] and a reduced rate of breastmilk HIV transmission (hazard ratio 0.40, 95% CI: 0.18 to 0.93). Having breastmilk drug concentration above the EC50 was also associated with lower odds of having detectable maternal HIV RNA (plasma OR 0.62, 95% CI: 0.45 to 0.85; breastmilk OR 0.42, 95% CI: 0.29 to 0.59). CONCLUSIONS: Ensuring adequate drug concentration is important for viral suppression and preventing breastmilk HIV transmission.

Maternal and neonatal outcomes among women with HIV infection and their infants in Malawi.

OBJECTIVE: To describe maternal and neonatal morbidity and mortality among women with HIV infection and their infants. METHODS: A secondary analysis was undertaken of data obtained in the BAN Study, a trial of postnatal antiretrovirals among pregnant women with HIV infection enrolled in 2004-2010. Mothers and infants had 13 scheduled visits through 48 weeks of follow-up. Serious maternal morbidity and mortality were examined at delivery (n=2791), from delivery to 6 weeks later (n=2369) and from 7 to 48 weeks (n=1980). Neonatal morbidity and mortality were examined (n=2685). RESULTS: Of 2791 deliveries, 169 (6.1%) were by cesarean (153 emergency). Compared with women with vaginal delivery, those with cesarean delivery had lower prenatal HIV viral loads (P=0.016) and increased odds of pre-eclampsia/eclampsia (odds ratio [OR] 10.8, 95% CI 4.4-26.8). Women with cesarean delivery also had increased odds of serious infection with 14 days of delivery (OR 3.0, 95% CI 1.3-7.4) and severe anemia (grade 3 or 4) by 6 weeks (OR 6.7, 95% CI 2.3-19.1). Infants born by cesarean had increased odds of a low 5-minute Apgar score (OR 8.1, 95% CI 3.5-18.6) and admission to an intensive care unit (OR 5.4, 95% CI 3.7-7.8). CONCLUSION: Odds of serious maternal and neonatal morbidity were higher after cesarean than vaginal delivery, despite lower maternal viral loads.

Effects of concurrent exposure to antiretrovirals and cotrimoxazole prophylaxis among HIV-exposed, uninfected infants.

BACKGROUND: Given the potential of cotrimoxazole preventive therapy (CPT) to prevent bacterial and malarial infections in HIV-exposed, uninfected (HEU) infants, it is important to evaluate the effects of its concurrent use with antiretroviral agents that have overlapping toxicity profiles. METHODS: We used data from the Breastfeeding, Antiretrovirals, and Nutrition study (2004-2010) to evaluate the association of CPT and antiretrovirals with hematologic measures (hemoglobin, neutrophil, and alanine aminotransferase levels) from 6 to 48 weeks of age in 2006 HEU infants in Lilongwe, Malawi. Hazards of severe outcomes (anemia, neutropenia, and elevated alanine aminotransferase), as defined by the National Institutes of Health, were compared using Cox regression models, according to time-varying CPT (implemented June 2006), antiretroviral treatment arm (maternal triple antiretroviral, infant nevirapine, or none during 6 months of breastfeeding), and their interaction. The effects of these treatments on hemoglobin, neutrophil, and alanine aminotransferase levels were assessed using linear mixed models. RESULTS: In Cox models, CPT was associated with an increase in severe neutropenia [hazard ratio 1.97 (1.01, 3.86)] and a decrease in severe anemia (hazard ratio 0.65 (0.48, 0.88)]. Interactions between CPT and antiretroviral treatment were not significant. By 36 weeks, there was a significant association of CPT with increased hemoglobin levels regardless of antiretroviral drug exposure. CONCLUSIONS: In addition to expected associations with increased hazard of severe neutropenia and decreased neutrophil count, CPT was associated with reduced hazard of severe anemia and higher infant blood hemoglobin. This provides further support for CPT use in HEU infants in malaria-endemic resource-limited settings where anemia is prevalent.

Maternal but Not Infant Anti-HIV-1 Neutralizing Antibody Response Associates with Enhanced Transmission and Infant Morbidity.

A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) (n = 42), compared to those that eventually acquired infection (n = 21), did not possess higher nAb responses against heterologous envelopes (P = 0.46) or their mothers' variants (P = 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (P = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (P = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (P = 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity.IMPORTANCE Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby.