Evaluation of GeneXpert and advanced biological laboratories UltraGene HCV diagnostic detection and performance against Roche real time PCR in Myanmar.

BACKGROUND: Developing countries experience limited access to HCV laboratory tests for different reasons. Providing near to real-time HCV testing and results especially to at-risk populations including those in rural settings for timely initiation to treatment is key. Within a rural Myanmar setting, we compared HCV diagnostic detection and quantification of the GeneXpert, and Advanced Biological Laboratories UltraGene-HCV assays against the gold standard and reference method Roche real-time HCV in Myanmar. METHODS: Blood samples from 158 high-risk individuals were assessed using three different methods at baseline. Results were checked for normality and log transformed. Log differences and bias between methods were calculated and correlated. Pearson's correlation coefficient was used to determine the association of HCV viral loads across all methods. The level of agreement with the standard method (Roche real time HCV) was assessed using Bland-Altman analyses. RESULTS: There was a strong positive correlation coefficient between all three methods with GeneXpert and Roche having the strongest, r = 0.96, (p<0.001). Compared to Roche, ABL (mean difference, 95 % limits of agreement; -0.063 and -1.4 to 1.3 Log10IU/mL) and GeneXpert (mean difference, 95 % limits of agreement; -0.28 and -0.7 to 1.8 Log10IU/mL) showed a good level of agreement with the GeneXpert being slightly superior. CONCLUSION: We demonstrate the excellent performance and no-inferiority, in terms of levels of agreements of both GeneXpert and ABL compared to the Roche platform and supporting the use of the POC assays as alternative a cost-effective methods in HCV detection and diagnosis in developing and low resource settings countries.

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.

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.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

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

Prescription of Antibacterial Drugs for HIV-Exposed, Uninfected Infants, Malawi, 2004-2010.

Antimicrobial drug resistance is a serious health hazard driven by overuse. Administration of antimicrobial drugs to HIV-exposed, uninfected infants, a population that is growing and at high risk for infection, is poorly studied. We therefore analyzed factors associated with antibacterial drug administration to HIV-exposed, uninfected infants during their first year of life. Our study population was 2,152 HIV-exposed, uninfected infants enrolled in the Breastfeeding, Antiretrovirals and Nutrition study in Lilongwe, Malawi, during 2004-2010. All infants were breastfed through 28 weeks of age. Antibacterial drugs were prescribed frequently (to 80% of infants), and most (67%) of the 5,329 prescriptions were for respiratory indications. Most commonly prescribed were penicillins (43%) and sulfonamides (23%). Factors associated with lower hazard for antibacterial drug prescription included receipt of cotrimoxazole preventive therapy, receipt of antiretroviral drugs, and increased age. Thus, cotrimoxazole preventive therapy may lead to fewer prescriptions for antibacterial drugs for these infants.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa.

BACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).

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.

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.

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.

HIV Prevention Among Women Who Use Substances And Report Sex Work: Risk Groups Identified Among South African Women.

This cross-sectional study presents baseline data from women (n = 641) in a community-based randomized trial in Pretoria, South Africa. Women were eligible if they reported recent alcohol or other drug (AOD) use and condomless sex. Latent class analyses were conducted separately for those who reported sex work and those who did not. Among those who reported sex work, a Risky Sex class (n = 72, 28%) and Low Sexual Risk class (n = 190, 73%) emerged. Those in the Risky Sex class were more likely to report that their last episode of sexual intercourse was with their boyfriend (vs. a client/other partner) compared with the Low Sexual Risk class (p < 0.001). Among participants who did not report sex work, a Drug-Using, Violence-Exposed, and Impaired Sex class (n = 53; 14%) and Risky Sex and Moderate Drinking class (n = 326; 86%) emerged. The findings suggest that interventions for women who engage in sex work should promote safer sexual behavior and empowerment with main partners. Women who use AODs, experience physical or sexual violence, and have impaired sex may be a key population at risk for HIV and should be considered for tailored behavioral interventions in conjunction with South Africa's plan to disseminate HIV prevention methods to vulnerable women. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT01497405.

Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals.

Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers (n = 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.

Seek, test, treat: substance-using women in the HIV treatment cascade in South Africa.

BACKGROUND: Women in South Africa who use alcohol and other drugs face multiple barriers to HIV care. These barriers make it difficult for women to progress through each step in the HIV treatment cascade from diagnosis to treatment initiation and adherence. This paper examines correlates of HIV status, newly diagnosed HIV status, and use of antiretroviral therapy (ART). METHODS: Outreach workers recruited sexually active Black African women who used substances in Pretoria as part of a U.S. National Institutes of Health-funded geographically clustered randomized trial examining the effect of an intervention to reduce alcohol and drug use as well as sexual risk behaviors. To address the question of interest in the current investigation, cross-sectional baseline data were used. At study enrollment, all participants (N = 641) completed an interview, and underwent rapid HIV testing and biological drug screening. Those who tested positive for HIV and were eligible for ART were asked about their barriers to initiating or adhering to ART. Bivariate and multivariable logistic regression analyses were conducted to determine correlates of HIV status, newly diagnosed HIV, and ART use. RESULTS: At enrollment, 55% of participants tested positive for HIV, and 36% of these women were newly diagnosed. In multivariable analyses of the entire sample, women who had completed 10th grade were less likely to be living with HIV (OR 0.69; CI 0.48, 0.99) and those from the inner city were more likely to be living with HIV (OR 1.83; CI 1.26, 2.67). Among HIV-positive participants, women were less likely to be newly diagnosed if they had ever been in substance abuse treatment (OR 0.15; CI 0.03, 0.69) or used a condom at last sex (OR 0.58; CI 0.34, 0.98) and more likely to be newly diagnosed if they were physically assaulted in the past year (OR 1.97; CI 1.01, 3.84). Among women eligible for ART, fewer were likely to be on treatment (by self-report) if they had a positive urine test for opiates or cocaine (OR 0.27; CI 0.09, 0.80). CONCLUSIONS: These results, although cross-sectional, provide some guidance for provincial authorities to address barriers to HIV care for sexually active, substance-using vulnerable women in Pretoria. Targeting the inner city with prevention campaigns, expanding and improving substance abuse treatment programs, linking clients with simultaneous HIV testing and treatment, and targeting women who have experienced sexual assault and violence may help the government achieve the UNAIDS 90-90-90 treatment target. Clinical Trials.gov NCT01497405 registered on December 1, 2011.

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.

Effect of Postnatal HIV Treatment on Clinical Mastitis and Breast Inflammation in HIV-Infected Breast-feeding Women.

BACKGROUND: The relationship between mastitis and antiretroviral therapy among HIV-positive, breast-feeding women is unclear. METHODS: In the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, conducted in Lilongwe, Malawi, 2369 mother-infant pairs were randomized to a nutritional supplement group and to one of three treatment groups: maternal antiretroviral therapy (ART), infant nevirapine (NVP) or standard of care for 24 weeks of exclusive breast-feeding and 4 weeks of weaning. Among 1472 HIV-infected women who delivered live infants between 2004 and 2007, we estimated cumulative incidence functions and sub-distribution hazard ratios (HR) of mastitis or breast inflammation comparing women in maternal ART (n = 487) or infant nevirapine (n = 492) groups to the standard of care (n = 493). Nutritional supplement groups (743 took, 729 did not) were also compared. RESULTS: Through 28-weeks post-partum, 102 of 1472 women experienced at least one occurrence of mastitis or breast inflammation. The 28-week risk was higher for maternal ART (risk difference (RD) 4.5, 95% confidence interval (CI) 0.9, 8.1) and infant NVP (RD 3.6, 95% CI 0.3, 6.9) compared to standard of care. The hazard of late-appearing mastitis or breast inflammation (from week 5-28) was also higher for maternal ART (HR 6.7, 95% CI 2.0, 22.6) and infant NVP (HR 5.1, 95% CI 1.5, 17. 5) compared to the standard of care. CONCLUSIONS: Mastitis or breast inflammation while breast-feeding is a possible side effect for women taking prophylactic ART and women whose infants take NVP, warranting additional research in the context of postnatal HIV transmission.

HIV-infected Children in Malawi Have Decreased Performance on the 6-minute Walk Test With Preserved Cardiac Mechanics Regardless of Antiretroviral Treatment Status.

AIM: The aims of this study were to 1) determine if cardiac disease can be detected in HIV-infected children by strain imaging and 2) to evaluate differences in exercise performance between HIV-infected children on antiretroviral therapy (ART) and HIV-infected children not yet on ART and in HIV-uninfected children by 6-minute walk tests (6MWTs). METHODS: This cross-sectional study evaluated cardiac function by echocardiogram and exercise performance by 6MWT in HIV-infected and HIV-uninfected children 4-18 years of age in Lilongwe, Malawi. Analyses compared HIV uninfected, HIV infected not yet on ART, and HIV infected on ART. Comparisons used χ(2) test, t test, analysis of variance and multiple linear regression. RESULTS: No differences were found in ejection fraction, shortening fraction or strain in 73 children not yet on ART, 149 on ART and 77 HIV-uninfected controls. As viral load increased, children had worse circumferential strain. In addition, children receiving ART had better circumferential strain than those not yet on ART. Increased CD4 percentage was associated with better longitudinal strain and farther 6MWT distance. As longitudinal strain worsened, the 6MWT distance decreased. HIV-infected children not yet on ART walked a mean of 25.8 m less than HIV-uninfected children, and HIV-infected children on ART walked 25.9 m less (P = 0.015 comparing 3 groups). CONCLUSIONS: HIV-uninfected children performed better on the 6MWT than HIV-infected children. Lower viral load, being on ART, and higher CD4 percentage were associated with better strain measures. Better longitudinal strain was associated with a farther 6MWT distance. Overall, ejection fraction, shortening fraction and strain measures between groups were similar, so cardiac strain did not detect cardiac dysfunction in this young population.

Maternal and Breastmilk Viral Load: Impacts of Adherence on Peripartum HIV Infections Averted-The Breastfeeding, Antiretrovirals, and Nutrition Study.

BACKGROUND: Antiretroviral (ARV) interventions are used to reduce HIV viral replication and prevent mother-to-child transmission. Viral suppression relies on adherence to ARVs. METHODS: A 2-phase study was conducted using data from the Breastfeeding, Antiretrovirals, and Nutrition study. We included mothers randomized to 28 weeks of postpartum ARVs with ≥1 plasma or breastmilk specimen. All mothers who transmitted HIV to their infants from 2-28 weeks (n = 31) and 15% of mothers who did not (n = 232) were included. Adherence was measured by pill count [categorized as poor (0%-80%), partial (81%-98%), and near perfect (>98%)]. Associations between adherence and breastmilk RNA were assessed using mixed-effects models. Cox models were used to estimate associations between breastmilk RNA and HIV transmission. Using Monte Carlo simulation, we estimated the number of transmissions that would occur had everyone randomized to maternal ARVs been 90% and 100% adherent. RESULTS: Partial or near perfect ARV adherence significantly reduced the odds of having detectable (≥40 copies/mL) breastmilk RNA, compared with poor adherence (Odds Ratio (OR) 0.23, 95% CI: 0.08 to 0.67; OR 0.36, 95% CI: 0.16 to 0.81, respectively). Detectable breastmilk RNA was associated with increased breastmilk transmission compared with undetectable breastmilk RNA (hazard ratio 3.8, 95% CI: 1.2 to 12.1). All transmitting mothers had ≥1 plasma viral load specimen >100 copies per milliliter. An estimated similar number of transmissions would occur with 90% adherence compared with 100%. CONCLUSIONS: Helping patients adhere to ARVs throughout breastfeeding is important for realizing the full potential of recommended ARV interventions to prevent mother-to-child HIV transmission. Maintaining plasma viral load <100 copies per milliliter may prevent breastmilk transmission.

The National Institutes of Health Fogarty International Center Global Health Scholars and Fellows Program: Collaborating Across Five Consortia to Strengthen Research Training.

As demand for global health research training continues to grow, many universities are striving to meet the needs of trainees in a manner complementary to research priorities of the institutions hosting trainees, while also increasing capacity for conducting research. We provide an overview of the first 4 years of the Global Health Program for Fellows and Scholars, a collaboration of 20 U.S. universities and institutions spread across 36 low- and middle-income countries funded through the National Institutes of Health Fogarty International Center. We highlight many aspects of our program development that may be of interest to other multinational consortia developing global health research training programs.

Cytomegalovirus IgG Level and Avidity in Breastfeeding Infants of HIV-Infected Mothers in Malawi.

Cytomegalovirus (CMV) infection is common among infants of HIV-infected mothers in resource-limited settings. We examined the prevalence and timing of infant CMV infection during the first year of life using IgG antibody and avidity among HIV-exposed infants in Malawi and correlated the results with the presence of detectable CMV DNA in the blood. The Breastfeeding, Antiretrovirals and Nutrition (BAN) study randomized 2,369 mothers and their infants to maternal antiretrovirals, infant nevirapine, or neither for 28 weeks of breastfeeding, followed by weaning. Stored plasma specimens were tested for CMV IgG and antibody avidity from a random subset of infants who had been previously tested with blood CMV PCR and had available specimens at birth and at 24 and 48 weeks of age. Ninety-four of 127 infants (74.0%) tested at 24 weeks of age had CMV IgG of low or intermediate avidity, signifying primary CMV infections. An additional 22 infants (17.3%) had IgG of high avidity; 19 of them had CMV DNA detected in their blood, indicating infant infections. Taken together, these results show that the estimated prevalence of CMV infection at 24 weeks was 88.9%. By 48 weeks of age, 81.3% of infants had anti-CMV IgG; most of them (70.9%) had IgG of high avidity. The CMV serology and avidity testing, combined with the PCR results, confirmed a high rate of primary CMV infection by 6 months of life among breastfeeding infants of HIV-infected mothers. The CMV PCR in blood detected most, but not all, infant CMV infections.