Unmet needs of high-risk mothers reduce success of antiretroviral treatment in HIV-infected infants

In the era of effective prevention of mother-to-child transmission of HIV, the same psychosocioeconomic factors that predispose to mother-to-child transmission also substantially increase the likelihood of antiretroviral therapy failure in infected infants. For HIV-infected infants to benefit from early infant diagnosis and treatment initiation, into which much funding and effort is now invested, it is vital that these unmet needs of high-risk mothers are urgently attended to. From an ongoing study of early infant diagnosis and treatment following in utero transmission in KwaZulu-Natal, South Africa, we describe four cases to highlight these challenges facing transmitting mothers that contribute to treatment failure in their infants

Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study

BACKGROUND: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. METHODS: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). FINDINGS: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. INTERPRETATION: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. FUNDING: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign

Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection

Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of>170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p=0.0005) and are more type I interferon-resistant (p=0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p=0.01) and more susceptible to HIV infection in vitro (p=0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p=0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males. Sex differences in the immune response to vaccines and infections have been well described in children and adults. Here the authors describe, in a cohort of 177 HIV-infected infants, innate immune sex differences in fetal life that increase female susceptibility to intrauterine HIV infection and increase the chances of subsequent HIV remission in infected males

Temporal association of rotavirus vaccination and genotype circulation in South Africa : observations from 2002 to 2014

BACKGROUND : Rotavirus vaccination has reduced diarrhoeal morbidity and mortality globally. The monovalent rotavirus vaccine was introduced into the public immunization program in South Africa (SA) in 2009 and led to approximately 50% reduction in rotavirus hospitalization in young children. The aim of this study was to investigate the rotavirus genotype distribution in SA before and after vaccine introduction. MATERIALS AND METHODS : In addition to pre-vaccine era surveillance conducted from 2002-2008 at Dr George Mukhari Hospital (DGM), rotavirus surveillance among children <5 years hospitalized for acute diarrhoea was established at seven sentinel sites in SA from April 2009 to December 2014. Stool specimens were screened by enzyme immunoassay and rotavirus positive specimens genotyped using standardised methods. RESULTS : At DGM, there was a significant decrease in G1 strains from pre-vaccine introduction (34%; 479/1418; 2002-2009) compared to post-vaccine introduction (22%; 37/170; 2010-2014; p for trend <0.001). Similarly, there was a significant increase in non-G1P[8] strains at this site (p for trend < 0.001). In expanded sentinel surveillance, when adjusted for age and site, the odds of rotavirus detection in hospitalized children with diarrhoea declined significantly from 2009 (46%; 423/917) to 2014 (22%; 205/939; p<0.001). The odds of G1 detection declined significantly from 2009 (53%; 224/421) to 2010-2011 (26%; 183/703; aOR=0.5; p<0.001) and 2012-2014 (9%; 80/905; aOR=0.1; p<0.001). Non-G1P[8] strains showed a significant increase from 2009 (33%; 139/421) to 2012-2014 (52%; 473/905; aOR=2.5; p<0.001). CONCLUSIONS : Rotavirus vaccination of children was associated with temporal changes in circulating genotypes. Despite these temporal changes in circulating genotypes, the overall reduction in rotavirus disease in South Africa remains significant.The expanded diarrhoea sentinel surveillance programme was funded by GlaxoSmithKline (E-Track 200238). NAP received personal fees from GlaxoSmithKline, Merck and Aspen Pharma. MJG received personal fees from GlaxoSmithKline and funding from PATH Vaccine Solutions. CC received personal fees from Sanofi Pasteur and Pfizer. SAM received personal fees from Pfizer and funding from PATH, Novartis and GlaxoSmithKline.http://www.elsevier.com/locate/vaccine2019-11-12hj2017Medical Virolog

Unmet needs of high-risk mothers reduce success of antiretroviral treatment in HIV-infected infants

In the era of effective prevention of mother-to-child transmission of HIV, the same psychosocioeconomic factors that predispose to mother-to-child transmission also substantially increase the likelihood of antiretroviral therapy failure in infected infants. For HIV-infected infants to benefit from early infant diagnosis and treatment initiation, into which much funding and effort is now invested, it is vital that these unmet needs of high-risk mothers are urgently attended to. From an ongoing study of early infant diagnosis and treatment following in utero transmission in KwaZulu-Natal, South Africa, we describe four cases to highlight these challenges facing transmitting mothers that contribute to treatment failure in their infants

NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis

Abstract Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (Ldha LysM−/− ) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD+ precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target