Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants: study protocol for a phase I trial.

BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.

Resistance rates among antiretroviral regimens in pregnant people living with HIV.

OBJECTIVES: To update nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) resistance rates and describe the frequency of HIV subtypes in a cohort of pregnant people living with HIV (PPLH) at a national Prevention of Mother-To-Child HIV Transmission (PMTCT) centre. METHODS: We evaluated genotypic resistance among PPLH during prenatal care who were antiretroviral therapy-naïve or experienced. We determined mutations by the Surveillance of Drug Resistance Mutations (SDRM) dataset and also focused on studying participants with intermediate or high resistance defined through the Stanford score. RESULTS: From 2018 to 2021, 1170 PPLH received prenatal care at the centre and 550 were genotyped. Among the 295 SDRMs, with respect to NRTI resistance mutations, there were 27/295 (9.2%) M184V/I, 14/295 (4.7%) T215Y/C/D/E/F/V/I/S and 12/295 (4.1%) M41L. For NNRTI, there were 75/295 (25.4%) K103N, 18/295 (6.1%) M230L and 14/295 (4.7%) G190A/E/S mutations. For PI, the most frequent mutations were 13/295 (4.4%) V82A/S/F/T, 12/295 (4.1%) M46I/L and 10/295 (3.4%) D30N. Based on the Stanford score, 36/224 (16%) naïve participants had one or more antiretroviral resistance mutations, 81% of whom had NNRTI resistance. In the treatment-experience group, 108/326 (33%) had one or more mutations, 91% of whom had NNRTI resistance. The most frequent HIV subtype was B (82.5%). CONCLUSIONS: Our findings suggest that continuous surveys of HIV genotype appear to be important tools to map the distribution and evolution of HIV subtypes and resistance to provide information to support treatment policies. Furthermore, concerns about the use of rilpivirine-containing regimens underscore the importance of resistance surveillance.

Knowledge about vertical transmission of HIV and associated factors among women living with HIV or AIDS attending antiretroviral therapy clinic, Western Ethiopia.

BACKGROUND: The United Nations Program on HIV or AIDS has committed to eliminating the vertical transmission of human immunodeficiency virus. However, significant number of newborn and children are acquiring HIV every year. Therefore, the aim of this study was to assess knowledge of mother on vertical transmission of HIV and associated factors among non-pregnant women receiving antiretroviral therapy in the West Wollega, Western Ethiopia. METHODS: A facility-based cross-sectional study design was used on a sample of 422 non-pregnant women attending antiretroviral therapy clinic in West Wollega from 26 February to 26 March 2019. Systematic sampling was used to select the study participants. Pretested and structured interviewer-administered questionnaires and telephone interview were used to collect the data. Multivariable logistic regression model was used to identify factors associated with the knowledge of mother on vertical transmission of HIV. Odds ratio along with 95% confidence interval were estimated to measure the strength of the association. Level of statistical significance was declared at p-value less than 0.05. RESULT: Out of total participants, 94.1% (95% confidence interval: (91.7%, 96.2%)) of them were knowledgeable about vertical transmission of HIV. Urban resident (adjusted odds ratio: 2.36, 95% confidence interval: (1.27, 4.39)), primary school (adjusted odds ratio: 2.94, 95% confidence interval: (1.11, 7.83)), secondary school (adjusted odds ratio: 3.39, 95% confidence interval: (1.53, 7.55)), being on antiretroviral therapy for greater than 2 years (adjusted odds ratio: 2.67, 95% confidence interval: 1.02, 6.99)), and having child living with HIV (adjusted odds ratio: 1.54, 95% confidence interval: (1.07, 3 .83)) were significantly associated with the knowledge of mother on vertical transmission of HIV. CONCLUSION: The study indicated that 5.9% of the women lack knowledge about vertical transmission of HIV. This knowledge associated with sociodemographic factors, such as residence, educational status, experiences of having child living with HIV, and being on antiretroviral therapy for greater than 2 years. Thus, interventions toward the elimination of new newborn HIV infections should consider these factors.

Predictors of early childhood HIV testing among children of sex workers living with HIV in Cameroon.

BACKGROUND: Despite recent progress, there exist gaps in the prevention of vertical HIV transmission program access and uptake in Cameroon. Female sex workers (FSW), many of whom are mothers, are disproportionately affected by HIV and have specific barriers to HIV testing and treatment access. Testing for HIV-exposed infants is crucial in monitoring for incident infection and timely intervention. This study explores the level of early childhood testing and also associations between antenatal care (ANC) attendance and other factors and early childhood HIV testing among FSW in Cameroon. METHODS: FSW were recruited to participate in an integrated biobehavioral survey in Cameroon between December 2015 and October 2016. Women were included in these analyses if they were living with HIV and had at least one living child. Both univariate and multivariable logistic regression were used to look at predictors of a child being tested for HIV before age five. RESULTS: A total of 481/2255 FSW were eligible for these analyses as they were HIV seropositive and had at least one living child at the time of the study. Women included in these analyses had a median age of 35(IQR 30-41). Nearly 70% reported none of their children had been tested for HIV before age five (326/481), and 3.5%(17/481) reported one or more of their children had been diagnosed with HIV. ANC attendance (adjusted OR 2.12, 95% CI: [1.02, 4.55]), awareness of HIV status (aOR 3.70[2.30, 5.93]), pregnancy intentions (aOR 1.89[1.16, 3.08]), and higher education (aOR 2.17[1.01, 4.71]) were all independently associated with increased odds of women having a greater proportion of children tested for HIV before age five. Regional differences in early childhood testing were also observed. CONCLUSION: Vertical transmission of HIV remains a challenge in Cameroon, and HIV testing among children of FSW living with HIV was very low. ANC attendance and promotion of the mother's health were associated with increased child HIV testing. For women at high risk of HIV and for whom engagement in the health system is low, strategies to promote and ensure ANC attendance are essential for their health and the health of their children.

Maternal Influences on Access to and Use of Infant ARVs and HIV Health Services in Uganda.

Vertical transmission of HIV is responsible for about 14 % of new HIV cases reported each year in sub-Saharan Africa. Barriers that prevent women from accessing and using antiretroviral medications (ARVs) for themselves and their infants perpetuate the epidemic. To identify influences on access to and use of infant HIV health services, specifically nevirapine administration, we conducted a mixed methods study among HIV-positive women in Uganda. This included a cross-sectional survey (n = 384) and focus group discussions (n = 6, 5-9 participants each). Of the 384 women, 80 % gave nevirapine to their infants within 72 h of birth. Factors independently associated with nevirapine administration were lack of maternal adherence to ARVs (AOR 3.55, 95 % CI 1.36-9.26) and attending a support group (AOR 2.50, 95 % CI 1.06-5.83). Non-health facility births were inversely related to nevirapine use (AOR 0.02, 95 % CI 0.003-0.09). Focus group discussions identified four themes impacting access and use: attending a support group, health care worker attitudes, lack of partner support, and poor health messaging regarding ARVs. Improving health care worker messaging regarding ARVs and providing women with needed support to access and use infant ARV prophylaxis is critical to overcoming access barriers. Eliminating these barriers may prevent numerous HIV infections each year saving the lives of many HIV-exposed infants.

A comprehensive review of the barriers and promoters health workers experience in delivering prevention of vertical transmission of HIV services in sub-Saharan Africa.

Despite significant biomedical and policy advances, 199,000 infants and young children in sub-Saharan Africa (SSA) became infected with HIV in 2013, indicating challenges to implementation of these advances. To understand the nature of these challenges, we sought to (1) characterize the barriers and facilitators that health workers encountered delivering prevention of vertical transmission of HIV (PVT) services in SSA and (2) evaluate the use of theory to guide PVT service delivery. The PubMed and CINAHL databases were searched using keywords barriers, facilitators, HIV, prevention of vertical transmission of HIV, health workers, and their synonyms to identify relevant studies. Barriers and facilitators were coded at ecological levels according to the Determinants of Performance framework. Factors in this framework were then classified as affecting motivation, opportunity, or ability, per the Motivation-Opportunity-Ability (MOA) framework in order to evaluate domains of health worker performance within each ecological level. We found that the most frequently reported challenges occurred within the health facility level and spanned all three MOA domains. Barriers reported in 30% or more of studies from most proximal to distal included those affecting health worker motivation (stress, burnout, depression), patient opportunity (stigma), work opportunity (poor referral systems), health facility opportunity (overburdened workload, lack of supplies), and health facility ability (inadequate PVT training, inconsistent breastfeeding messages). Facilitators were reported in lower frequencies than barriers and tended to be resolutions to challenges (e.g., quality supervision, consistent supplies) or responses to an intervention (e.g., record systems and infrastructure improvements). The majority of studies did not use theory to guide study design or implementation. Interventions addressing health workers' multiple ecological levels of interactions, particularly the health facility, hold promise for far-reaching impact as distal factors influence more proximal factors. Incorporating theory that considers factors beyond the health worker will strengthen endeavors to mitigate barriers to PVT service delivery.

High rates of baseline antiretroviral resistance among HIV-infected pregnant women in an HIV referral centre in Rio de Janeiro, Brazil.

In order to understand antiretroviral resistance during pregnancy and its impact on HIV vertical transmission, we performed a cross-sectional analysis of 231 HIV-infected pregnant women who fulfilled Brazilian guidelines for antiretroviral testing and had antiretroviral genotypic testing performed between April 2010 and October 2012. At entry into prenatal care, the mean CD4 cell count for this cohort of patients was 406 cells/mm(3) (95% CI: 373-438 cells/mm(3)), while the mean HIV RNA was 24,394 copies/ml (95% CI: 18,275-30,513 copies/ml). Thirty-six women (16%) had detectable antiretroviral-resistant mutations. By 34 weeks gestation, 75% had achieved HIV RNA <400 copies/ml. Our logistic regression model showed the odds of harbouring antiretroviral-resistant virus with a baseline CD4 cell count of <200 cells/mm(3) was eight times that of subjects with CD4 cell counts >500 CD4 cells/mm(3) (95% CI 1.5-42.73). Six infants were HIV infected, four born to mothers with detectable viraemia at 34 weeks and two born to mothers who were lost to follow up. Antiretroviral resistance is common in prenatal care but did not increase vertical transmission if viral load was appropriately suppressed. Genotyping should be considered in Brazil in order to assist initiation of appropriate combination antiretroviral therapy during pregnancy to suppress viral load to avoid vertical transmission.

Análise do programa de prevenção da transmissão vertical do vírus HIV na ONG Associação Céu e Terras, Guiné - Bissau, 2007-2011 / Analysis of the Program for Prevention of Vertical Transmission of HIV virus in the NGO Associação Céu e Terras, Guinea - Bissau, 2007 - 2011

Introdução: Com o surgimento da epidemia da AIDS na década de 80, vários têm sido os desafios enfrentados pela sociedade, devido à rápida disseminação, em escala global. A epidemia acomete cerca de 34 milhões nos diversos continentes, e segundo a UNAIDS (2012), a maior parcela está em países em desenvolvimento. O continente africano, com mais de 800 milhões de habitantes, em 54 países, é o que mais tem sofrido os impactos da doença, apresentando a maior parcela de infectados pelo vírus HIV no mundo, com cerca de 23,5 milhões de infectados registrados. Assim como globalmente, a preocupação que tem suscitado debates é a crescente feminização dessa epidemia em Guiné-Bissau, aumentando as taxas de transmissão vertical do vírus HIV, que, segundo as últimas projeções do país (PEN III, 2012), o risco estimado foi de 8,9 por cento. O advento do antirretroviral (Zidovudina), em 1994, a partir da publicação do protocolo 076 da ACTG veio mudar o cenário da transmissão vertical. Em Guiné-Bissau, a chegada dos antirretrovirais, em 2006, constituiu uma nova fase na luta contra a disseminação do vírus, em particular, no âmbito da transmissão vertical, proporcionando melhor qualidade de vida e chances de uma criança nascer sem AIDS. A ONG Céu e Terras atua no país desde 2001, e, em julho de 2007, adotou o protocolo recomendado pela OMS: tríplice terapia e amamentação exclusiva, visando à redução da transmissão vertical. Objetivo - Analisar a atuação da ONG Associação Céu e Terras quanto à prevenção da transmissão vertical do vírus HIV no contexto da Guiné-Bissau, a partir da introdução do novo protocolo da tríplice terapia antirretroviral e amamentação exclusiva. Método - É um estudo descritivo de dados secundários de mães e de seus filhos, mães estas inscritas no programa da instituição (ONG) Associação Céu e Terras em Bissau, República da Guiné-Bissau, no período de julho de 2007 a junho de 2011...

Introduction: With the emergence of the AIDS epidemic in the decade of the eighties. Around the world, there are several challenges faced by society due to its rapid dissemination in global scale. The epidemic affects approximately 34 million people around the world, according to UNAIDS, the largest portion is observed in third world. The African continent with over 800 million inhabitants, which contains 54 countries, is what most has suffered the impact of the disease presenting the largest portion of HIV patients in the world, with about 23.5 million infected registered. As globally, the concern that has sparked debates is the increasing feminization of the virus in Guinea - Bissau, the country which consequently increased rates of vertical transmission of HIV, which according to recent projections, the risk is estimated at 8.9 percent (PEN III,2012). The advent of antiretroviral (zidovudine) in 1994, from the publication of 076 protocol of the ACTG come to change the scenario of vertical transmission. In Guinea-Bissau, the arrival of antiretrovirals in 2006, marked a new phase in the fight against the spread of the vírus particularly in the context of vertical transmission, providing more life quality and chances of a child born without AIDS. The NGO Associação Céu e Terras acts in the country since 2001, and in 2007 adopted the protocol recommended by WHO with triple therapy and exclusive breastfeeding, in order to reduce vertical transmission in the country. Objective - Analyze the performance of the NGO Associação Céu e Terras as the prevention of vertical HIV transmission in the context of Guinea-Bissau. Examine the proposal from the introduction of the new protocol of triple antiretroviral therapy, exclusive breastfeeding, 2007 2011...

Promoting safe infant feeding practices - the importance of structural, social and contextual factors in Southern Africa.

There has been significant progress towards the goal of eliminating vertical transmission of HIV by 2015. However, a question that remains is how we can most effectively prevent late postnatal transmission of HIV through infant feeding. Guidelines published by the World Health Organization in 2010 have been widely adopted. These guidelines place strong emphasis on exclusive breastfeeding, in some countries over-turning a prior emphasis on formula feeding. Where available, provision of antiretroviral treatment for HIV-positive mothers or prophylaxis for infants offers additional protection against vertical transmission through infant feeding. However, merely changing guidelines is not sufficient to change practice, particularly with regard to culturally sanctioned forms of feeding, such as mixed feeding. This commentary highlights structural, social and contextual barriers to effective implementation of the guidelines and suggests ways to address some of these barriers.