Where are the pregnant and breastfeeding women in new pre-exposure prophylaxis trials? The imperative to overcome the evidence gap

Pregnant and breastfeeding populations are at substantial risk of acquiring HIV in some settings, yet are underrepresented in clinical trials of new pre-exposure prophylaxis (PrEP) agents. Several PrEP formulations are in development (eg, vaginal rings, long-acting injectables, and other modalities). Pregnant and breastfeeding populations are typically excluded from initial clinical trials. We identified 14 PrEP trials of novel agents in non-pregnant or non-breastfeeding populations, and six phase 1–3 trials and open label extensions among pregnant and breastfeeding populations, that are currently ongoing or complete. A framework shift is needed to consider the ethical costs of excluding pregnant and breastfeeding populations at risk for HIV in PrEP clinical trials and promote inclusion to maximise the benefits from PrEP tools in the pipeline. Research on new PrEP agents should include pregnant and breastfeeding populations to avoid delays in reaching those who could benefit from PrEP after efficacy is established.https://www.thelancet.com/journals/lanhiv/homehj2023Paediatrics and Child Healt

Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study.

INTRODUCTION In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants. METHODS All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval. RESULTS Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs. CONCLUSIONS ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding

RATIONAL ANTIRETROVIRAL DRUG USE IN PREGNANT AND POSTPARTUM WOMEN LIVING WITH HIV.

Effective antiretroviral therapy is critical during pregnancy for women living with HIV (WLHIV) for the health of both the mother and the fetus, but there are knowledge gaps in the pharmacology of new HIV drugs, physiologic changes affecting drug disposition, and safety in pregnancy that prevent efficient and effective deployment of our most promising new HIV drugs in pregnant women. The objective of this thesis is to advance our knowledge of the pharmacology and safety of several HIV drugs – darunavir (DRV)/ritonavir (RTV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF)--in pregnant and post-partum women, using tools such as non-compartmental pharmacokinetic analytic and pharmacometric (population pharmacokinetic modeling) approaches. Research goals include describing DRV, RTV and TDF pharmacokinetics (PK) in pregnancy, identifying predictive covariates for tenofovir disposition in pregnant women using TDF, and understanding the safety and efficacy of TDF and TAF use in pregnant WLHIV, with the overall goal of optimizing HIV therapeutics for pregnant WLHIV. The five-parts of this thesis are as follows: 1) Chapter 1 introduces HIV in pregnancy using data from the Pediatric AIDS Clinical Trials Group (PACTG 076), the first randomized clinical trial of zidovudine versus placebo during pregnancy, and then discussed physiologic changes during pregnancy that affect drug disposition; current state of research involving pregnant women; implications of excluding pregnant women from drug trials using cobicistat as an example; and ethical issues surrounding pharmacologic studies involving pregnant women. 2) Chapter 2 discussed findings from a non-compartmental PK study of darunavir-boosted-ritonavir; 3) Chapter 3 examined a population-PK study of tenofovir in pregnant and postpartum women living with HIV using TDF; 4) Chapter 4 explored the pharmacoepidemiology of TDF when compared to TAF in pregnant women living with HIV; 5) and Chapter 5 concludes this thesis. The major research questions of chapters 2 and 3 focus on understanding the effects of the physiologic changes during pregnancy on drug PK, and patient-specific factors that account for variability in drug disposition. Chapter 4 focuses on understanding the safety and efficacy of TDF and TAF use in pregnant women living with HIV and their fetuses

2016 Pipeline Report HIV and TB

HIV and TB: Drugs, Diagnostics, Vaccines, Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies in Developmen

Prevention of mother to child transmission of hepatitis B

Hepatitis B virus (HBV) is a major cause of morbidity and mortality worldwide with a high prevalence in resource limited settings (RLS) like the Thailand-Myanmar border (6.2%). In these settings the main route of transmission is from mother to child (MTCT). Chronic HBV infection can progress into liver failure, liver cirrhosis and liver cancer which lead to death in 25% of the perinatally infected patients. There is no curative treatment for HBV and the main target to stop the HBV epidemic is preventing MTCT. The current strategy for preventing MTCT is by vaccination, a birth dose vaccine followed by three additional vaccinations later in life, combined with the administration of hepatitis B immunoglobulins (HBIG) after birth. In RLS these strategies are challenging due to home deliveries, people living far away from clinics, absence of a cold chain and presence of out-of-pocket expenditure. Moreover, even with perfect administration of HBIG, birth dose and three vaccinations, MTCT can still occur in 8-32% of the cases. An additional way of preventing HBV transmission is by maternal treatment with Tenofovir Disoproxil Fumarate (TDF), that reduces the HBV DNA load to a minimum at the time of delivery. TDF after rapid diagnostic test is a cost-effective option in a RLS if given at the correct time and dosage. Focusing on the wellbeing of mothers and children would not only support HBV elimination but also contribute to strengthening maternal and child health and achieving the health component of the Sustainable Development Goals in the wider context

Informational materials: Dual prevention pill

Informational materials being used in a dual prevention pill study in South Africa

Clinical Relevance of Drug Interactions in People Living with Human Immunodeficiency Virus on Antiretroviral Therapy—Update 2022: Systematic Review

Background: The clinical outcomes of antiretroviral drugs may be modified through drug interactions; thus, it is important to update the drug interactions in people living with HIV (PLHIV). Aim: To update clinically relevant drug interactions in PLHIV on antiretroviral therapy with novel drug interactions published from 2017 to 2022. Methods: A systematic review in Medline/PubMed database from July 2017 to December 2022 using the Mesh terms antiretroviral agents and drug interactions or herb–drug interactions or food–drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full-text access were retrieved. The clinical relevance of drug interactions was grouped into five levels according to the gravity and probability of occurrence. Results: A total of 366 articles were identified, with 219 (including 87 citation lists) were included, which allowed for the identification of 471 drug interaction pairs; among them, 291 were systematically reported for the first time. In total 42 (14.4%) and 137 (47.1%) were level one and two, respectively, and 233 (80.1%) pairs were explained with the pharmacokinetic mechanism. Among these 291 pairs, protease inhibitors (PIs) and ritonavir/cobicistat-boosted PIs, as well as integrase strand transfer inhibitors (InSTIs), with 70 (24.1%) and 65 (22.3%) drug interaction pairs of levels one and two, respectively, were more frequent. Conclusions: In PLHIV on antiretroviral therapy, we identify 291 drug interaction pairs systematically reported for the first time, with 179 (61.5%) being assessed as clinically relevant (levels one and two). The pharmacokinetic mechanism was the most frequently identified. PIs, ritonavir/cobicistat-boosted PIs, and InSTIs were the antiretroviral groups with the highest number of clinically relevant drug interaction pairs (levels one and two).Committee for Development Research (CODI)Sustainability program (2018–2019), Universidad de Antioqui

Neuropsychiatric effects of tenofovir in comparison with other antiretroviral drugs.

Tenofovir is a widely used antiretroviral medication indicated to treat adults and children infected with HIV. Current guidelines for the management of HIV infection recommend tenofovir disoproxil fumarate (TDF) as a component of the preferred first-line combination antiretroviral therapy. The efficacy, tolerability, prolonged half-life allowing for once-daily administration, and availability as a component of several fixed-dose formulations make TDF an attractive choice for treatment-naive and treatment-experienced HIV-infected patients. TDF is also widely used as a component of postexposure prophylaxis in noninfected individuals. Most importantly, it has been recently approved for use as pre-exposure prophylaxis for noninfected adults and adolescents to reduce the risk of HIV transmission. With increasing use of TDF among adults and children, understanding of the potential for drug-associated side effects is important. This review focuses on the neuropsychiatric effects of tenofovir in adults and children with HIV infection in comparison with other antiretroviral drugs