A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).

Implementation of a new program of gestational diabetes screening and management in Morocco: a qualitative exploration of health workers' perceptions.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with an increased risk for a future type 2 diabetes mellitus in women and their children. As linkage between maternal health and non-communicable diseases, antenatal care plays a key role in the primary and secondary prevention of GDM associated adverse outcomes. While implementing a locally adapted GDM screening and management approach through antenatal care services at the primary level of care, we assessed its acceptability by the implementing health care providers. METHODS: As part of a larger implementation effectiveness study assessing a decentralized gestational diabetes screening and management approach in the prefecture of Marrakech and the rural district of Al Haouz in Morocco, we conducted four focus group discussions with 29 primary health care providers and seven in-depth interviews with national and regional key informants. After transcription of data, we thematically analyzed the data using a combined deductive and inductive approach. RESULTS: The intervention of screening and managing women with gestational diabetes added value to existing antenatal care services but presented an additional workload for first line health care providers. An existing lack of knowledge about gestational diabetes in the community and among private health care physicians required of public providers to spend more time on counselling women. Nurses had to adapt recommendations on diet to the socio-economic context of patients. Despite the additional task, especially nurses and midwives felt motivated by their gained capacity to detect and manage gestational diabetes, and to take decisions on treatment and follow-up. CONCLUSIONS: Detection and initial management of gestational diabetes is an acceptable strategy to extend the antenatal care service offer in Morocco and to facilitate service access for affected pregnant women. Despite its additional workload, gestational diabetes management can contribute to the professional motivation of primary level health care providers. TRIAL REGISTRATION: clinicaltrials.gov; NCT02979756.

Towards achieving the fast-track targets and ending the epidemic of HIV/AIDS in Ethiopia: Successes and challenges.

BACKGROUND: Ethiopia has adopted the global plan to end the epidemic of HIV/AIDS. The aim of this study was to assess the progress made towards achieving this plan. METHODS: A review and analysis of national population-based surveys, surveillance, and routine programme data was executed. The data analysis was conducted using Excel 2016 and Stata 14 (StataCorp LP, College Station, TX, USA). RESULTS: Between 2011 and 2016, the number of HIV-related deaths dropped by 58%, while that of new HIV infections dropped by only 6%. Discriminatory attitudes declined significantly from 77.9% (95% confidence interval (CI) 77.3-78.4%) in 2011 to 41.5% (95% CI 40.6-42.4%) in 2016. Around 79% of adult people living with HIV (PLHIV) were aware of their HIV status; 90% of PLHIV who were aware of their HIV status were taking antiretroviral treatment (ART) and 88% of adult PLHIV on ART had viral suppression in 2016. The proportion of people aged 15-49 years who had ever been tested for HIV and had received results increased from 39.8% (95% CI 39.2-40.4%) in 2011 to 44.8% (95% CI 44.2-45.4%) in 2016. This proportion was very low among children below age 15 years at only 6.2% (95% CI 5.9-6.5%). Among regions, HIV testing coverage varied from 13% to 72%. Female sex workers had lower coverage for HIV testing (31%) and ART (70%) than the national average in the adult population. International funding for HIV dropped from more than US$ 1.3 billion in 2010-2012 to less than US$ 800 million in 2016-2018. CONCLUSIONS: Ethiopia is on track to achieve the targets for HIV testing, ART, viral suppression, and AIDS-related deaths, but not for reductions in new HIV infections, discriminatory attitudes, and equity. Ending the epidemic of HIV/AIDS requires a combined response, including prevention and treatment, tailored to key populations and locations, as well as increased funding.

Ebola virus disease outbreak in Guinea: what effects on prevention of mother-to-child transmission of HIV services?

BACKGROUND: An unprecedented epidemic of Ebola virus disease (EVD) affected Guinea in 2014 and 2015. It weakened the already fragile Guinean health system. This study aimed to assess the effects of the outbreak on Prevention of Mother-to-Child Transmission of HIV (PMTCT) services in 2014. METHODS: We conducted a cross-sectional retrospective study. Data was collected from 60 public health centers (30 in the EVD affected areas and 30 in the unaffected areas). The comparison of PMTCT indicators between the period before Ebola (2013) and during Ebola (2014) was done using the t- test for the means and the Chi-square test for the proportions. RESULTS: This study showed a substantial and significant reduction in the mean number of antenatal care visits (ANC) in the affected localities, 1617 ± 53 in 2013 versus 1065 ± 29 in 2014, p = 0.0004. This would represent 41% drop in health facilities' performance. On the other hand, in the unaffected localities, the fall was not significant. The same observations were made about the number of HIV tests performed for pregnant women and the number of HIV positive pregnant women initiating ARVs. The study also noted an increase in the proportion of women tested HIV+ but who did not receive ARVs (12% in 2013 versus 44% in 2014) and HIV+ pregnant women who delivered at home (18% in 2014 versus 7% in 2013). CONCLUSION: This study showed that PMTCT services, which are one of the key services to improve maternal and child health, were affected in Guinea during this Ebola outbreak in 2014 compared to 2013.

The uncertain future of lay counsellors: continuation of HIV services in Lesotho under pressure.

Between 2006 and 2011, when antiretroviral therapy (ART) was scaled up in a context of severe human resources shortages, transferring responsibility for elements in human immunodeficiency virus (HIV) care from conventional health workers to lay counsellors (LCs) contributed to increased uptake of HIV services in Lesotho. HIV tests rose from 79 394 in 2006 to 274 240 in 2011 and, in that same period, the number of people on ART increased from 17 352 to 83 624. However, since 2012, the jobs of LCs have been at risk because of financial and organizational challenges. We studied the role of LCs in HIV care in Lesotho between 2006 and 2013, and discuss potential consequences of losing this cadre. Methods included a case study of LCs in Lesotho based on: (1) review of LC-related health policy and planning documents, (2) HIV programme review and (3) workload analysis of LCs. LCs are trained to provide HIV testing and counselling (HTC) and ART adherence support. Funded by international donors, 487 LCs were deployed between 2006 and 2011. However, in 2012, the number of LCs decreased to 165 due to a decreasing donor funds, while administrative and fiscal barriers hampered absorption of LCs into the public health system. That same year, ART coverage decreased from 61% to 51% and facility-based HTC decreased by 15%, from 253 994 in 2011 to 215 042 tests in 2012. The workload analysis indicated that LCs work averagely 77 h per month, bringing considerable relief to the scarce professional health workforce. HIV statistics in Lesotho worsened dramatically in the recent era of reduced support to LCs. This suggests that in order to ensure access to HIV care in an under-resourced setting like Lesotho, a recognized and well-supported counsellor cadre is essential. The continued presence of LCs requires improved prioritization, with national and international support.

Beyond health aid: would an international equalization scheme for universal health coverage serve the international collective interest?

It has been argued that the international community is moving 'beyond aid'. International co-financing in the international collective interest is expected to replace altruistically motivated foreign aid. The World Health Organization promotes 'universal health coverage' as the overarching health goal for the next phase of the Millennium Development Goals. In order to provide a basic level of health care coverage, at least some countries will need foreign aid for decades to come. If international co-financing of global public goods is replacing foreign aid, is universal health coverage a hopeless endeavor? Or would universal health coverage somehow serve the international collective interest?Using the Sustainable Development Solutions Network proposal to finance universal health coverage as a test case, we examined the hypothesis that national social policies face the threat of a 'race to the bottom' due to global economic integration and that this threat could be mitigated through international social protection policies that include international cross-subsidies - a kind of 'equalization' at the international level.The evidence for the race to the bottom theory is inconclusive. We seem to be witnessing a 'convergence to the middle'. However, the 'middle' where 'convergence' of national social policies is likely to occur may not be high enough to keep income inequality in check.The implementation of the international equalization scheme proposed by the Sustainable Development Solutions Network would allow to ensure universal health coverage at a cost of US$55 in low income countries-the minimum cost estimated by the World Health Organization. The domestic efforts expected from low and middle countries are far more substantial than the international co-financing efforts expected from high income countries. This would contribute to 'convergence' of national social policies at a higher level. We therefore submit that the proposed international equalization scheme should not be considered as foreign aid, but rather as an international collective effort to protect and promote national social policy in times of global economic integration: thus serving the international collective interest.

The HIV/AIDS epidemic in sub-Saharan Africa: thinking ahead on programmatic tasks and related operational research.

Until now, we have all been desperately trying to run behind the HIV/AIDS epidemic and catch up with it, but despite all our efforts, the epidemic remains well ahead of us. In 2010, the antiretroviral treatment (ART) gap was about 60%, AIDS-related deaths were almost two million a year, and on top of these figures, for every one person started on ART, there were two new HIV infections. What is needed to change this situation is to think ahead of the epidemic in terms of the programmatic tasks we will be faced with and try to act boldly in trying to implement those tasks. From a programmatic perspective, we: a) highlight what needs to fundamentally change in our thinking and overall approach to the epidemic; and b) outline a number of key task areas for implementation and related operational research.