Perceptions of HIV cure and willingness to participate in HIV cure-related trials among people enrolled in the Netherlands cohort study on acute HIV infection

BACKGROUND: People who initiate antiretroviral therapy (ART) during acute HIV infection are potential candidates for HIV cure-related clinical trials, as early ART reduces the size of the HIV reservoir. These trials, which may include ART interruption (ATI), might involve potential risks. We explored knowledge and perception of HIV cure and willingness to participate in cure-related trials among participants of the Netherlands Cohort Study on Acute HIV infection (NOVA study), who started antiretroviral therapy immediately after diagnosis of acute HIV infection. METHODS: We conducted 20 in-depth qualitative interviews with NOVA study participants between October–December 2018. Data were analyzed thematically, using inductive and iterative coding techniques. FINDINGS: Most participants had limited knowledge of HIV cure and understood HIV cure as complete eradication of HIV from their bodies. HIV cure was considered important to most participants, mostly due to the stigma surrounding HIV. More than half would consider undergoing brief ATI during trial participation, but only one person considered extended ATI. Viral rebound and increased infectiousness during ATI were perceived as large concerns. Participants remained hopeful of being cured during trial participation, even though they were informed that no personal medical benefit was to be expected. INTERPRETATION: Our results highlight the need for thorough informed consent procedures with assessment of comprehension and exploration of personal motives prior to enrollment in cure-related trials. Researchers might need to moderate their expectations about how many participants will enroll in a trial with extended ATI

Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency

A leading pharmacological strategy toward HIV cure requires "shock" or activation of HIV gene expression in latently infected cells with latency reversal agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs, we used fungal secondary metabolites as a source of bioactive molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the positive transcription elongation factor b (P-TEFb) inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex, to be significantly reduced upon GTX treatment of CD4+ T cells. GTX directly disrupted 7SK snRNP by targeting La-related protein 7 (LARP7), releasing active P-TEFb, which phosphorylated RNA polymerase II (Pol II) C-terminal domain (CTD), inducing HIV transcription

Growth and welfare in mixed health system financing with physician dual practice in a developing economy: a case of Indonesia

Based on Indonesia’s hybrid BPJS Kesehatan health system, we analyze for welfare-optimal government financing strategy in an economy with a mixed health system using an endogenous growth framework with physician dual practice. We find the model solution to produce two vastly different regimes in terms of policy implications: a “high” public-sector congestion regime as in the benchmark case of Indonesia, and a “low” public-sector congestion, high capacity regime. In the former, welfare-optimal health financing strategy appears to be promoting private health service. In contrast, in the low-congestion, high capacity regime, a welfare-optimal strategy is to do the opposite of increasing government physician wage at the expense of private health subsidy. These results highlight the importance of developing a benchmarking system that measures the actual degree of congestion faced by the public health service in a developing economy, as it ultimately would influence the optimal health financing strategy to be pursued

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study

Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per mu L). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Copyright (C) The TenoRes Study Group. Open Access article distributed under the terms of CC BY

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study

Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per mu L). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Copyright (C) The TenoRes Study Group. Open Access article distributed under the terms of CC BY

Why don't some women attend antenatal and postnatal care services?: a qualitative study of community members' perspectives in Garut, Sukabumi and Ciamis districts of West Java Province, Indonesia

<p>Abstract</p> <p>Background</p> <p>Antenatal, delivery and postnatal care services are amongst the recommended interventions aimed at preventing maternal and newborn deaths worldwide. West Java is one of the provinces of Java Island in Indonesia with a high proportion of home deliveries, a low attendance of four antenatal services and a low postnatal care uptake. This paper aims to explore community members' perspectives on antenatal and postnatal care services, including reasons for using or not using these services, the services received during antenatal and postnatal care, and cultural practices during antenatal and postnatal periods in Garut, Sukabumi and Ciamis districts of West Java province.</p> <p>Methods</p> <p>A qualitative study was conducted from March to July 2009 in six villages in three districts of West Java province. Twenty focus group discussions (FGDs) and 165 in-depth interviews were carried out involving a total of 295 respondents. The guidelines for FGDs and in-depth interviews included the topics of community experiences with antenatal and postnatal care services, reasons for not attending the services, and cultural practices during antenatal and postnatal periods.</p> <p>Results</p> <p>Our study found that the main reason women attended antenatal and postnatal care services was to ensure the safe health of both mother and infant. Financial difficulty emerged as the major issue among women who did not fulfil the minimum requirements of four antenatal care services or two postnatal care services within the first month after delivery. This was related to the cost of health services, transportation costs, or both. In remote areas, the limited availability of health services was also a problem, especially if the village midwife frequently travelled out of the village. The distances from health facilities, in addition to poor road conditions were major concerns, particularly for those living in remote areas. Lack of community awareness about the importance of these services was also found, as some community members perceived health services to be necessary only if obstetric complications occurred. The services of traditional birth attendants for antenatal, delivery, and postnatal care were widely used, and their roles in maternal and child care were considered vital by some community members.</p> <p>Conclusions</p> <p>It is important that public health strategies take into account the availability, affordability and accessibility of health services. Poverty alleviation strategies will help financially deprived communities to use antenatal and postnatal health services. This study also demonstrated the importance of health promotion programs for increasing community awareness about the necessity of antenatal and postnatal services.</p

Tracing of Lateral Pterygoid Muscle-Related Neurons in the Trigeminal Brainstem Nuclei in the Rat

Retrograde transport of fluorescent tracers (diamidino yellow and true blue) was used to study the arrangement of brainstem neurons innervating the lateral pterygoid muscle in the rat. The lateral pterygoid motoneurons were located in the dorsolateral (jaw-closing) part of the trigeminal motor nucleus with clear somatotopy in the caudal part of the nucleus. No muscle-related neurons were present in the mesencephalic trigeminal nucleus. Histological examination of serial sections of lateral pterygoid muscles confirms the notion that, at least in the rat, this muscle is devoid of muscle spindles

Organization of neuronal clusters in the mesencephalic trigeminal nucleus of the rat:Fluorescent tracing of temporalis and masseteric primary afferents

The organization of neuronal clusters in the rat mesencephalic trigeminal nucleus (Mes V) was analysed using fluorescent tracing techniques. Simultaneous injections of fluorescent compounds (True blue and Diamidino yellow) were made unilaterally in the masseter and temporalis muscle, or in the masseteric and temporalis nerve. Examination of labeled neurons in frozen brainstem sections showed that (1) the arrangement of temporalis and masseteric primary afferent neurons in the mesencephalic trigeminal nucleus is not somatotopic; (2) primary afferent neurons of both muscles are located at all rostrocaudal levels; and (3) clustering of temporalis, of temporalis and masseteric, and of masseretic afferent neurons occurs at all levels throughout the nucleus

Afferent Projections to the Mesencephalic Trigeminal Nucleus in the Rat

The anatomical pathways from the parvocellular reticular formation and medulla oblongata to the mesencephalic trigeminal nucleus (Mes V) were investigated in the rat by means of the anterograde tracer Phaseolus vulgaris leukoagglutinin. P. vulgaris was injected into the rostral ventromedial medulla, rostral and caudal ventrolateral medulla, the parvocellular reticular formation and surrounding regions. Rostral medullary regions and the parvocellular reticular formation projected to Mes V although the bilaterality, extent and density of the projections originating in these reticular structures showed clear variations. In experiments in which dorsolateral reticular areas were involved, we found the projections to the bilateral trigeminal nuclei to be most prominent. More caudal areas, including the spinal trigeminal nucleus caudalis, showed no projections to Mes V. The present experiments show, for the first time, the existence of ipsilateral and crossed projections from the reticular formation to the Mes V. These pathways are possibly involved in direct modulation of trigeminal reflexes