Tenofovir for prevention of mother to child transmission of hepatitis B in migrant women in a resource-limited setting on the Thailand-Myanmar border: a commentary on challenges of implementation.

BACKGROUND: The aim of this manuscript is to highlight challenges in the implementation of maternal tenofovir disoproxil fumarate (tenofovir) for prevention of mother to child transmission (PMTCT) of hepatitis B virus (HBV) in resource limited setting. Current preventive strategies in resource-limited settings fail mainly due to prohibitive costs of hepatitis B immunoglobulin (HBIG) and a high proportion of homebirths, meaning both HBIG and hepatitis B birth dose vaccine are not given. A new strategy for PMTCT without the necessity of HBIG, could be daily tenofovir commenced early in gestation. Implementation challenges to early tenofovir for PMTCT can provide insight to elimination strategies of HBV as the burden of disease is high in resource-limited settings. METHODS: Challenges encountered during implementation of a study of tenofovir for PMTCT before 20 weeks gestation in rural and resource-limited areas on the Thailand-Myanmar border were identified informally from trial study logbooks and formally from comments from patients and staff at monthly visits. ClinicalTrials.gov Identifier: NCT02995005. MAIN BODY: During implementation 171 pregnant women were hepatitis B surface antigen (HBsAg) positive by point of-care test over 19 months (May-2018 until Dec-2019). In this resource-limited setting where historically no clinic has provided tenofovir for PMTCT of HBV, information provided by staff resulted in a high uptake of study screening (95.5% (84/88) when offered to pregnant women. False positive point-of-care rapid tests hinder a test and treat policy for HBV and development of improved rapid tests that include HBeAg and/or HBV DNA would increase efficiency. Integrated care of HBV to antenatal care, transport assistance and local agreements to facilitate access, could increase healthcare at this critical stage of the life course. As safe storage of medication in households in resource-limited setting may not be ideal, interactive counseling about this must be a routine part of care. CONCLUSION: Despite challenges, results from the study to date suggest tenofovir can be offered to HBV-infected women in resource-limited settings before 20 weeks gestation with a high uptake of screening, high drug accountability and follow-up, with provision of transportation support. This commentary has highlighted practical implementation issues with suggestions for strategies that support the objective of PMTCT and the World Health Organization goal of HBV elimination by 2030.

Knowledge regarding hepatitis B mother-to-child transmission among healthcare workers in South China.

To determine the knowledge regarding hepatitis B virus (HBV) mother-to-child transmission (MTCT) and its prevention and treatment among healthcare workers (HCWs) in Guangdong Province, China, an HBV endemic area. An HBV knowledge questionnaire was administered to 900 HCWs from the 3rd Affiliated Hospital of Sun Yat-Sen University and 2 rural hospitals in Guangdong Province. The 27 items in the questionnaire fell into 3 sections: HBV MTCT general knowledge, respondents' practices of preventing HBV MTCT and awareness of the resources of preventing HBV MTCT. The data collected were coded and analysed using SPSS software version 20. In total, 503 of 900 HCWs responded to the survey (response rate: 55.9%). Eighty-four individuals responded correctly to all of the knowledge questions: 58 were doctors, and 26 were nurses (P < .05). Doctors more often performed practices than nurses (t = 3.591, P < .01). Participants from the infectious disease department demonstrated a significantly higher proportion of correct answers and resource utilization than other specialties (χ2  = 14.052, 7.998, P < .01). In terms of the average knowledge score, t test or ANOVA showed that there were significant differences between the specialty groups (t = 3.110, P < .01), hospital level groups (t = 2.337, P < .05) and age groups (F = 3.020, P < .05). Respondents' initiative increased with hospital level and age (t = 2.993, 7.493, P < .01). A considerable percentage of HCWs has misconceptions about HBV MTCT. Healthcare workers, in particular nurses, those working in noninfectious disease departments or township hospitals and younger medical staff, lack systematic and comprehensive knowledge about HBV MTCT and are in urgent need of HBV-related training.

Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.

Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.

A syringe exchange programme in prison as prevention strategy against HIV infection and hepatitis B and C in Berlin, Germany.

In two prisons in Berlin, Germany, provision of sterile injection equipment for injecting drug users (IDUs) started in 1998. To assess the programme's impact, the frequency of injecting drug use and syringe sharing, and the incidence of HIV, HBV, and HCV infection were determined in a follow-up study. Of all IDUs (n=174), 75% continued to inject. After the project start the level of syringe sharing declined from 71% during a 4-month period of previous imprisonment to 11% during the first 4 months of follow-up, and to virtually zero thereafter. Baseline seroprevalences for HIV, HBV, and HCV were 18, 53, and 82%. HIV and HCV seroprevalence at baseline was significantly associated with drug injection in prison prior to the project start. No HIV and HBV seroconversions, but four HCV seroconversions occurred. The provision of syringes for IDUs in appropriate prison settings may contribute to a substantial reduction of syringe sharing. However, the prevention of HCV infection requires additional strategies.

Effect of isomalt consumption on faecal microflora and colonic metabolism in healthy volunteers.

Due to its low digestibility in the small intestine, a major fraction of the polyol isomalt reaches the colon. However, little is known about effects on the intestinal microflora. During two 4-week periods in a double-blind, placebo-controlled, cross-over design, nineteen healthy volunteers consumed a controlled basal diet enriched with either 30 g isomalt or 30 g sucrose daily. Stools were collected at the end of each test phase and various microbiological and luminal markers were analysed. Fermentation characteristics of isomalt were also investigated in vitro. Microbiological analyses of faecal samples indicated a shift of the gut flora towards an increase of bifidobacteria following consumption of the isomalt diet compared with the sucrose diet (P<0.05). During the isomalt phase, the activity of bacterial beta-glucosidase decreased (P<0.05) whereas beta-glucuronidase, sulfatase, nitroreductase and urease remained unchanged. Faecal polyamines were not different between test periods with the exception of cadaverine, which showed a trend towards a lower concentration following isomalt (P=0.055). Faecal SCFA, lactate, bile acids, neutral sterols, N, NH3, phenol and p-cresol were not affected by isomalt consumption. In vitro, isomalt was metabolized in several bifidobacteria strains and yielded high butyrate concentrations. Isomalt, which is used widely as a low-glycaemic and low-energy sweetener, has to be considered a prebiotic carbohydrate that might contribute to a healthy luminal environment of the colonic mucosa.

Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86.

Although chloroquine (CQ) monotherapy is now generally inadequate for the treatment of Plasmodium falciparum malaria in northern Ghana--recently, 58% of 225 children failed treatment by day 14--use of the drug continues because of its low cost and wide availability. The risk factors associated with CQ-treatment failure in this region of Africa, including the T76 mutation in the chloroquine resistance transporter (pfcrt) gene and the Y86 mutation in the multidrug resistance (pfmdr1) gene of P. falciparum, have now been investigated, and genotype-failure indices (GFI) have been calculated. Treatment failure was found to be associated with young age, poor nutritional status, pfcrt T76 and pfmdr1 Y86, and early treatment failure (ETF) was also associated with high parasitaemia. The presence and concentration of 'residual' CQ in the blood of patients immediately before they were treated with CQ for the present study appeared to have no effect on outcome. Presence at recruitment of pfcrt T76 or pfmdr1 Y86 or both mutations increased the risk of treatment failure by 3.2-, 2.4- and 4.5-fold, and the risk of ETF by 9.8-, 2.7- and 10.2-fold, respectively. The pfcrt T76 GFI for clinical and all treatment failures were 2.8 and 1.4, respectively. These indices were relatively low in the younger children, those with malnutrition, and those with high parasitaemias when treated. Residual CQ did not affect the GFI substantially. Both pfcrt T76 and, to a lesser extent, pfmdr1 Y86 would be useful tools for the surveillance of CQ resistance in northern Ghana. In the current transition phase to alternative first-line treatment for P. falciparum malaria, it should be possible to provide estimates of the level of CQ resistance by monitoring the prevalences of these mutations.

Imported leishmaniasis in Germany 2001-2004: data of the SIMPID surveillance network.

Leishmaniasis is a rare, non-notifiable disease in Germany. Epidemiological and clinical data, therefore, are scarce. Most infections seen in Germany are contracted outside the country. The German surveillance network for imported infectious diseases (Surveillance Importierter Infektionen in Deutschland, or SIPMID) recorded 42 cases of imported leishmaniasis (16 visceral, 23 cutaneous, and 3 mucocutaneous) from January 2001 to June 2004. Although most infections were acquired in European Mediterranean countries, the risk of infection was highest for travelers to Latin America. HIV coinfection was observed significantly more often in patients with visceral leishmaniasis than in patients with cutaneous/mucocutaneous leishmaniasis (31 vs. 4%, p=0.02). The median time to a definitive diagnosis was 85 days in cases of visceral leishmaniasis and 61 days in cases of cutaneous/mucocutaneous leishmaniasis, reflecting the unfamiliarity of German physicians with leishmanial infections. Visceral leishmaniasis was treated most frequently with amphotericin B, whereas cutaneous/mucocutaneous leishmaniasis was treated with a variety of local and systemic therapies. The findings presented here should serve to increase awareness as well as improve clinical management of leishmaniasis in Germany.

Circulating concentrations of cardiac proteins in complicated and uncomplicated Plasmodium falciparum malaria.

In an unmatched case-control study of 63 non-immune European patients with uncomplicated (n = 52) and complicated (n = 11) falciparum malaria, serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin, troponin T and creatin kinase-muscle brain were compared. Elevated levels of NT-proBNP and H-FABP indicated myocardial impairment in complicated but not in uncomplicated falciparum malaria. The clinical impact of these findings remains to be evaluated. The pathophysiology of cardiac impairment in complicated falciparum malaria warrants further investigation.

Efficacy of chloroquine in the treatment of uncomplicated, Plasmodium falciparum malaria in northern Ghana.

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to growing malaria-attributable morbidity and mortality in sub-Saharan Africa. However, the extent and degree of such resistance vary considerably between endemic areas. Data on CQ resistance in northern Ghana are almost entirely lacking. The therapeutic efficacy of CQ in uncomplicated malaria was therefore assessed, in a standard, 14-day protocol, in 225 children aged <5 years in Tamale, in the Northern region of Ghana. Early treatment failure (ETF) was observed in 11% of the children and late treatment failure in 18%. High initial parasite density and young age were independent predictors for ETF. Resistant parasitological responses (RI-RIII) were seen in 57% of the cases that could be classified. More than half of these responses occurred in children fulfilling the criteria for adequate clinical response (ACR), indicating a considerable lack of agreement between parasitological and clinical outcome. During the follow-up period, haemoglobin levels increased by approximately 1g/dl not only in patients with ACR but also in those who experienced clinical failure more than 1 week post-treatment. As CQ-treatment failure occurred in >25% of the children and more than half of the parasitological responses indicated resistance, current recommendations for the treatment of uncomplicated malaria in young children in northern Ghana have to be reconsidered.

Renal dysfunction in children with uncomplicated, Plasmodium falciparum malaria in Tamale, Ghana.

In a study performed in Tamale, in the Northern region of Ghana, cystatin C, a new and sensitive indicator of the glomerular filtration rate (GFR), was used to estimate the frequency of renal dysfunction in 78 children with uncomplicated, Plasmodium falciparum malaria. The excretion in urine of albumin, immunoglobulin G and alpha1-microglobulin was also investigated. Plasma concentrations of cystatin C were found to be elevated in 17% of the children, indicating subclinical impairment of renal function. As most (85%) of the children had glomerular as well as tubular patterns of proteinuria, it appears that both glomerulonephritis and damage to tubular cells often occur in P. falciparum malaria.