Deciphering the Complex Distribution of Human Immunodeficiency Virus Type 1 Subtypes among Different Cohorts in Northern Tanzania.

Increased understanding of the genetic diversity of HIV-1 is challenging but important in the development of an effective vaccine. We aimed to describe the distribution of HIV-1 subtypes in northern Tanzania among women enrolled in studies preparing for HIV-1 prevention trials (hospitality facility-worker cohorts), and among men and women in an open cohort demographic surveillance system (Kisesa cohort). The polymerase encompassing partial reverse transcriptase was sequenced and phylogenetic analysis performed and subtype determined. Questionnaires documented demographic data. We examined factors associated with subtype using multinomial logistic regression, adjusted for study, age, and sex. Among 140 individuals (125 women and 15 men), subtype A1 predominated (54, 39%), followed by C (46, 33%), D (25, 18%) and unique recombinant forms (URFs) (15, 11%). There was weak evidence to suggest different subtype frequencies by study (for example, 18% URFs in the Kisesa cohort versus 5-9% in the hospitality facility-worker cohorts; adjusted relative-risk ratio (aRR) = 2.35 [95% CI 0.59,9.32]; global p = 0.09). Compared to men, women were less likely to have subtype D versus A (aRR = 0.12 [95% CI 0.02,0.76]; global p = 0.05). There was a trend to suggest lower relative risk of subtype D compared to A with older age (aRR = 0.44 [95% CI 0.23,0.85] per 10 years; global p = 0.05). We observed multiple subtypes, confirming the complex genetic diversity of HIV-1 strains circulating in northern Tanzania, and found some differences between cohorts and by age and sex. This has important implications for vaccine design and development, providing opportunity to determine vaccine efficacy in diverse HIV-1 strains

A systematic review of hepatitis B screening economic evaluations in low- and middle-income countries

Background: Chronic hepatitis B infection is a significant cause of morbidity and mortality worldwide; low- and middle-income countries (LMICs) are disproportionately affected. Economic evaluations are a useful decision tool to assess costs versus benefits of hepatitis B virus (HBV) screening. No published study reviewing economic evaluations of HBV screening in LMICs has been undertaken to date. Methods: The following databases were searched from inception to 21 April 2017: MEDLINE, PubMed, EMBASE, CINAHL Plus, the Cochrane Library, Global Health and the Cost-effectiveness Analysis Registry. English-language studies were included if they assessed the costs against the benefits of HBV screening in LMICs. PROSPERO registration: CRD42015024391, 20 July 2015. Results: Nine studies fulfilled the eligibility criteria. One study from Thailand indicated that adding hepatitis B immunoglobulin (HBIG) to HBV vaccination for newborns following screening of pregnant women might be cost-effective for some LMICs, though inadequate total funding and health infrastructure were likely to limit feasibility. A similar study from China indicated a benefit to cost ratio of 2.7 from selective HBIG administration to newborns, if benefits were considered from a societal perspective. Of the two studies assessing screening amongst the general adult population, a single cost-benefit analysis from China found a benefit to cost ratio (BCR) of 1.73 with vaccination guided by HBV screening of adults aged 21–39, compared to 1.42 with vaccination with no screening, both from a societal perspective. Community-based screening of adults in The Gambia with linkage to treatment yielded an incremental cost per disability-adjusted life year averted of $566 (in 2017 USD), less than two-times gross domestic product per capita for that country. Conclusions: Screening with ‘catch-up’ vaccination for younger adults yielded benefits above costs, and screening linked with treatment has shown cost-effectiveness that may be affordable for some LMICs. However, interpretation needs to account for total cost implications and further research in LMICs is warranted as there were only nine included studies and evidence from high-income countries is not always directly applicable

Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI

Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and costimulatory molecules, but relatively little is known about the biochemical pathways that regulate this function. We used the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucinal (PSI) to demonstrate that DC antigen presentation is NFkappaB dependent. As PSI is not a specific inhibitor of NFkappaB, we reproduced this finding using a very specific approach, namely adenoviral gene transfer of IkappaBalpha, the naturally occurring inhibitor of NFkappaB. The mechanism for this inhibition of DC antigen presentation involves at least three aspects of antigen presenting function: down-regulation of HLA class II, down-regulation of CD86, and inhibition of the immunostimulatory cytokines IL-12 and TNF-alpha. In the light of the marked down-regulation of antigen-presentation cell function, it was of interest to investigate what effects exposure to PSI-treated DC might have on T cell function. It was found that immunological tolerance was induced, as challenge of T cells previously exposed to PSI-treated DC, with normal DC from the same donor did not restore their response, despite the presence of viable T cells. There were also changes in T cell surface markers, with down-regulation of CD3 and CD25 expression, and inhibition of the production of Th1 cytokines like IL-2 and IFN-gamma. These results demonstrates that NFkappaB is an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this has implications for the development of therapeutic agents for use in multiple conditions, including transplantation, allergy and autoimmune diseases

Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study

Background Despite the introduction of immunisation for hepatitis B virus (HBV) in the 1990s, HBV-related morbidity and mortality remain high in sub-Saharan Africa. Identification and treatment of asymptomatic people with chronic HBV infection should reduce the disease burden. We therefore assessed the feasibility of a screen-and-treat programme for HBV infection in The Gambia, west Africa, and estimated the proportion of HBV-infected people who had significant liver disease in need of treatment. Methods Between Dec 7, 2011, and Jan 24, 2014, individuals living in randomly selected communities in western Gambia were offered hepatitis B surface antigen (HBsAg) screening via a point-of-care test. The test was also offered to potential blood donors attending the central hospital in the capital, Banjul. HBsAg-positive individuals were invited for a comprehensive liver assessment and were offered treatment according to international guidelines. We defined linkage to care as visiting the liver clinic at least once. Eligibility for treatment was judged in accordance with the 2012 European Association for the Study of the Liver guidelines. Findings HBsAg screening was accepted by 5980 (weighted estimate 68·9%, 95% CI 65·0–72·4) of 8170 adults from 27 rural and 27 urban communities and 5559 (81·4%, 80·4–82·3) of 6832 blood donors. HBsAg was detected in 495 (8·8%, 7·9–9·7) individuals in communities and 721 (13·0%, 12·1–13·9) blood donors. Prevalence was higher in men (239 [10·5%, 8·9–12·1] of 2328 men vs 256 [7·6%, 6·5–8·7] of 3652 women; p=0·004) and middle-aged participants. Linkage to care was high in the communities, with 402 (81·3%) of 495 HBsAg-positive individuals attending the clinic. However, only 300 (41·6%) of 721 HBsAg-positive people screened at the blood bank linked into care. Of those who attended the clinic, 18 (4·4%, 2·5–7·7) patients from the communities and 29 (9·7%, 6·8–13·6) from the blood bank were eligible for treatment. Male sex was strongly associated with treatment eligibility (odds ratio 4·35, 1·50–12·58; p=0·007). Interpretation HBV infection remains highly prevalent in The Gambia. The high coverage of community-based screening, good linkage into care, and the small proportion of HBsAg carriers who need treatment suggest that large-scale screening and treatment programmes are feasible in sub-Saharan Africa

Deciphering the Complex Distribution of Human Immunodeficiency Virus Type 1 Subtypes among Different Cohorts in Northern Tanzania

Background: Increased understanding of the genetic diversity of HIV-1 is challenging but important in the development of an effective vaccine. We aimed to describe the distribution of HIV-1 subtypes in northern Tanzania among women enrolled in studies preparing for HIV-1 prevention trials (hospitality facility-worker cohorts), and among men and women in an open cohort demographic surveillance system (Kisesa cohort). Methods: The polymerase encompassing partial reverse transcriptase was sequenced and phylogenetic analysis performed and subtype determined. Questionnaires documented demographic data. We examined factors associated with subtype using multinomial logistic regression, adjusted for study, age, and sex. Results: Among 140 individuals (125 women and 15 men), subtype A1 predominated (54, 39%), followed by C (46, 33%), D (25, 18%) and unique recombinant forms (URFs) (15, 11%). There was weak evidence to suggest different subtype frequencies by study (for example, 18 % URFs in the Kisesa cohort versus 5–9 % in the hospitality facility-worker cohorts; adjusted relative-risk ratio (aRR) = 2.35 [95 % CI 0.59,9.32]; global p = 0.09). Compared to men, women were less likely to have subtype D versus A (aRR = 0.12 [95 % CI 0.02,0.76]; global p = 0.05). There was a trend to suggest lower relative risk of subtype D compared to A with older age (aRR = 0.44 [95 % CI 0.23,0.85] per 10 years; global p = 0.05). Conclusions: We observed multiple subtypes, confirming the complex genetic diversity of HIV-1 strains circulating i