Clinical predictors of low CD4 count among HIV-infected pulmonary tuberculosis clients: A health facility-based survey

Objectives. The study aimed to determine the clinical and laboratory predictors of a low CD4+ cell count

Identification and Visualization of CD8+ T Cell Mediated IFN-γ Signaling in Target Cells during an Antiviral Immune Response in the Brain

CD8+ T cells infiltrate the brain during an anti-viral immune response. Within the brain CD8+ T cells recognize cells expressing target antigens, become activated, and secrete IFNγ. However, there are no methods to recognize individual cells that respond to IFNγ. Using a model that studies the effects of the systemic anti-adenoviral immune response upon brain cells infected with an adenoviral vector in mice, we describe a method that identifies individual cells that respond to IFNγ. To identify individual mouse brain cells that respond to IFNγ we constructed a series of adenoviral vectors that contain a transcriptional response element that is selectively activated by IFNγ signaling, the gamma-activated site (GAS) promoter element; the GAS element drives expression of a transgene, Cre recombinase (Ad-GAS-Cre). Upon binding of IFNγ to its receptor, the intracellular signaling cascade activates the GAS promoter, which drives expression of the transgene Cre recombinase. We demonstrate that upon activation of a systemic immune response against adenovirus, CD8+ T cells infiltrate the brain, interact with target cells, and cause an increase in the number of cells expressing Cre recombinase. This method can be used to identify, study, and eventually determine the long term fate of infected brain cells that are specifically targeted by IFNγ. The significance of this method is that it will allow to characterize the networks in the brain that respond to the specific secretion of IFNγ by anti-viral CD8+ T cells that infiltrate the brain. This will allow novel insights into the cellular and molecular responses underlying brain immune responses

AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study.

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results

The HIV-1 Subtype C Epidemic in South America Is Linked to the United Kingdom

Background: The global spread of HIV-1 has been accompanied by the emergence of genetically distinct viral strains. Over the past two decades subtype C viruses, which predominate in Southern and Eastern Africa, have spread rapidly throughout parts of South America. Phylogenetic studies indicate that subtype C viruses were introduced to South America through a single founder event that occurred in Southern Brazil. However, the external route via which subtype C viruses spread to the South American continent has remained unclear.Methodology/Principal Findings: We used automated genotyping to screen 8,309 HIV-1 subtype C pol gene sequences sampled within the UK for isolates genetically linked to the subtype C epidemic in South America. Maximum likelihood and Bayesian approaches were used to explore the phylogenetic relationships between 54 sequences identified in this screen, and a set of globally sampled subtype C reference sequences. Phylogenetic trees disclosed a robustly supported relationship between sequences from Brazil, the UK and East Africa. A monophyletic cluster comprised exclusively of sequences from the UK and Brazil was identified and dated to approximately the early 1980s using a Bayesian coalescent-based method. A sub-cluster of 27 sequences isolated from homosexual men of UK origin was also identified and dated to the early 1990s.Conclusions: Phylogenetic, demographic and temporal data support the conclusion that the UK was a crucial staging post in the spread of subtype C from East Africa to South America. This unexpected finding demonstrates the role of diffuse international networks in the global spread of HIV-1 infection, and the utility of globally sampled viral sequence data in revealing these networks. Additionally, we show that subtype C viruses are spreading within the UK amongst men who have sex with men

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95$1237 (1181–1293) in the control group. The incremental cost-effectiveness ratio was $128 (59–257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to$80 (15–275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to$121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research

Renal dysfunction among anti-retroviral therapy naive HIV infected patients in Zimbabwe

No Abstract

Hepatitis B and C infection at a large public sector hospital clinic: is it a burden?

Background: Co-infections have become significant causes of morbidity and mortality in Human Immunodeficiency Virus (HIV) infected people. Due to shared routes of transmission, co-infection of HIV with Hepatitis B (HBV) and/or Hepatitis C (HCV) should be expected. In Zimbabwe, screening for both viruses in HIV infected people prior to treatment is not routinely practised despite the World Health Organisation (WHO) guidelines (2013) prioritising treatment where these co-infections exist.Objective: To determine the prevalence of HBV and HCV infection in HIV infected adults at a public sector HIV clinic in Zimbabwe and to determine risk factors associated with these infections.Design and Setting: An analytical cross-sectional survey carried out among systematically randomly sampled HIV infected patients coming for treatment between March and July 2012 at Parirenyatwa Hospital Opportunistic Infection Clinic.Materials and Methods: Blood samples were tested for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibodies (anti-HCV). Demographic data and exposure to risk factors were collected.Results: 228 antiretroviral therapy (ART) naive adults were enrolled. 7.9% (18/228) were HBsAg positive and 0.9% (2/228) were anti-HCV positive. None of the participants were infected with both viruses. Conclusions: The prevalence of HBV has not changed during this HIV era and there is no significant HCV infection in this public sector clinic which serves quite a large sector of the population that lives in Harare, Zimbabwe. Based on these results, there is no need for HCV screening but HBV screening prior to ART initiation may be required

Hepatitis B and C infection at a large public sector hospital clinic: Is it a burden?

Background:  Co-infections have become significant causes of morbidity and mortality in Human Immunodeficiency Virus (HIV) infected people. Due to shared routes of transmission, co-infection of HIV with Hepatitis B (HBV) and/or Hepatitis C (HCV) should be expected. In Zimbabwe, screening for both viruses in HIV infected people prior to treatment is not routinely practised despite the World Health Organisation (WHO) guidelines (2013) prioritising treatment where these co-infections exist.Objective: To determine the prevalence of HBV and HCV infection in HIV infected adults at a public sector HIV clinic in Zimbabwe and to determine risk factors associated with these infections.  Design and Setting:  An analytical cross-sectional survey carried out among systematically randomly sampled HIV infected patients coming for treatment between March and July 2012 at Parirenyatwa Hospital Opportunistic Infection Clinic.Materials and Methods:  Blood samples were tested for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibodies (anti-HCV).  Demographic data and exposure to risk factors were collected. Results: 228 antiretroviral therapy (ART) naive adults were enrolled. 7.9% (18/228) were HBsAg positive and 0.9% (2/228) were anti-HCV positive. None of the participants were infected with both viruses.Conclusions: The prevalence of HBV has not changed during this HIV era and there is no significant HCV infection in this public sector clinic which serves quite a large sector of the population that lives in Harare, Zimbabwe. Based on these results, there is no need for HCV screening but HBV screening prior to ART initiation may be required