Spillover HIV prevention effects of a cash transfer trial in East Zimbabwe: evidence from a cluster-randomised trial and general-population survey

Background Benefits of cash transfers (CTs) for HIV prevention have been demonstrated largely in purposively designed trials, commonly focusing on young women. It is less clear if CT interventions not designed for HIV prevention can have HIV-specific effects, including adverse effects. The cluster-randomised Manicaland Cash Transfer Trial (2010–11) evaluated effects of CTs on children’s (2–17 years) development in eastern Zimbabwe. We evaluated whether this CT intervention with no HIV-specific objectives had unintended HIV prevention spillover effects (externalities). Methods Data on 2909 individuals (15–54 years) living in trial households were taken from a general-population survey, conducted simultaneously in the same communities as the Manicaland Trial. Average treatment effects (ATEs) of CTs on sexual behaviour (any recent sex, condom use, multiple partners) and secondary outcomes (mental distress, school enrolment, and alcohol/cigarette/drug consumption) were estimated using mixed-effects logistic regressions (random effects for study site and intervention cluster), by sex and age group (15–29; 30–54 years). Outcomes were also evaluated with a larger synthetic comparison group created through propensity score matching. Results CTs did not affect sexual debut but reduced having any recent sex (past 30 days) among young males (ATE: − 11.7 percentage points [PP] [95% confidence interval: -26.0PP, 2.61PP]) and females (− 5.68PP [− 15.7PP, 4.34PP]), with similar but less uncertain estimates when compared against the synthetic comparison group (males: -9.68PP [− 13.1PP, − 6.30PP]; females: -8.77PP [− 16.3PP, − 1.23PP]). There were no effects among older individuals. Young (but not older) males receiving CTs reported increased multiple partnerships (8.49PP [− 5.40PP, 22.4PP]; synthetic comparison: 10.3PP (1.27PP, 19.2PP). No impact on alcohol, cigarette, or drug consumption was found. There are indications that CTs reduced psychological distress among young people, although impacts were small. CTs increased school enrolment in males (11.5PP [3.05PP, 19.9PP]). Analyses with the synthetic comparison group (but not the original control group) further indicated increased school enrolment among females (5.50PP [1.62PP, 9.37PP]) and condom use among younger and older women receiving CTs (9.38PP [5.90PP, 12.9PP]; 5.95PP [1.46PP, 10.4PP]). Conclusions Non-HIV-prevention CT interventions can have HIV prevention outcomes, including reduced sexual activity among young people and increased multiple partnerships among young men. No effects on sexual debut or alcohol, cigarette, or drug consumption were observed. A broad approach is necessary to evaluate CT interventions to capture unintended outcomes, particularly in economic evaluations. Trial registration ClinicalTrials.gov, NCT00966849. Registered August 27, 2009.

Genes, Cells, and MiRNAs

Novel methods to treat HF include gene, cell and microRNA delivery. There have been few gene therapy trials in HF. The CUPID I and II trials with AAV1.SERCA2a showed unconvincing results. The STOP-HF trial using direct intra-myocardial injection of a non-integrating plasmid vector carrying stromal cell-derived factor-1 showed no clinical effects and the AC6 gene transfer trial used IC infusion of escalating doses of Ad5.hAC6 was similarly negative. Despite high hopes stem cell trials to date in HF have not shown convincing clinical benefits. More recent clinical trials in this area have investigated the injection of cell stimulating paracrine factors (peptides, small molecules, hormone-like molecules) without actual cell delivery. Micro-RNA’s (miRNAs) are small non-coding RNA strands, comprising 19-25 nucleotides, that have a distinct signalling role and a various patterns of expression in ischaemic myocardium, hypertrophy, cardiomyopathies, and overt HF. They act at the post-transcriptional regulation level. Numerous novel miRNAs have been discovered, and their in-depth role has been characterised. miRNAs can serve as therapeutic substances or therapeutic targets in a range of cardiovascular diseases. Clinical trials are likely in the near future.

Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders

Hematopoietic stem cell (HSC)–targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of β-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for β-thalassemia has begun in France, and one patient with transfusion-dependent HbE/β-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34+ cells genetically modified with a β-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.