The President's Emergency Plan for AIDS Relief and adult mortality: A replication study of HIV development assistance effects in Sub-Saharan African countries.

The US budget for global health funding, which was by far the largest of similar funding in the world, increased from US $1.3 billion in 2001 to more than US $10 billion in recent years. More than 54% of this funding was allocated to the Global Fund to Fight HIV/AIDS through the US President's Emergency Plan for AIDS Relief (PEPFAR) in Africa. However, recent studies indicate contradictory results regarding the effectiveness of PEPFAR. One by Bendavid, Holmes, Bhattacharya, and Miller shows positive effects of PEPFAR in reducing adult mortality in Africa, while another by Duber, Coates, Szekeras, Kaji, and Lewis finds that there are no significant differences in reducing adult mortality in countries that received PEPFAR funding vs countries that did not. Due to their potential impact on policy decisions regarding critical global health funding, we wanted to assess why the results are discrepant. To do this, we replicated the Bendavid study. The replication provides verification that the study replicable and that the analytic choices of the authors are robust to different assumptions or restrictions. This allows us to assess the different choices and data available to the two research groups and draw some conclusions about why the results may be different. Then, focusing on two of the prominently discrepant studies, i.e., the Bendavid study (1998-2008) and the Duber study (2000-2006), we establish why the two studies are in disagreement. We apply appropriate individual-level and country-level analytical methodology as used by Bendavid over the analytical time period used for the Duber study (2000-2006), which originally focused on nationally aggregated data and differed in some key focus countries. For our first objective, we replicated the original Bendavid study findings and our findings support their conclusion that between 1998-2008 all-cause mortality decreased significantly more (OR = 0.84, CI, 0.72-0.99) in countries that implemented PEPFAR. For our second objective (Bendavid's data and methodology applied to Duber's study period), we found reduction in all cause adult mortality to be borderline insignificant (OR = 0.87 CI, 0.75-1.01, p = 0.06), most possibly reflecting the abbreviated fewer number of events and sample size over a shorter period. Therefore, our overall analyses are consistent with the conclusion of positive impact of the PEPFAR program in reducing adult mortality. We believe that the discrepancy observed in the original studies mainly a reflection of shortcomings in the analytical approach necessitated by the Duber study's nationally aggregated dataset or "may reflect a lack of data quality" in the Duber study (Duber, et al. 2010).

Preventing HIV and HSV-2 through knowledge and attitudes: A replication study of a multi-component community-based intervention in Zimbabwe.

INTRODUCTION: Approximately two-thirds of HIV-infected individuals reside in sub-Saharan Africa. The region accounts for 68% of the new HIV infections occurring worldwide with almost one-half of these infections being among young adults aged 12-24 years. Cowan and colleagues conducted a community-based, multi-component HIV intervention aimed at youth in rural Zimbabwe. Despite some changes in knowledge and attitudes, the community-based intervention did not affect the prevalence of HIV or HSV-2. We selected this frequently cited study for replication since it incorporates individual-, community-, and structural- level intervention components that are often considered in global HIV/AIDS prevention programs. Additionally, the intervention could be easily scaled-up, which is especially important in the context of limited resources. Although this study indicated no intervention effects in reducing HIV, the authors acknowledged some key methodological challenges. Our replication analysis provided important insights regarding the impact of these challenges to the interpretation of the results of this study. METHODS: Our replication study focused on replicating Cowan's findings and assessing the robustness of Cowan's results to alternative analytical models based on their study design. We determined how out-migration occurring during Cowan's study may have affected the population characteristics, the intervention exposure level, and the study findings. While the original intervention targeted knowledge and attitudes as a mechanism to decrease HIV/HSV-2, the Cowan study evaluated the intervention effects on knowledge, attitudes, and prevalence of HIV or HSV-2 separately. To better identify the pathway describing the interrelationship among the intervention and knowledge, attitudes, and prevalence of HIV or HSV-2, we assessed whether increases in knowledge or attitudes were associated with decreased HIV or HSV-2 prevalence. RESULTS: We replicated the original findings with minor discrepancies during the pure replication. Our additional analyses revealed that the study population characteristics changed over time in ways that may have affected outcomes. These changes also affected the levels of intervention exposure, with 48.7% males and 75.5% females of the intervention group receiving low-level exposure. Both genders with higher level intervention exposure experienced higher increments in multiple knowledge, attitude, and sexual risk behavior outcomes. Unfortunately, these did not translate to a significant reduction in HIV or HSV-2 regardless of the level and combination of knowledge and attitude domains. However, males receiving high-level intervention exposure compared to control indicated significantly lower odds of having HIV or HSV-2 under a Bayesian modeling paradigm. CONCLUSIONS: Our findings suggest a more robust conclusion on the study intervention effects. Further study based on a design that more consistently maximizes the exposure level of the intervention is necessary and should ideally be an evaluated goal in similar studies. Evaluation of the intervention impact for key subgroups of the target population is important and would better advise the use and scale-up of the evaluated interventions in various contexts. Our observation of a consistent lack of relationship between knowledge/attitudes and HIV/HSV-2 suggests a need to explore and include relevant additional and or complementary interventions, e.g., promoting effective skills in reducing risky sexual behaviors and addressing cultural and structural bottlenecks that may reduce HIV/HSV-2 risk among youth.

Cash transfers and HIV/HSV-2 prevalence: A replication of a cluster randomized trial in Malawi.

INTRODUCTION: In this paper we perform a replication analysis of "Effect of a cash transfer programme for schooling on prevalence of HIV and herpes simplex type 2 in Malawi: a cluster randomised trial" by Sarah Baird and others published in "The Lancet" in 2012. The original study was a two-year cluster randomized intervention trial of never married girls aged 13-22 in Malawi. Enumeration areas were randomized to either an intervention involving cash transfer (conditional or unconditional of school enrollment) or control. The study included 1708 Malawian girls, who were enrolled at baseline and had biological testing for HIV and herpes simplex virus type 2 (HSV-2) at 18 months. The original findings showed that in the cohort of girls enrolled in school at baseline, the intervention had an effect on school enrollment, sexual outcomes, and HIV and HSV-2 prevalence. However, in the baseline school dropout cohort, the original study showed no intervention effect on HIV and HSV-2 prevalence. METHODS: We performed a replication of the study to investigate the consistency and robustness of key results reported. A pre-specified replication plan was approved and published online. Cleaned data was obtained from the original authors. A pure replication was conducted by reading the methods section and reproducing the results and tables found in the original paper. Robustness of the results were examined with alternative analysis methods in a measurement and estimation analysis (MEA) approach. A theory of change analysis was performed testing a causal pathway, the effect of intervention on HIV awareness, and whether the intervention effect depended on the wealth of the individual. RESULTS: The pure replication found that other than a few minor discrepancies, the original study was well replicated. However, the randomization and sampling weights could not be verified due to the lack of access to raw data and a detailed sample selection plan. Therefore, we are unable to determine how sampling influenced the results, which could be highly dependent on the sample. In MEA it was found that the intervention effect on HIV prevalence in the baseline schoolgirls cohort was somewhat sensitive to model choice, with a non-significant intervention effect for HIV depending on the statistical model used. The intervention effect on HSV-2 prevalence was more robust in terms of statistical significance, however, the odds ratios and confidence intervals differed from the original result by more than 10%. A theory of change analysis showed no effect of intervention on HIV awareness. In a causal pathway analysis, several variables were partial mediators, or potential mediators, indicating that the intervention could be working through its effect on school enrollment or selected sexual behaviors. CONCLUSIONS: The effect of intervention on HIV prevalence in the baseline schoolgirls was sensitive to the model choice; however, HSV-2 prevalence results were confirmed. We recommend that the results from the original published analysis indicating the impact of cash transfers on HIV prevalence be treated with caution.

Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients.

BACKGROUND: Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed. METHODS: PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched. RESULTS: A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0-16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively. CONCLUSIONS: The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.