Laura Skrip

Effect of Ebola Progression on Transmission and Control in Liberia

BACKGROUND The Ebola outbreak that is sweeping across West Africa is the largest, most volatile, and deadliest Ebola epidemic ever recorded. Liberia is the most profoundly affected country, with more than 3500 infections and 2000 deaths recorded in the past 3 months. OBJECTIVE To evaluate the contribution of disease progression and case fatality on transmission and to examine the potential for targeted interventions to eliminate the disease. DESIGN Stochastic transmission model that integrates epidemiologic and clinical data on incidence and case fatality, daily viral load among survivors and nonsurvivors evaluated on the basis of the 2000-2001 outbreak in Uganda, and primary data on contacts of patients with Ebola in Liberia. SETTING Montserrado County, Liberia, July to September 2014. MEASUREMENTS Ebola incidence and case-fatality records from 2014 Liberian Ministry of Health and Social Welfare. RESULTS The average number of secondary infections generated throughout the entire infectious period of a single infected case, R, was estimated as 1.73 (95% CI, 1.66 to 1.83). There was substantial stratification between survivors (RSurvivors), for whom the estimate was 0.66 (CI, 0.10 to 1.69), and nonsurvivors (RNonsurvivors), for whom the estimate was 2.36 (CI, 1.72 to 2.80). The nonsurvivors had the highest risk for transmitting the virus later in the course of disease progression. Consequently, the isolation of 75% of infected individuals in critical condition within 4 days from symptom onset has a high chance of eliminating the disease. LIMITATION Projections are based on the initial dynamics of the epidemic, which may change as the outbreak and interventions evolve. CONCLUSION These results underscore the importance of isolating the most severely ill patients with Ebola within the first few days of their symptomatic phase. PRIMARY FUNDING SOURCE National Institutes of Health.

Statistical power and validity of Ebola vaccine trials in Sierra Leone: a simulation study of trial design and analysis

BACKGROUND Safe and effective vaccines could help to end the ongoing Ebola virus disease epidemic in parts of west Africa, and mitigate future outbreaks of the virus. We assess the statistical validity and power of randomised controlled trial (RCT) and stepped-wedge cluster trial (SWCT) designs in Sierra Leone, where the incidence of Ebola virus disease is spatiotemporally heterogeneous, and is decreasing rapidly. METHODS We projected district-level Ebola virus disease incidence for the next 6 months, using a stochastic model fitted to data from Sierra Leone. We then simulated RCT and SWCT designs in trial populations comprising geographically distinct clusters at high risk, taking into account realistic logistical constraints, and both individual-level and cluster-level variations in risk. We assessed false-positive rates and power for parametric and non-parametric analyses of simulated trial data, across a range of vaccine efficacies and trial start dates. FINDINGS For an SWCT, regional variation in Ebola virus disease incidence trends produced increased false-positive rates (up to 0·15 at α=0·05) under standard statistical models, but not when analysed by a permutation test, whereas analyses of RCTs remained statistically valid under all models. With the assumption of a 6-month trial starting on Feb 18, 2015, we estimate the power to detect a 90% effective vaccine to be between 49% and 89% for an RCT, and between 6% and 26% for an SWCT, depending on the Ebola virus disease incidence within the trial population. We estimate that a 1-month delay in trial initiation will reduce the power of the RCT by 20% and that of the SWCT by 49%. INTERPRETATION Spatiotemporal variation in infection risk undermines the statistical power of the SWCT. This variation also undercuts the SWCTs expected ethical advantages over the RCT, because an RCT, but not an SWCT, can prioritise vaccination of high-risk clusters. FUNDING US National Institutes of Health, US National Science Foundation, and Canadian Institutes of Health Research.

National- and state-level impact and cost-effectiveness of nonavalent HPV vaccination in the United States

Significance Vaccination protects against human papilloma virus (HPV)-induced cervical cancer, but coverage varies markedly across the United States. The nonavalent vaccine produces greater health benefits than the bivalent and quadrivalent vaccines at a lower societal cost. Because of the impact of herd immunity, any expansion in coverage will be much more effective in reducing cancer incidence and healthcare costs if targeted in those states with the lowest coverage. Because of interstate migration and the long duration between HPV infection and resultant cervical cancer, much of the benefit of vaccination will be realized beyond a state’s borders. Therefore, both cervical cancer incidence and expenditure can be substantially reduced if the states coordinate policies to promote expansion of coverage, particularly for the new nonavalent vaccine. Every year in the United States more than 12,000 women are diagnosed with cervical cancer, a disease principally caused by human papillomavirus (HPV). Bivalent and quadrivalent HPV vaccines protect against 66% of HPV-associated cervical cancers, and a new nonavalent vaccine protects against an additional 15% of cervical cancers. However, vaccination policy varies across states, and migration between states interdependently dilutes state-specific vaccination policies. To quantify the economic and epidemiological impacts of switching to the nonavalent vaccine both for individual states and for the nation as a whole, we developed a model of HPV transmission and cervical cancer incidence that incorporates state-specific demographic dynamics, sexual behavior, and migratory patterns. At the national level, the nonavalent vaccine was shown to be cost-effective compared with the bivalent and quadrivalent vaccines at any coverage despite the greater per-dose cost of the new vaccine. Furthermore, the nonavalent vaccine remains cost-effective with up to an additional 40% coverage of the adolescent population, representing 80% of girls and 62% of boys. We find that expansion of coverage would have the greatest health impact in states with the lowest coverage because of the decreasing marginal returns of herd immunity. Our results show that if policies promoting nonavalent vaccine implementation and expansion of coverage are coordinated across multiple states, all states benefit both in health and in economic terms.

Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis.

Previous studies suggested that metformin is associated with decreased risk of cancer; however, results specifically addressing the potential association with prostate cancer were limited and contradictory. This study considers the association between metformin and the incidence, mortality and recurrence of prostate cancer by performing a meta‐analysis of observational studies.

Quantifying Poverty as a Driver of Ebola Transmission

Background Poverty has been implicated as a challenge in the control of the current Ebola outbreak in West Africa. Although disparities between affected countries have been appreciated, disparities within West African countries have not been investigated as drivers of Ebola transmission. To quantify the role that poverty plays in the transmission of Ebola, we analyzed heterogeneity of Ebola incidence and transmission factors among over 300 communities, categorized by socioeconomic status (SES), within Montserrado County, Liberia. Methodology/Principal Findings We evaluated 4,437 Ebola cases reported between February 28, 2014 and December 1, 2014 for Montserrado County to determine SES-stratified temporal trends and drivers of Ebola transmission. A dataset including dates of symptom onset, hospitalization, and death, and specified community of residence was used to stratify cases into high, middle and low SES. Additionally, information about 9,129 contacts was provided for a subset of 1,585 traced individuals. To evaluate transmission within and across socioeconomic subpopulations, as well as over the trajectory of the outbreak, we analyzed these data with a time-dependent stochastic model. Cases in the most impoverished communities reported three more contacts on average than cases in high SES communities (p<0.001). Our transmission model shows that infected individuals from middle and low SES communities were associated with 1.5 (95% CI: 1.4–1.6) and 3.5 (95% CI: 3.1–3.9) times as many secondary cases as those from high SES communities, respectively. Furthermore, most of the spread of Ebola across Montserrado County originated from areas of lower SES. Conclusions/Significance Individuals from areas of poverty were associated with high rates of transmission and spread of Ebola to other regions. Thus, Ebola could most effectively be prevented or contained if disease interventions were targeted to areas of extreme poverty and funding was dedicated to development projects that meet basic needs.

Effectiveness of UNAIDS targets and HIV vaccination across 127 countries

Significance Despite extraordinary advances in the treatment of HIV, the global pandemic has yet to be reversed. We developed a mathematical model for 127 countries to evaluate Joint United Nations Program on HIV/AIDS (UNAIDS) targets for expanding diagnosis and treatment of the infected, and partially efficacious HIV vaccination. Under the current levels of diagnosis and treatment, we estimated 49 million new HIV cases globally from 2015 to 2035. Achieving the ambitious UNAIDS target is predicted to avert 25 million of these new infections, with an additional 6.3 million averted by the 2020 introduction of a 50%-efficacy vaccine. Our study provides country-specific impacts of a partially effective HIV vaccine and demonstrates its importance to the elimination of HIV transmission globally. The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035. Achieving the Joint United Nations Program on HIV/AIDS 95–95–95 target was estimated to avert 25 million [20M, 33M] of these new infections, and an additional 6.3 million [4.8M, 8.7M] reduction was projected with the 2020 introduction of a 50%-efficacy vaccine gradually scaled up to 70% coverage. This added benefit of prevention through vaccination motivates imminent and ongoing clinical trials of viable candidates to realize the goal of HIV control.

The Impact of Enhanced Screening and Treatment on Hepatitis C in the United States

BACKGROUND The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatitis C virus (HCV) is limited by low screening and treatment rates, particularly among people who inject drugs (PWIDs). METHODS To evaluate the levels of screening and treatment with interferon-free DAAs that are required to control HCV incidence and HCV-associated morbidity and mortality, we developed a transmission model, stratified by age and by injection drug use, and calibrated it to epidemiological data in the United States from 1992 to 2014. We quantified the impact of administration of DAAs at current and at enhanced screening and treatment rates, focusing on outcomes of HCV incidence, prevalence, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and mortality from 2015 to 2040. RESULTS Increasing annual treatment of patients 4-fold-from the approximately 100 000 treated historically to 400 000-is predicted to prevent 526 084 (95% confidence interval, 466 615-593 347) cases of cirrhosis and 256 315 (201 589-316 114) HCV-associated deaths. By simultaneously increasing treatment capacity and increasing the number of HCV infections diagnosed, total HCV prevalence could fall to as low as 305 599 (222 955-422 110) infections by 2040. Complete elimination of HCV transmission in the United States through treatment with DAAs would require nearly universal screening of PWIDs, with an annual treatment rate of at least 30%. CONCLUSIONS Interferon-free DAAs are projected to achieve marked reductions in HCV-associated morbidity and mortality. Aggressive expansion in HCV screening and treatment, particularly among PWIDs, would be required to eliminate HCV in the United States.

Impact of Schistosoma mansoni on Malaria Transmission in Sub-Saharan Africa

Background Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children. Methodology We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high-risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni–malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities. Principal Findings Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities. Conclusions/Significance Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also reduce malaria transmission and disease burden.

Interrupting Ebola Transmission in Liberia Through Community-Based Initiatives

On 6 March 2014, Ebola virus disease spread from Guinea to Liberia, sparking an unprecedented outbreak. At the peak of the epidemic in western Africa, Liberia was the most affected country (1). Despite its extraordinary resource constraintsper capita gross domestic product is much lower than that of Guinea or Sierra Leone (2)Liberias steep epidemic trajectory was reversed several weeks before that of those countries. This article details the community-based initiative (CBI) that was instrumental to the shift in transmission dynamics. In the design of public health strategies, organizational and cultural sensitivity, as well as an awareness of infrastructure constraints, are fundamental to promoting adherence to policy recommendations (3, 4). Inadequate consideration of these factors hindered the initial top-down Ebola response in western Africa. Slum and ethnic settlements tend to have cultures characterized by rituals of prevailing tribal groups and a strong sense of connectedness among persons who have lived together for decades. Externally led interventions, such as quarantine and body collection, that did not engage regarded community leaders led to distrust for and underuse of these interventions. In addition, the infrastructural constraints of these impoverished communities, including the lack of running water and overcrowding, made such recommendations as hand washing and isolation of the sick inapplicable (Table). Table. Community Reaction to Misalignment Between Cultural Practice and Public Health Policies In August 2014, unmitigated transmission in West Point, Monrovias largest slum, was recognized as a potentially insurmountable threat to disease containment. Here, we focus on the outbreak in West Point as a case study that can inform the future control of Ebola in the worlds most challenging settings. A Case Study: West Point The first suspected case in West Point was reported to the National Ebola Incident Management System on 6 August 2014. The slum was particularly vulnerable to intense transmission given the cramped conditions of more than 80000 persons living in less than a half square kilometer without municipal water or a sewage system and only 1 physician for the entire community (5). Poverty compounded the distrust of external authorities, including skepticism about whether the Ebola outbreak was real (6). Initially, no Ebola treatment unit facilities were available in West Point to isolate infected patients. A holding center was opened for interim isolation. When it began to receive patients from outside of West Point, unrest erupted over concern that disease was being imported into the community. On 18 August, the center was ransacked and contaminated materials were looted. To prevent the spread of Ebola, the government quarantined the entire slum on 20 August using police and military forces, leading to clashes with the community and the death of a boy shot in his legs. Members of the Ebola Incident Management System with ties to the local community recognized that a less-invasive approach would be needed to achieve acceptance of the interventions. Although West Point residents typically resist government policies, trust for community leaders is unwavering. Harnessing the cooperation of local leaders to build trust between the community and public health authorities was paramount to the successful control of Ebola. On 17 September, a district-wide program was piloted to enhance awareness of and participation in response efforts, with an external team of public health advisors providing guidance (Figure). Coordinators from the Ministry of Health identified districts with active Ebola transmission to engage with the CBI. Community, tribal, and religious leaders, as well as other stakeholders, were invited to an open meeting where they were encouraged to express their thoughts about the Ebola response and propose ways to facilitate public health efforts. The community then organized a team to comprehensively map the area to assess human resource requirements. Figure. Components of the CBI. CBI = community-based initiative. The community leaders who attended the initial meeting recruited community members for a 1-day training session on active surveillance. Each CBI-employed community member was assigned approximately 25 households for daily surveillance. At the training session, county-level CBI coordinators reviewed data collection forms with community members. Supervisors received and were trained to use a mobile telephone preloaded with a user-friendly application for submitting data in real time to inform rapid-response action by case investigation, contact tracing, burial, and ambulance teams. Trained community members collected forms each day that reported on the sick, dead, visitors, and other factors that influenced Ebola transmission in their communities. A hierarchical reporting and coordinating structure was executed, with the community members submitting these forms to their immediate supervisors, who sent aggregate data to the district-level supervisors. The United Nations Development Programme funded CBI training and employed community members and coordinators. Altogether, 6500 persons were employed and equipped for 6 months at a cost of approximately

Strategies to prevent future Ebola epidemics

65000 (U.S. dollars). Within 24 hours of launching the CBI in West Point, 42 persons with Ebola-like symptoms were identified and transported to Ebola treatment units. Furthermore, the CBI uncovered 34 deaths from suspected Ebola and several secret burials that had not been reported as a result of mistrust of authorities or concern about stigma. The CBI team and local leaders developed a procedure to deliver food and offer social support to make household-based quarantine of contacts feasible. Ultimately, the door-to-door assessments in West Point were accomplished by 152 active case finders, 15 psychosocial support workers, 8 supervisors, and 2 district leaders. After the success in West Point, the Liberian Ministry of Health commissioned a scale-up of the CBI to Ebola hotspots throughout Montserrado County. By 21 September, the CBI was deployed in 6 districts. The implementation of these initiatives substantially improved contact-tracing cooperation and adherence to case isolation. For cases in the districts where the CBI was being implemented, the average number of contacts reported increased from 7.6 to 9.9 and mean time from symptom onset to isolation decreased from 6.5 to 4.7 days. This decrease in duration until isolation is crucial to reduce transmission, because viral load and thus infectiousness of patients with Ebola increase substantially over the course of infection (7). Latest Outbreak In July 2015, a new outbreak emerged in Margibi County, Liberia, where a teenage boy with Ebola was misdiagnosed with malaria. Contact-tracing efforts and the CBI were deployed in parallel to follow known contacts and conduct community-driven surveillance, respectively. A CBI team of 75 community members visited 397 households in the vicinity, identifying 126 contacts who were followed for 21 days. This community mobilization curtailed transmission before any tertiary cases emerged. The success of this effort starkly contrasts with the spiraling epidemic observed a year before, fueled by a similar number of secondary cases before the CBI was initiated. Conclusion By engaging and empowering local communities, the CBI was instrumental to cooperation with contact tracing and accelerating case isolation. This strategy is both feasible and effective in the resource-constrained settings of many western African countries. Leaders of the Liberian CBI are currently advising the Sierra Leone Ministry of Health on the implementation of community-driven efforts to control its outbreak that has yet to be extinguished. More broadly, the momentum of community involvement spurred by the Ebola response provides an opportunity for sustained improvement in the public health infrastructure in Liberia and other western African countries.