Defining stopping criteria for ending randomized clinical trials that investigate the interruption of transmission of soil-transmitted helminths employing mass drug administration

Abstract

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage—indicated by mathematical models as necessary for breaking transmission—will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences measured at six months after the last round of MDA and the impact of MDA coverage levels were evaluated to see if the likelihood of bounce-back or elimination could reliably be assessed at that point, rather than after two years of subsequent surveillance. The analyses suggest that all clusters should be assessed for transmission interruption after two years of surveillance, unless transmission interruption can be effectively ruled out through evidence of low treatment coverage. Models suggest a tight range of homogenous prevalence estimates following high coverage MDA across clusters which do not allow for discrimination between bounce back or transmission interruption within 24 months following cessation of MDA.

The impact of community-wide, mass drug administration on aggregation of soil-transmitted helminth infection in human host populations

“…Knowledge regarding the extent of compliance within a population targeted for treatment can contribute towards an understanding of whether or not to stop randomised STH control trials, such as DeWorm3, earlier than originally planned [18,21]. If compliance is consistently poor there is little point in continuing treatment, monitoring and evaluation since transmission elimination is unlikely to occur.…”

“…The impact of successive rounds of MDA on STH prevalence is the primary focus of the Bill & Melinda Gates Foundation funded DeWorm3 project in India, Malawi and Benin [18]. This project is investigating whether a communitywide MDA-only approach to STH treatment, would be sufficient to reach a prevalence threshold below which helminth parasite populations cannot sustain transmission, thus leading to transmission elimination [19][20][21]. All STH species reproduce sexually within a human host to produce fertile eggs.…”

“…When the mean worm burden in a population falls to very low levels, the likelihood of both a male and female worm residing within a single human host becomes very small. A "breakpoint" is reached when the worm population can no longer sustain reproduction, resulting in the interruption of transmission even in the absence of further treatment [20,21].…”

Baseline patterns of infection in regions of Benin, Malawi and India seeking to interrupt transmission of soil transmitted helminths (STH) in the DeWorm3 trial

“…Despite reductions in morbidity, in areas of endemic infection the current approach focusing on morbidity control may not reduce the overall prevalence of infection below levels needed to interrupt transmission[ 5 , 6 ]. Poor sanitation and hygiene, coupled with large reservoirs of infection in untreated individuals (including non-pregnant adults and children missed by current programs), serve to perpetuate transmission in many low-resource settings.…”

“…A recent trial in Kenya demonstrated that community-wide treatment was more effective than school-based treatment in reducing hookworm prevalence and intensity[ 9 ]. Mathematical models suggest that transmission interruption of STH may be possible with MDA alone, provided coverage of a substantial portion of the community is achieved repeatedly and individual compliance to treatment is high over many rounds of treatment[ 6 ]. The feasibility of such an approach depends on the underlying transmission intensity in a community, which is affected by a variety of factors including the demography of the targeted population, levels of access to clean water and sanitation, hygiene behaviours, population movement, and characteristics of the built and natural environment, as well as the intensity and frequency of prior deworming in the population[ 5 ].…”