By Kate Hawkins
The second day of the South Africa meeting on Female Genital Schistosomiasis was as engaging as the first with a host of keynote speakers who were diverse in terms of their discipline, approach, and geographical and institutional locations. If you missed our notes on the first day you can find them here…
First up was Charles King, of the Center for Global Health and Diseases, Case Western Reserve University and the Schistosomiasis Consortium for Operational Research and Elimination (SCORE). He explained the methodology behind the disability-adjusted life year (DALY) system which calculates years of life lost and years lost to disability. DALYS are often used to prioritise health interventions and are important in terms of getting particular health conditions onto the global policy agenda and stimulating action. He told us,
“If you are at the bottom of the DALY league table you are out in terms of the priority given to your health issue.”
But is this the DALY the right measure in a world where multiple infections are the rule? There is evidence that schistosomiasis interacts with HIV and that helminths effect people with TB, and malaria. Helminths during pregnancy impair infant HIB vaccine response in the child. In older children (5-18 years) there is an impact of combined infections: children with Schistosoma haematobium infection, hook worm and malaria are more likely to have anaemia and growth retardation. They are shorter, less able to do active physical activity, experience more school absence, worse cognitive scores, and worse performance at school and none of these are presently factored into the DALY score.
Simply put, the DALY calculations are based on the assumption that people can only have one condition at a time. Furthermore if your condition goes undiagnosed (as it currently does in the case of Female Genital Schistosomiasis) you will not get it counted. Under the DALY system if there is comorbidity and someone dies the death is attributed to the ‘most important’ disease. But the decision about what disease is important is made by a small group of people in the US rather than by consensus among researchers and clinicians from low- and middle-income countries. So often this decision does not take into account the context of disease nor fallibilities of the health reporting system in sub-Africa where cause of death is often enigmatic. Furthermore, it also does not appropriately measure the often distressing effects of infertility in terms of mental ill health and family breakdown.
Amadou Garba, World Health Organisation, gave us an overview of the current state of play in terms of Neglected Tropical Diseases. Looking at the data reported in the WHO preventive chemotherapy databank, he explained that there was 12.7% global coverage for schistosomiasis treatments with praziquantel in 2013. In Africa, this is just 14.2%, a mere fraction of what should be expected. He argued that more countries need to introduce preventive chemotherapy and expand coverage at country level to all districts that require it. Merck donations of praziquantel have increased from 26.9 million in 2012 to 104 million in 2015. The biggest part of this donation goes to the Africa region which is the most endemic area in the world. So whilst insufficient medicines used to be the barrier to scale up this is no longer the case. This then, however, raises the question of how the low-level distribution of donated drugs will be sustained so they do not become stalled within the health system, something which COUNTDOWN will hope to address.
Multiple sessions in the meeting touched upon the need to begin schistosomiasis treatment programmes before children begin school. Amaya Bustinduy, of St George’s University, provided more evidence on the need to increase access to praziquantel at an earlier age, starting from six months of age. She explained how pediatric doses of praziquantel are currently extrapolated from adult data which, as typical of other medicines, is a flawed assumption. To formally test this her work in Uganda clearly showed that a 60 mg/kg dose gave a better egg reduction and cure rates against Schistosoma mansoni. Egg counts were supplemented by antigen testing (urine) which also favoured higher dosing as well. Amaya posed the question, are we giving the right dose for the right outcome? Typical of pharmacokinetic/dynamics studies which are very technically demanding, she extrapolated her findings using a simulated data set of 5000 children. This modelling showed that they only approach a target of 90% parasitological cure in 3 year old girls when they have a dose of 80 mg/kg. In school age children it is only when they get to 80mg/kg that we get acceptable cure rates. There are gendered differences, in that boys needed higher doses than girls. This is ground-breaking research showing how mis-leading the direct extrapolation of dosing from adults to children was. As a take home message, if you treat schistosomiasis before school age you can prevent up to 6 years of ill health in children which drew importance to the need of a suitable pediatric formulation of the drug and rapid deployment.
As Herman Feldmeier was unable to attend his lecture was presented by Peter Leutcher, on potential therapies for Female Genital Schistosomiasis and future clinical studies. He outlined how previous studies have shown that schistosomiasis haematobium is already present in girls, persists in women of reproductive age and may affect genital, urinary and intestinal tract simultaneously or subsequently. Taken together this means Female Genital Schistosomiasis is a multi-organ disease. So far the only drug used for the treatment of Female Genital Schistosomiasis is praziquantel. However, praziquantel’s efficacy depends on the response of the individual to treatment, the developmental stage of schistosome worms (praziquantel has limited efficacy on immature adult worms), where the worms are in your body (larval stages in the lungs often have insufficient drug exposure), and other medicines you might be taking. In review, it is safe to assume that a single dose of praziqunatel (40mg/kg) cures less than 50% of patients with schistosomiasis highlighting that multiple praziquantel treatments with higher dosing need to be investigated.
The clinical pathology of Female Genital Schistosomiasis reflects local inflammatory responses in the vulva, vagina or cervix; inflammation-related abnormalities account for ≥ 80% of all abnormalities; inflammation occurs in all layers of epithelium including blood vessels; inflammation is the result of a complex immune response; inflammation is associated with presence of viable eggs and worms. In a study in selected patients with Female Genital Schistosomiasis Richter et al. observed that after a single treatment with praziquantel some types of lesions resolved and others remained unchanged demonstrating a complex patho-physiology.
Many different kinds of outcome measures were used to assess the efficacy of praziquantel. This ranged from infertility to complaints and signs such as sandy patches or contact bleeding. Outcomes were assessed at very different intervals from 2 weeks to 12 months. In one study there was no reduction at all and in other studies it was up to 73%.
So we can conclude that none of the previous treatment studies was appropriately designed; there was not a single randomized controlled trial. The true efficacy of praziquantel in treating Female Genital Schistosomiasis has never been formally assessed as there has been no control of reinfection, which is of course difficult to rule out in out-patient settings. Different outcome measures were used and, therefore, no conclusion about the efficacy of praziquantel is possible.
To address this deficiency, Peter outlined how an expert group has conceived a randomized controlled trial with three treatment arms. In group A patients will receive the standard treatment, that means a single dose of praziquantel. In group B patients receive three doses of praziquantel. Dose one is given immediately after diagnosis. Dose two is given one day later and dose three is given two days later. In group C patients receive an identical treatment as those in group B. In addition, they receive another dose of praziquantel after five weeks and a final dose after 10 weeks. These additional doses are foreseen to kill schistosomula which have developed in the meantime to adult worms and to prevent reinfection to establish. Patients are followed up 5, 10 and 16 weeks after initial treatment. He suggested that this study would arm us with the type of information that we need to respond adequately to Female Genital Schistosomiasis.
But how can we can take action on the diagnosis of Female Genital Schistosomiasis now rather than later? Part of this solution requires tools so that health workers recognise Female Genital Schistosomiasis when they see it. Sibone Mocumbi, Head of Gynecology, Hospital Central de Maputo, presented on the deployment of one exciting new tool, the Female Genital Schistosomiasis Pocket Atlas.
Sibone explained that lesions in Female Genital Schistosomiasis may mimic any neoplastic infection in the female genital tract. Health care workers know very little about it and so they don’t take the opportunities that they have to treat it. Women are often misclassified as having Sexually Transmitted Infections (STIs) and lab diagnosis is not sufficient.
The Pocket Atlas is a tool for low-resource settings to enable health care professionals to identify Female Genital Schistosomiasis and avoid unnecessary radical surgery and misdiagnosis of STIs. It contains pictures and outlines the methods for examining patients and the symptoms to expect. It will be disseminated for free especially in the rural areas where schistosomiasis is endemic. It was put together in concert with gynaecologists, doctors, nurses, and clinicians. It will be available in English, French and Portuguese. They will also be creating a poster, online versions of the Atlas, a PowerPoint presentation, video, and a website. Watch this space!
To further clarify the action of praziquantel the final presentation of the day, by Collen Masimirembwa (African Institute of Biomedical Science and Technology, Zimbabwe) addressed our lack of knowledge about the pharmacological effects of this drug. Pharmacokinetics is the absorption, distribution, metabolism and excretion of drug as it metabolises in the body. If you understand this it helps you understand how often to give the drug and how much you should give. At the moment our practice is driven by observation. But we don’t know how much of the drug should be in the blood and that is important. With drugs like praziquantel you can lose a lot of the active ingredients in the gut and that which is absorbed is quickly metabolised by the liver by a complex set of cytochrome P450 oxidases. Understanding this will allow us to better understand the differences between individuals when it comes to efficacy. Currently we know very little about the distribution across the body so we don’t know if it is exactly restricted to the blood or if it goes into other tissues and lasts there much longer. If we are eager to push forward with paediatric formulations we need better data on this following along the lines of the seminal data presented earlier by Amaya. It would also assist us with understanding drug interactions – such as with those of other NTDs or HIV. Collen cautioned that there may be serious interactions with TB drugs. During questions, Russ Stothard raised pointed out that the unusual position of the adult schistosome population in the body, largely residing in the hepatic portal vein, which means the schistosome has a very different surrounding drug environment to that which we can measure within the peripheral blood stream.
After the final break-out session the workshop reconvened in a plenary session led by Eryun Kjetland which was a brainstorming and question and answer session with the audience about where to go next and how to do it. It was remarked at how supportive, refreshing and collegiate this symposium was and so the meeting finished on a real high. Many people pledged to take forward action at home based on what they had heard either in informing their local Ministries of Health, revising their teaching content or providing access to samples for further testing. The conference organisers will be arranging some official communications on lessons learned and next steps via the conference website and a working group on Female Genital Schistosomiasis/HIV will be formed to ensure the network is sustained. COUNTDOWN will be sure to advertise them here and on other social media. If you have any questions about the meeting feel free to leave a comment below and we will get back to you. Thank you for reading.
Photo courtesy of Trygve Utstumo under a Creative Commons License. You can view more images here…