Female Genital Schistosomiasis and its impact on HIV: Round up of Day Two

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…

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COUNTDOWN in South Africa – new friendships, thoughts and directions

By Russell Stothard, Liverpool School of Tropical Medicine

Returning from Magaliesburg in South Africa and sitting here early on a Saturday morning in Heathrow waiting for a flight to a snowy Manchester, I am really proud of what COUNTDOWN has achieved this past week. As both co-organiser and participant in the International Workshop on NTDs and importance of Female Genital Schistosomiasis (FGS) and its impact on HIV/AIDS, I represented both the Liverpool School of Tropical Medicine and our research consortium. Moreover, I was joined by Kate Hawkins our communications expert and by colleagues from Ghana, Benjamin Marfo who was representing Nana Biritwum, and Margaret Gyapong. We were also expecting Louis-Albert Tchuem-Tchuente from Cameroon to join us but he was called away last minute to Nigeria to represent WHO-AFRO in revision of their national Neglected Tropical Disease (NTD) plan but very fortunate given our future there.

Once in Magaliesburg and as co-organiser with Myra Taylor (The University of KwaZulu-Natal), Eryun Kejtland (The Oslo University Hospital), Jutta Reinhard-Rupp and Claudia Cecalupo (Merck-Serono), we finalised on-site arrangements. This included tailoring the agenda with the final list of participants who were set to arrive the next day, 75 in total and collectively coming from USA, Europe and Sub-Saharan Africa. We then performed a detailed cross-check and walk-through of all on-site logistics whilst being made aware of frequent power outages and their contingencies. Our Monday evening review meeting, for example, was held by candle-light owing to a particularly impressive electrical storm disrupting local supplies that night. Of course, there were surprises and for me it was being nominated by my co-organisers to give the Tuesday evening welcome dinner speech, a well set ambush perhaps despite our prior weekly teleconference calls from November!

So with microphone in hand and overcoming my nerves in front of such a very distinguished audience inclusive of WHO-Geneva and international donors, I gave my personal expectations for the following days. This was to be a very good thing for I find the most important beginning point of any small conference is to develop a friendly and social dialogue with its participants. This is crucial if you want to see the fruits of frank and open discussions evolve as often first undertaken by people who have never before met and also come to the agenda with very divergent experiences. Thus to do so from the onset people must be made to feel comfortable within such a larger group, and that their own opinion and contribution was to be valued and considered evenly with our own expectations.

Indeed the fruits of informed conversation grew and at the end of the workshop, it was evident that this was a key achievement of this meeting for all became increasingly animated and excited by this new cross-talk between NTDs and HIV. We discovered shared ground and addressed several issues ranging from access to diagnostics and treatment, gender and age-related inequities, primary health care services and better clinical management to future steps and studies to be taken and turned into best policies and optimal practices.

Kate, Margaret, Benjamin and I felt very motivated with the outcomes from this meeting and how it will be turned into tangible research and future policy repositioning within Ghana, starting this coming week (so my thanks to Margaret and Benjamin for being so quick to take action)! Indeed, we look forward to supporting this research uptake with targeted studies to be undertaken on the ground when deemed appropriate. This will be further discussed and developed across our partners within our inception workshop during the second week of March in the Liverpool School of Tropical Medicine, so you will hear more in due course.

So key highlights for me this past week? I had the good fortune to arrive at the airport with Barbara Mukasa from Mildmay and with it the opportunity to chat about our experiences in Uganda while waiting for transportation. As I have conducted many field surveys in the remoter areas of her country for NTDs, I have always been impressed by the community outreach that Mildmay has had in facilitating access to health services for HIV and AIDS. I have only met Barbara a couple of times before and only discussed with her intestinal schistosomiasis which is more prevalent in Uganda but in this conference with the focus on urogenital schistosomiasis she really grasped the importance of FGS in the context of her own work both in children and in adults.

Moreover, Barbara gave a really touching presentation highlighting the holistic view Mildmay has in supporting children as well as their carers, with real honesty by appreciating the often shortcomings of human behaviour which can range from the darker side of deception and violence to the lighter side of compassion and love. In the context of safe childhood, with a gynaecological disease such as FGS we should also remain vigilant to often cryptic signs of sexual abuse and coercion as well as the unfortunate stigmatisation and low self-esteem that this disease can induce with its signs and symptoms. This made me think more deeply about the pressing need for social science studies and assessment of burden of disease at the psycho-social level.

Other personal highlights included: seeing Kate very busy blogging and Tweeting about the issues being raised and helping me to get to grips with the newer side of social media; reading Alan Fenwick’s blog about our workshop after the first day from his perspective as Director of the Schistosomiasis Control Initiative; meeting with Refilwe Sello a HIV/reproductive health specialist from the FHI360 South African office and seeing her become enthused about NTDs; meeting again Peter Leutcher who I had last seen in 1997 in Madagascar while working with the Institut Pasteur Antananarivo and listening to his really authoritative keynote address on Male Genital Schistosomiasis and its implications; and finally helping my colleagues Myra, Eryun and Jutta draw attention to the need and use of donated praziquantel in South Africa by supporting direct engagement with stakeholders from the local Ministry and local HIV-action groups.

But what did I learn? In line with my own research on techniques and tools for diagnosis of schistosomiasis, there is an unmet need for new diagnostics for female genital schistosomiasis, especially in girls younger that their first sexual debut where a gynaecological examination cannot be performed for obvious reasons. Better access to praziquantel treatment in both pre-school-age and school-age is crucial if we are to prevent the later occurrence of FGS where it can be measured albeit with rather cumbersome invasive methods, i.e. by colposcopy. To that end, my colleague Amaya Bustinduy drew attention to the common plight of pre-school-aged children and that we must consider higher praziquantel dosing than the present 40 mg/kg and at shorter intervals, biannual or more for example, rather than the annual treatment regime. All this to be also set within access to Anti Retroviral Therapies in children with schistosomiasis-HIV co-infections, and we will revise our syllabus within our joint Diploma of Tropical Medicine and Hygiene teaching at Liverpool and London.

Arriving now in Manchester and taken as a whole, COUNTDOWN is well set to address these issues by fostering the scale-up of NTD control by focused implementation research tapping into newly formed research networks, which is something I am very privileged to lead and will promote this coming week in WHO-Geneva at a technical advisory group on diagnostics for schistosomiasis.

Calling time on urogenital schistosomiasis

Sally Theobald, COUNTDOWN Consortium & Research in Gender and Ethics: Building stronger health systems (RinGs)

I spent many of my teenage years living in Malawi, enjoying swimming in beautiful Lake Malawi. Wind on to age 30, and I was struggling to get pregnant. Eventually, following illness, I was diagnosed with schistosomiasis by a consultant and colleague at the Liverpool School of Tropical Medicine. I was told that I had probably been infected for a while and that it might be affecting my fertility. So I took praziquantel, the only available drug against the parasite, and soon after I was pregnant. Today my first born daughter is 10 years old.  Whilst the links between urogenital schistosomiasis, sub-fertility and HIV have become increasingly well-established over my first born daughter’s life time, a combined and robust health systems action that brings together neglected tropical disease, sexual and reproductive health and HIV communities to address and scale up treatment for urogenital schistosomiasis is sadly lacking.

It is 20 years since the Beijing Women’s Conference and the International Conference Population and Development and the sexual and reproductive community have been taking stock on progress, challenges and future priorities. I attended a research agenda setting meeting on sexual and reproductive health, rights and gender at the WHO on 12th and 13th of January, where we discussed how to best decide priorities for action. Scaling up treatment for urogenital schistosomiasis is arguably a win-win.

The global burden of disease

Schistosomiasis is wide spread and there are two forms of disease, intestinal and urogenital. An estimated 600 million people are at risk of being infected and approximately 200-220 million people are living with schistosomiasis in Africa. Of the people infected with urogenital schistosomiasis it is thought that between about 100 and 120 million suffer from urinary and reproductive tract damage, which also impacts directly with HIV co-infection and sub-fertility in general. Typically many adolescent girls and women exhibit several symptoms in their lower genital tract where overt bleeding and unpleasant discharge, general discomfort and pain during sex can lead to low self-esteem, depression and stigma.

Peter Hotez estimates that globally there are between 67-200 million cases of urogenital schistosomiasis among girls and women. Hotez argues that between 20 million and 150 million girls are affected, possibly making it one of the most common gynaecological conditions in sub-Saharan Africa but unfortunately much under-reported. Urogenital schistosomiasis, as in my experience, also affects fertility and it is estimated to reduce a woman’s reproductive health capacity by up to 75%.

The links between urogenital schistosomiasis in women (female genital schistosomiasis) and HIV are well established. Writing in the Lancet, Stoever and colleagues argue that up to 75% of girls and women infected with female genital schistosomiasis develop often irreversible lesions in the vulva, vagina, cervix, and uterus, creating a lasting entry point for HIV and discuss how research in Zimbabwe showed that women with female genital schistosomiasis had a threefold increased risk of having HIV. In a recent review of the evidence Pamela Mbabazi and colleagues argue that “Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects”.

 Gender, equity and rights

There is remarkable overlap between the maps showing high HIV prevalence in Africa (particularly amongst women and adolescents girls) and those showing cases of female genital schistosomiasis. A complex interplay of biological, social and cultural factors means that young women are particularly vulnerable to HIV in sub-Saharan Africa. Gender norms also shape exposure to urogenital schistosomiasis, with women being particularly responsible for activities involving water in many communities (washing, cleaning, collecting water etc). Drawing on work from Ghana, Vlassoff and Manderson have shown that women interact with water significantly more often than men.

What to do?

Several tens of millions of praziquantel tablets are now donated each year by Merck-KGaA for mass drug administration campaigns as a cost-effective method to protect people from the urogenital schistosomiasis. Hotez argues that by preventing female genital schistosomiasis in sexually active women we have an innovative and timely opportunity to reduce and likely much reduce HIV transmission throughout many rural areas of sub-Saharan Africa.

But in infected communities treatment also needs to start early.

Stoever and colleagues argue that periodic and regular treatment with praziquantel from when children are first infected should prevent the development of genital lesions, which increase HIV risk and cause gynaecological problems. Treatment, however, may need to be started even earlier as the extent and burden of schistosomiasis in pre-school-aged children is being more fully described.

To make progress in this area we need joint action between the HIV, sexual and reproductive health and neglected tropical disease communities. Health workers and communities need more information on the multiple impacts of urogenital schistosomiasis and how it can be treated.

The lack of action to date on urogenital schistosomiasis clearly illustrates the importance of new partnerships and new approaches to scaling up strategies to address neglected tropical diseases. COUNTDOWN, a new initiative in Cameroon, Ghana and Liberia, will be paying close attention to the potential role of close-to-community providers such as drug distributors in providing an interface between communities and health systems.   We will also evaluate how to deliver equitable drug delivery for schistosomiasis through the inclusion of preschool-aged-children, out-of-school-children and adults. The Director of COUNTDOWN is helping to co-organise a meeting in South Africa later in the month where several members of COUNTDOWN will also attend. It brings together world leaders in the field of schistosomiasis, HIV and paediatrics to present on the current state and future direction of research on female genital schistosomiasis.

COUNTDOWN is set to foster and to stimulate others in thinking of innovative ways of prompting a synergistic approach to neglected tropical diseases which crosses sectors and builds strength in national health systems.

If you would like to find out more follow us on Twitter or email Rachael Thompson.

Photo courtesy of Andrew Whalley. Children at Dusk.