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…


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.

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

By Kate Hawkins, COUNTDOWN

COUNTDOWN is happy to support and be a part of the International Scientific Workshop on Neglected Tropical Diseases (NTDs) which is currently taking place in South Africa. The theme of the meeting is how schistosomiasis, in particular Female Genital Schistosomiasis, impacts on HIV. On day one we were joined by some brilliant speakers who provided six keynote addresses to help provide  context for discussions in subsequent breakout sessions for each topic.

Tsakani Furumele, Director, Communicable Disease Control, National Department of Health, South Africa gave an overview of combined control policies. She outlined how NTDs effect the poorest of the poor. But because they do not often kill people they are often marginalised in broader conversations on health. However, they impair physical and intellectual capacities perpetuating the cycle of poverty. At least 79% of endemic countries are co-endemic for at least 5 of the NTDs. Africa bears half of the global burden. She argued that,

Stimulating financing for NTDs requires an evidence base and if we cannot provide it the chances of us getting support are very, very slim.”

There are a number of regional and global policies to guide action in this area such as the WHA Resolution 66.12 and the WHO strategic plan for NTDs in the Africa region as well as the London Declaration. Whilst in South Africa the various HIV guidance policies stress that integration is necessary and that there is no one size fits all approach there are still barriers that effect the integration of NTDs into this portfolio and would affect action on Female Genital Schistosomiasis. These barriers include that: not all stakeholders are involved in the process of policy formulation; there are financial constraints related to the potential costs of integrated programmes; logistical and organisational limitations mean that cross policy and sectoral action is extremely difficult; and demographic heterogeneity is also an issue. To overcome these barriers we need advocacy and information sharing so that all have access to the evidence and we need facilitate joint programming and partnership and this will mobilise political will for action on NTDs.

Gita Ramjee, Director, HIV prevention Research Unit, South African Medical Research Council/London School of Hygiene and Tropical Medicine presented on Women and HIV. She outlined how there are 35.3 million people living with HIV and every hour 50 young women are newly infected. There are various overlaps of a number of factors related to Female Genital Schistosomiasis and HIV for example, their impact on vaginal mucosa, that they both effect the poorest, the relation with gender inequality, and that they effect reproductive functions.

Gita suggested that there are a range of sexually transmitted infections (STIs) which effect the genitals and there are similarities between what STIs do and what Female Genital Schistosomiasis does. Several cross sectional studies reported association between Female Genital Schistosomiasis and HIV. In addition to increasing susceptibility to infection it may also increase progression of disease by raising viral load in individuals who are infected. Further research is required to determine the contributing role of Female Genital Schistosomiasis and other NTDs on HIV incidence in Sub-Saharan Africa.

Eyrun Kjetland, Research Fellow, Norwegian Centre for Imported and Tropical Diseases, Oslo University Hospital was our third speaker and presented on Female Genital Schistosomiasis. Eyrun explained that the pertinent symptoms of Female Genital Schistosomiasis are malodorous discharge, secondary infertility and spot bleeding and that even children have symptoms. Taken together these symptoms can be confusing for the child and initiate low self-esteem, especially at a sensitive period before their first sexual debut.  Whilst these symptoms can resolve with treatment with praziquantel this does not affect lesions in the vagina and cervix that have already formed which stay even if the S. haematobium eggs are dead. Also people can test negative when given a urine test but still be affected by the disease. Old, calcified S. haematobium eggs in genital tissue have been found to increase the density of HIV-receptive CD4 cells. Female Genital Schistosomiasis may be a cofactor for HIV transmission in endemic areas, and the association between schistosomiasis and HIV has been corroborated by several scientific groups. However the evidence base that can be drawn on for the association between HIV and Female Genital Schistosomiasis is small and still limited to a group of key experts.

This led one audience member to comment:

“Do we need to keep proving the links beyond doubt? Or should we just say that the effects of schisto and HIV are enough to treat. The fact that there could be an association is reason enough to start and continue with the collaborative effort of evidence gathering. For me, for now, I need to have started yesterday!”

Peter Leutsher, who is based at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, gave a fascinating overview of  Male Genital Schistosomiasis.  He explained that most of what we know is from post-mortem studies from the 1970s which were then acceptable but today are not. It appears, however, that the seminal vesicles, prostate and vans deferens are most effected by Male Genital Schistosomiasis. Male Genital Schistosomiasis causes pelvic pain, dysuria, painful erection and ejaculation and haematospermia.  There has been a study that found that the quality of sperm in men with genital schistosomiasis was poorer.

The chronic inflammation and recruitment of lymphocytes and eosinophils to the male genital tract in men with genital shistosomiasis may increase the HIV viral load in semen as well as the associated inflammatory cytokines which may also influence the immunology of the mucosal surface of the receiving partner. This may increase the likelihood of transmission of HIV from the man to his female partner (but also in men who have sex with men who were alluded to but not specifically mentioned). Peter is currently involved in an exciting Randomised Control Trial with men living with HIV and schistosomiasis in Zimbabwe to study whether praziquantel effects the viral load of semen.

Lester Chitsulo, formerly from the WHO, public health consultant from Malawi led us through the challenges in reaching women of child bearing age (15-29 years) with schistosomiasis because of medicine regulations and recommendations and the way that programmes are currently implemented. In Malawi women of childbearing age make up 21% of the total population. 81% live in rural areas and 15% have never been to school. At any one time up to 30% of these women could be pregnant or breastfeeding children. There is some confusion among government agencies and clinicians about how safe it is to give praziquantel to women who are pregnant or breastfeeding. Because you can’t always determine whether women are pregnant or not they are often routinely excluded from large-scale treatment campaigns. Furthermore mass drug administration usually takes place through programmes with children of school age. There are often operational advantages to integrating different programmes for NTDs. However programmes that target lymphatic filariasis, onchocerciasis and soil transmitted helminths cannot include pregnant women.

Lester suggested that praziquantel is safe for use in pregnant and breastfeeding women and that there is a need to do better collection of epidemiological data to see who among women of childbearing age actually need treating. If women who are pregnant are left out then they should be followed up in the maternal and child health services that the women routinely attend following delivery.

Many of the open questions and loose ends were picked up in the breakout sessions which were reported back to the audience via rapporteurs. We look forward to a similarly enlightening round of presentations on the second and final day of the conference.

Photo by Albert González Farran, UNAMID, you can find more of his photos online here…