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Female genital schistosomiasis and HIV/AIDS: Reversing the neglect of girls and women

  • Peter J. Hotez ,

    hotez@bcm.edu

    Affiliations Texas Children’s Hospital Center for Vaccine Development, National School of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America, Department of Biology, Baylor University, Waco, Texas, United States of America

  • Wendy Harrison,

    Affiliation Schistosomiasis Control Initiative, Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom

  • Alan Fenwick,

    Affiliation Schistosomiasis Control Initiative, Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom

  • Amaya L. Bustinduy,

    Affiliation Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Camilla Ducker,

    Affiliation Uniting to Combat NTDs, London, United Kingdom

  • Pamela Sabina Mbabazi,

    Affiliation Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland

  • Dirk Engels,

    Affiliation Uniting to Combat NTDs, London, United Kingdom

  • Eyrun Floerecke Kjetland

    Affiliations Regional Advisory Unit for Imported and Tropical Diseases, Department of Infectious Diseases, Ullevaal, Oslo University Hospital, Oslo, Norway, Discipline of Public Health Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

Female genital schistosomiasis and HIV/AIDS: Reversing the neglect of girls and women

  • Peter J. Hotez, 
  • Wendy Harrison, 
  • Alan Fenwick, 
  • Amaya L. Bustinduy, 
  • Camilla Ducker, 
  • Pamela Sabina Mbabazi, 
  • Dirk Engels, 
  • Eyrun Floerecke Kjetland
PLOS
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Since the 2000s, we have known that female genital schistosomiasis (FGS) is likely the most neglected gynecologic condition and HIV/AIDS cofactor across sub-Saharan Africa. To date, the global health and HIV/AIDS communities have not used the opportunity to prevent new HIV/AIDS infections through highly cost-effective schistosomiasis control and elimination in Africa. But recently, this situation may be shifting toward the better.

FGS is caused by the terminal-spine parasite eggs released from the female Schistosoma haematobium parasite. When the eggs are deposited in the tissues of the cervix and lower female genital tract, the presence of the eggs, combined with host inflammation and increased vascularity in the cervicovaginal mucosa, produces typical intravaginal lesions that result in genital itching and pain, bleeding, and dyspareunia [14]. In addition, eggs deposited in the uterus and fallopian tubes can result in infertility [2, 3]. There are also associated and profound mental health effects from social stigma, such as depression and marital discord [1, 2], and the condition frequently gets confounded with sexually transmitted infections.

FGS is also incredibly common. Approximately two-thirds of Africa’s 200 million schistosomiasis cases are caused by S. haematobium, and it is estimated that up to three-quarters of girls and women with S. haematobium infection have FGS [5]. On this basis, FGS may represent sub-Saharan Africa’s most common gynecologic condition, affecting tens of millions of girls and women [6]. Yet, FGS in not mentioned in most medical textbooks, nor in the lay press, which has further compounded the very low awareness about the condition.

As if this information were not bad enough, several large epidemiological studies show that FGS is responsible for up to a three- to four-fold increase in horizontal transmission of HIV/AIDS [2, 7, 8], whereas a regression analysis of prevalence of S. haematobium infection and HIV in sub-Saharan African countries found that each S. haematobium infection per 100 individuals resulted in a 3% relative increase in HIV prevalence [9].

Given the high prevalence and incidence of FGS and its strong geographic overlap with HIV/AIDS in countries such as Malawi, Mozambique, South Africa, Tanzania, Zimbabwe, and elsewhere, it stands to reason that FGS would be identified as a leading HIV/AIDS cofactor in Africa, and that mass drug administration (MDA) with the antiparasitic drug, praziquantel, would represent an important strategy for HIV/AIDS prevention. Indeed, two transmission modeling studies found that in rural Zimbabwe, praziquantel MDA is a highly cost-effective means of reducing HIV/AIDS transmission [10, 11]. Now that praziquantel is being donated free of charge to sub-Saharan Africa by the German-based Merck KgaA for treatment of school-age children [12], praziquantel MDA may represent one of the most cost-effective means of contributing to HIV/AIDS prevention in Africa.

From the beginning of efforts to integrate MDA with praziquantel with other neglected tropical diseases (NTDs) amenable to MDA, there have been calls to link these activities with HIV/AIDS prevention efforts in Africa. Such efforts could include combining praziquantel MDA with antiretroviral treatment and pre-exposure prophylaxis (PrEP) programs, as well as other measures [1315]. Indeed, multiple (and peer-reviewed) scientific papers have been written on this subject [1321], but they have largely appealed to the community of scientists and public health experts committed to NTDs. Therefore, although “preaching to the converted” has helped to unify the NTDs community, it has (so far) done little to stimulate the global HIV/AIDS community toward accepting the importance of praziquantel MDA as a key component of strategies to prevent new infections of HIV/AIDS. For that reason, there was at best only modest progress on this front from the major global organizations committed to HIV/AIDS prevention, including UNAIDS, the One Campaign, the Clinton Foundation, the US President’s Emergency Plan for AIDS Relief (PEPFAR), and the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM). However, this situation may soon improve.

Over the last five years, the case to incorporate praziquantel MDA into HIV/AIDS treatment programs has advanced even further due to new and important developments. They include the successful testing of a new prodispersable formulation of praziquantel suitable for use in treating young (preschool age) children to prevent the onset of the genital lesions leading to FGS, together with expanded treatment programs for young children and pregnant women [20, 2224], improved FGS diagnostic technologies and algorithms [2531], and expanded surveillance for FGS [23, 24]. Also, there are now better basic science tools available, including a new mouse model and the applications of genomics, proteomics, metabolomics, and gene editing technologies and an expanded array of immunological reagents, to understand the pathogenesis of FGS [3235]. Such studies could provide fundamental information on how FGS damages host tissues and leads to increased susceptibility to HIV/AIDS. Additionally, efforts have been made to develop FGS vaccines alongside HIV/AIDS vaccines, with several schistosomiasis vaccines now in clinical testing [36]. There are also efforts in place to improve local advocacy and health education around FGS [37].

Through such developments, could anti-schistosomal control efforts, including MDA, become essential elements in the HIV/AIDS prevention programmes? So far the uptake has been extremely slow. But now, both the Department of Control of NTDs at the World Health Organization, together with UNAIDS, are working towards joint programs of policy and advocacy to create some paradigm-changing shifts. Similarly, there is an urgency to integrate schistosomiasis treatments into broader health systems for women’s health, including antenatal programs, HIV/AIDS prevention programs, and cervical cancer screening clinics [23, 24, 38].

Realizing that declines in new HIV/AIDS infections remain too slow, especially in younger women aged 15–24 years who are twice as likely to be living with HIV than men [39]—in 25 countries, of which 18 in sub-Saharan Africa—UNAIDS launched its Prevention 2020 Road Map [40] calling for innovative combination prevention packages, in addition to HIV screening, counseling, and treatment programs. Since 2017, several parallel sessions have taken place at international AIDS and Women’s conferences—including the 22nd International AIDS Conference held in Amsterdam, the Netherlands in 2018—calling for a more holistic approach to women’s health and HIV. More specifically, the integration of services for HIV, FGS, Human Papilloma Virus (HPV), and cervical cancer prevention and control is called for, to improve reproductive health services and save women’s lives [4142]. In early 2019, UNAIDS and WHO are scheduled to issue a joint Advocacy Brief on FGS and HIV.

In the meantime, the major organizations focused on integrated control and elimination of NTDs, including the WHO, continue to expand praziquantel MDA efforts in concert with the Merck KGaA donations. According to the WHO, despite making impressive gains in 2017, we are still falling short of meeting the minimum target of treating at least 75% of the African children who require regular and periodic administration of praziquantel [43]. These efforts could largely be accelerated (sustainably) were countries allowed to include them in all-out HIV/AIDS prevention and care programs supported by PEPFAR and GFATM. Incorporation with major AIDS organizations might also allow an expansion of efforts in Africa to mobilize communities, create demand for holistic female reproductive health services, and address the social stigma and mental health issues of FGS, which, for now, largely remain ignored except for a handful of one-off efforts. Additionally, medical training materials must be updated to include FGS. The clinical research community—including primary health care nurses in remote areas, pediatricians, and gynecologists—should engage in the development of appropriate treatment protocols for patients who develop FGS.

The overall neglect of the serious consequences of FGS represents an affront to the girls and women of Africa and their families in poverty-stricken communities. We have the supporting data and tools to both prevent FGS and reduce HIV/AIDS transmission in Africa. We shouldn’t continue to leave this extraordinary opportunity on the table, unused.

References

  1. 1. Kjetland EF, Hegertun IE, Baay MF, Onsrud M, Ndhlovu PD, Taylor M (2014) Genital schistosomiasis and its unacknowledged role on HIV transmission in the STD intervention studies. Int J STD AIDS. 2014 Sep;25(10):705–15. pmid:24621458
  2. 2. Downs JA, Mguta C, Kaatano M, Mitchell B, Bang H, Simplice H, et al. (2011) Urogenital schistosomiasis in women of reproductive age in Tanzania’s Lake Victoria Region. Am J Trop Med Hyg 84(3): 364–9. pmid:21363971
  3. 3. Woodall PA, Kramer MR (2018) Schistosomiasis and infertility in East Africa. Am J Trop Med Hyg 98(4): 1137–44. pmid:29313478
  4. 4. Jourdan PM, Roald B, Poggensee G, Gundersen SG, Kjetland EF (2011) Increased vascularity in cervicovaginal mucosa with Schistosoma haematobium infection. PLoS Negl Trop Dis 5(6): e1170 pmid:21666790
  5. 5. Kjetland EF, Kurewa EN, Ndhiovu PD, Midzi N, Guanzura L, Mason PR, et al. (2008) Female genital schistosomiasis—a differential diagnosis to sexually transmitted disease: genital itch and vaginal discharge as indicators of genital Schistosoma haematobium morbidity in a cross‐sectional study in endemic rural Zimbabwe. Trop Med Int Health 13(12): 1509–17. pmid:19055625
  6. 6. Hotez PJ (2013) Female genital schistosomiasis (FGS): Sub-Saharan Africa’s secret scourge of girls and women. PLoS Speaking of Medicine. https://blogs.plos.org/speakingofmedicine/2013/05/06/female-genital-schistosomiasis-fgs-sub-saharan-africas-secret-scourge-of-girls-and-women/. [cited 9 September 2018].
  7. 7. Kjetland EF, Ndhlovu PD, Gomo E, Mduluza T, Midzi N,Gwanzura L, et al. (2006) Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS 20(4): 593–600. pmid:16470124
  8. 8. Brodish PH, Singh K (2016) Association between Schistosoma haematobium exposure and human immunodeficiency virus infection among females in Mozambique. Am J Trop Med Hyg 94(5): 1040–4. pmid:26976893
  9. 9. Neffo-Mbah MLN, Poolman EM Drain PK, Coffee MP, van der Werf MJ, Galvani AP (2013) HIV and Schistosomas haematobium prevalences correlate in sub-Saharan Africa. Trop Med Int Health 18(10): 1174–9. pmid:23952297
  10. 10. Neffo-Mbah MLN, Poolman E, Atkins KE, Orenstein EW, Meyers LA, Townsend JP, et al. (2013) Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa—the case of Zimbabwean women. PLoS Negl Trop Dis 7(8): e2346. pmid:23936578
  11. 11. Neffo-Mbah NLN, Kjetland EF, Atkins KE, Poolman EM, Orenstein EW, Meyers LA, et al. (2013) Cost-effectiveness of a community-based intervention for reducing the transmission of a Schistosoma haematobium and HIV in Africa. Proc Natl Acad Sci USA 110(21):8750.
  12. 12. Merck KgaA, Schistosomiasis. https://www.emdgroup.com/en/company/responsibility/our-strategy/health/schistosomiasis.html. [cited 9 September 2018].
  13. 13. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD (2006). Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 3(5):e102. pmid:16435908
  14. 14. Noblick J, Skolnik R, Hotez PJ (2011) Linking global HIV/AIDS treatments with national programs for the control and elimination of the neglected tropical diseases. PLoS Negl Trop Dis 5(7): e1022. pmid:21814582
  15. 15. Hotez PJ, Mistry N, Rubinstein J, Sachs JD (2011) Integrating neglected tropical diseases into AIDS, tuberculosis, and malaria control. N Engl J Med. 2011 Jun 2;364(22):2086–9. pmid:21631320
  16. 16. Hotez PJ, Fenwick A (2009) Schistosomiasis in Africa: an emerging tragedy in our new global health decade. PLoS Negl Trop Dis 3(9): e485. pmid:19787054
  17. 17. Hotez PJ, Fenwick A, Kjetland EF (2009) Africa’s 32 cents solution for HIV/AIDS. PLoS Negl Trop Dis 3(5): e430. pmid:19479041
  18. 18. Hotez PJ, Engels D, Fenwick A, Savioli L (2010) Africa is desperate for praziquantel. Lancet 376(9740): 496–8. pmid:20709217
  19. 19. Hotez P, Whitham M (2014) Helminth infections: a new global women’s health agenda. Obstet Gynecol 123(1): 155–60. pmid:24463676
  20. 20. Christinet V, Lazdins-Helds JK, Stothard JR, Reinhard-Rupp J (2016) Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease. Int J Parasitol 46(7): 395–404. pmid:27063073
  21. 21. Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, Downs JA (2011) Examining the Relationship between Urogenital Schistosomiasis and HIV Infection. PLoS Negl Trop Dis 5(12): e1396. pmid:22163056
  22. 22. Reinhard-Rupp J, Klohe K (2017) Developing a comprehensive response for treatment of children under 6 years of age with schistosomiasis: research and development of a pediatric formulation of praziquantel. Infect Dis Poverty 6(1):122. pmid:28768535
  23. 23. Bustinduy AL, Friedman JF, Kjetland EF, Ezeamama AE, Kabatereine NB, Sothard JR, et al. (2016) Expanding praziquantel (PZQ) access beyond mass drug administration programs: paving a way forward for a pediatric PZQ formulation for schistosomiasis. PLoS Negl Trop Dis 10;9: e0004946.
  24. 24. Bustinduy AL, Stothard JR, Friedman JF (2017) Paediatric and maternal schistosomiasis: shifting the paradigms. Br Med Bull 123(1): 115–25. pmid:28910994
  25. 25. Norseth HM, Ndhlouvu PD, Kleppa E, Randrianasolo BS, Jourdan PM, Roald B, et al. (2014) The colposcopic atlas of schistosomiasis in the lower female genital tract based on studies in Malawi, Zimbabwe, Madagascar, and South Africa. PLoS Negl Trop Dis 8(11): e3229. pmid:25412334
  26. 26. Ramarokoto CE, Kildemoes AO, Randrianasolo BS, Ravoniarimbinina P, Ravaoalimalala VE, Leutscher P, et al. (2014) Eosinophil granule proteins ECP and EPX as markers for a potential early-stage inflammatory lesion in female genital schistosomiasis (FGS). PLoS Negl Trop Dis 8(7): e2974. pmid:25033206
  27. 27. Holmen SD, Kleppa E, Lillebo K, Pillay P, van Lieshout L, Taylor M, et al. (2015) The first step toward diagnosing female genital schistosomiasis by computer image group. Am J Trop Med Hyg 93(1): 80–6.
  28. 28. Holmen SD, Kjetland EF, Taylor M, Kleppa E, Lellebo K, Gundersen SG, et al. (2015) Colourimetric image analysis as a diagnostic tool in female genital schistosomiasis. Med Eng Phys 37(3): 309–14. pmid:25630808
  29. 29. Holmen S, Galappaththi-Arachchige HN, Kleppa E, Pillay P, Naicker T, Taylor M, et al. (2016) Characteristics of blood vessels in female genital schistosomiasis: paving the way for objective diagnostics at the point of care. PLoS Negl Trop Dis 10(4): e0004628. pmid:27073857
  30. 30. Hsieh MH, Le L (2017) Diagnosing urogenital schistosomiasis: dealing with diminishing returns. Trends Parasitol 33(5): 378–87. pmid:28094201
  31. 31. Galappaththi-Arachchige HN, Holmen S, Koukournari A, Kleppa E, Pillay P, Sebitloane M, et al. (2018) Evaluating diagnostic indicators of urogenital Schistosoma haematobium infection in young women: a cross sectional study in rural South Africa. PLoS ONE 13(2): e0191459. pmid:29451887
  32. 32. Richardson ML, Fu CL, Pennington LF, Honeycutt JD, Odegaard JI, Hsieh YJ, Hammam O, Conti SL, Hsieh MH (2014) A new mouse model for female genital schistosomiasis. PLoS Negl Trop Dis 8(5): e2825. pmid:24786606
  33. 33. Brindley PJ, Hotez PJ (2013) Break out: urogenital schistosomiasis and Schistosoma haematobium in the post-genomic era 7(3): e1961.
  34. 34. Hotez PJ (2017) The poverty-related neglected diseases: why basic research matters. PLoS Biol 15(11): e2004186. pmid:29121043
  35. 35. Siddappa NB, Hemashettar G, Shanmuganathan V, Semenya AA, Sweeney ED, Paul KS, et al. (2011) Schistosoma mansoni enhances host susceptibility to mucosal but not intravenous challenge by R5 Clade C SHIV. PLoS Negl Trop Dis 5(8): e1270. pmid:21829749
  36. 36. Hotez Peter J., Bottazzi Maria Elena, Bethony Jeffrey and Diemert David D. Advancing the Development of a Human Schistosomiasis Vaccine Trends in Parasitology, 2019-02-01, Volume 35, Issue 2, Pages 104–108, pmid:30455112
  37. 37. Yirenya-Tawiah DR, Ackumey MM, Bosompem KM (2016) Knowledge and awareness of genital involvement and reproductive health consequences of urogenital schistosomiasis in endemic communities in Ghana: a cross-sectional study. Reprod Health 13(1): 117. pmid:27655032
  38. 38. Friedman JF, Olveda RM, Mirochnick MH, Bustinduy AL, Elliott AM (2018) Praziquantel for the treatment of schistosomiasis during human pregnancy. Bull World Health Organ 96(1):59–65. pmid:29403101
  39. 39. UNAIDS fact sheet World AIDS day 2018: 2017 Global HIV statistics. http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf. [cited 30 November 2018].
  40. 40. UNAIDS Joint United Nations Programme on HIV/AIDS. HIV Prevention 2020 Road Map. 2017. http://www.unaids.org/sites/default/files/media_asset/hiv-prevention-2020-road-map_en.pdf. [cited 26 September 2018].
  41. 41. BRIGHT Research. Female Genital Schistosomiasis at an HIV Conference. https://brightresearch.org/fgs-at-an-hiv-conference/. [cited 26 September 2018].
  42. 42. UNAIDS Joint United Nations Programme on HIV/AIDS. The need for a holistic approach to women and HIV. Feature Stories. March 16, 2018. http://www.unaids.org/en/resources/presscentre/featurestories/2018/march/20180316_holistic-approach-to-women-and-hiv. [cited 26 September 2018].
  43. 43. World Health Organization (2017) Schistosomiasis and soil-transmitted helminthiases: number of people treated in 2016. Weekly Epidemiol Rec 8 December 92(49): 749–60.