Citation: Hotez PJ, Fenwick A, Kjetland EF (2009) Africa's 32 Cents Solution for HIV/AIDS. PLoS Negl Trop Dis 3(5): e430. doi:10.1371/journal.pntd.0000430
Published: May 26, 2009
Copyright: © 2009 Hotez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this study.
Competing interests: PJH and AF are Co-Founders of the Global Network for Neglected Tropical Disease Control, and PJH is an inventor on two international patents on hookworm vaccines. AF is Director of the Schistosomiasis Control Initiative.
By preventing urogenital schistosomiasis in sexually active females through simple and low-cost methods, we have an innovative and timely opportunity to reduce and possibly interrupt HIV/AIDS transmission throughout many rural areas of sub-Saharan Africa.
More than 90% of the world's 207 million cases of schistosomiasis occur in sub-Saharan Africa , making this condition (as well as hookworm infection) one of the most common neglected tropical diseases in the region ,. Based on additional information that schistosomiasis causes chronic anemia and inflammation associated with severe disability among children, adolescents, and young adults, the disease burden resulting from schistosome infections in Africa may actually rival better known conditions such as HIV/AIDS, tuberculosis, and malaria ,.
Approximately two-thirds of the cases of schistosomiasis in sub-Saharan Africa result from urinary tract infections caused by Schistosoma haematobium. Shown in Figure 1 is a map of the geographic distribution of urinary schistosomiasis in Africa, in which the major foci of infection occur in southeastern Africa, i.e., Kenya, Malawi, Mozambique, Tanzania, Zimbabwe, South Africa, and Zambia; in West Africa, i.e., Burkina Faso, Mali, Niger, and Nigeria; and in Angola and Sudan. However, urinary schistosomiasis has been almost eliminated from Egypt . Of the estimated 112 million cases of S. haematobium infection in sub-Saharan Africa, approximately 70 million are associated with hematuria, 18 million with major bladder wall pathology, and 9.6 million with major hydronephrosis leading to severe kidney damage . The results from Egypt suggest that these consequences may be avoidable provided that regular praziquantel treatment reaches school-age children at risk.
Figure 1. Global distribution of S. haematobium Infection in Africa (As Well As S. japonicum and S. mekongi Infections in Asia) from the World Health Organization.
Reprinted with the permission of the WHO (from page 16 in , image WHO 92721).doi:10.1371/journal.pntd.0000430.g001
In addition, there is yet another and largely hidden condition associated with chronic S. haematobium infection. Studies from the S. haematobium–endemic areas of sub-Saharan Africa indicate that between 33% and 75% of infected women also suffer from female genital schistosomiasis (FGS) of the lower genital tract . FGS results from deposition of the schistosome eggs in the uterus, cervix, vagina, or vulva, and the ensuing host inflammation is comprised of granulomas, fibrosis, and angiogenesis (pathological localized blood vessel formation) ,. The cervix and the vagina are the most common sites of egg deposition, although post-mortem studies have revealed that the upper genital tract is also frequently involved . FGS was identified as an established clinical feature of S. haematobium infection in Africa beginning in the 1950s and early 1970s ,, but it is only within the last two decades that its full clinical spectrum has been revealed , , –. The pathognomonic lesions associated with S. haematobium infection in the female genitals are mucosal grainy sandy patches linked to egg granulomas, which are usually associated with mucosal bleeding (especially “contact bleeding” during pelvic examination or sexual intercourse) and abnormal blood vessels . The homogenous yellow sandy patches of FGS may mimic the sexually transmitted diseases (STDs) and have been found to be associated with a variety of important clinical manifestations including bleeding disorders, dyspareunia, pelvic and lower abdominal pain, vaginal discharge, pollakisuria, stress incontinence, and infertility ,,,.
Now there is new evidence indicating that the sandy patches of FGS increase susceptibility to HIV/AIDS –. Schistosomiasis occurs predominantly in rural areas, and although HIV/AIDS is often considered an urban or semi-urban infection, there are also important and emerging foci of epidemic AIDS in African rural communities . A cross-sectional study from a rural Zimbabwean community reveals that women aged 20 to 49 with FGS exhibit a 3-fold risk of having HIV relative to women without FGS . Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry in a manner similar to that described for STDs such as viral infection from herpes simplex virus 2 or human papillomavirus, or syphilis , –. Alternatively, contact bleeding could promote direct entry of HIV into the bloodstream, or the CD4+ cells present in schistosome egg granulomas could provide a nidus for HIV viral entry and replication .
Regardless of the mechanism, it is important to establish whether anti-schistosomal treatment could represent an innovative HIV/AIDS prevention strategy. Towards this end, praziquantel is both a highly effective and low-cost anti-schistosomal therapy and a prophylactic agent against schistosomal morbidity in adults. The London-based Schistosomiasis Control Initiative (SCI) is currently working with ministries of health to conduct appropriate national control programs for schistosomiasis and other helminth infections . In Burkina Faso, SCI has shown that when provided as a single mass treatment in Burkina Faso praziquantel can reduce the prevalence of S. haematobium infection by 84% among girls and 78% overall for at least 2 years –. SCI has also demonstrated similar successes in the other seven sub-Saharan African countries where it operates . SCI is currently developing country-specific strategies based on annual or biannual treatment of school-age children according to collected epidemiological evidence of prevalence and intensity of infections, and based on the World Health Organization (WHO) recommendations . The WHO strategy is of mass drug administration (MDA) with praziquantel for all school-age children (enrolled and not enrolled) once every 2 years in moderate risk communities where the prevalence of schistosomiasis exceeds 10%, and annually where the prevalence exceeds 50% . Among women with FGS, praziquantel will result in parasitological cure and halt the appearance of new ova in the urine and presumably in the genital tract . However, while there are instances when treatment will also reverse some of the lower genital tract abnormalities associated with FGS , regrettably praziquantel anthelminthic therapy among adult women (with established genital schistosomiasis) does not alleviate genital lesions, contact bleeding, or vessel abnormalities . Therefore, based on the presumed mechanism by which FGS promotes HIV infection, it is unlikely that praziquantel treatment of affected adults will interrupt the horizontal transmission of HIV/AIDS.
Our hypothesis is that treatment of younger females at risk of schistosomiasis is therefore critical, and that praziquantel treatment of young school-age girls will prevent the development of FGS and therefore represent an innovative AIDS prevention strategy in areas of HIV and S. haematobium transmission. In a cross-sectional study in northern Zimbabwe, women who report having received praziquantel treatment before the age of 20 exhibited an absence of sandy patches and contact bleeding that was independent of adult waterbody contact . Based on this study, we believe there is an urgent need to demonstrate the impact of praziquantel on HIV transmission in prospective studies among school-age girls living in HIV/AIDS and schistosomiasis co-endemic areas, such as in the southeastern countries of Malawi, Mozambique, Tanzania, and Zimbabwe, areas which exhibit high prevalences of both S. haematobium and HIV infections (Figures 1 and 2). We further support efforts to seek additional funds in order to investigate this innovative HIV/AIDS control tool. There is also some evidence that Schistosoma mansoni infection could result in FGS, although at a lower rate than S. haematobium infection ; this also warrants further study, particularly given that vaccines against both S. haematobium and S. mansoni infection are under development ,.
Figure 2. Global Distribution of HIV/AIDS in Africa, Showing the HIV Prevalence (%) in Adults (15–49) in Africa, 2007.
Reprinted with the permission of UNAIDS (from page 39 in , Figure 2.8).doi:10.1371/journal.pntd.0000430.g002
However, we also feel that the evidence for FGS promoting HIV transmission is sufficiently compelling that it would be unethical to withhold mass treatment for many years while awaiting the results of a prospective study that follows school-age girls as they become sexually active women (and exposed to HIV). Van der Werf et al. estimate there are 56 million African school-age children with S. haematobium infection , and presumably 28 million S. haematobium–infected school-age girls. There are also another 14 million preschool children and 7 million infected preschool girls in Africa (Table 1). Based on the estimate that between 33% and 75% of women infected with S. haematobium also exhibit signs and symptoms of FGS , and taking the value of 54% as the mean of these ranges, it follows that approximately 19 million girls could develop FGS over the next decade in sub-Saharan Africa. With an appropriate school-based praziquantel treatment regime (annually in highly endemic areas), it would be possible to prevent 16 million cases of FGS in sub-Saharan Africa through this approach. This assumes that bi-annual praziquantel treatments can reduce the prevalence of schistosomiasis by 84% as shown previously in Burkina Faso . Although outside of South Africa there are not well-established incidence figures for HIV/AIDS in the region, the Joint United Nations Programme on HIV/AIDS (UNAIDS) reports that 1.9 million new cases of HIV/AIDS occurred in sub-Saharan Africa in 2007 , representing 0.25% of the total population of 770 million in the region . By extrapolation we can estimate that among a cohort of 16 million women with FGS having a 3-fold increased risk of HIV/AIDS (representing 0.75% of this population), we could potentially prevent up to 120,000 new cases of HIV/AIDS through regular praziquantel treatments in the next decade. Almost certainly, this figure is a conservative estimate. In addition, schistosomiasis is known to cause hematospermia and increased levels of immunological activity in sperm (including increased leukocytes and elevated cytokine levels), decreasing after treatment ,. For anatomical reasons, male genital schistosomiasis does not appear to make men more susceptible to HIV/AIDS. However, dually infected men have been hypothesized to increase the risk of HIV/AIDS transmission to women through higher HIV viral loads in seminal ejaculate –35. The viral loads in semen of schistosomiasis-infected males has not yet been investigated.
MDA of praziquantel is both low cost and cost efficient. The SCI has determined that even considering all of the delivery costs, the mass treatment program of school-age children in Burkina Faso was conducted for only $0.32 per child . Therefore, 70 million children infected with S. haematobium could be treated for $22 million, which, if repeated bi-annually for 10 years, would cost approximately $112 million (Table 1). By comparison, PEPFAR (the US President's Emergency Plan for AIDS Relief) is projected to spend $18.8 billion over the next 5 years (representing the largest international health initiative ever devoted to a single disease), including $1.34 billion annually in support of treatment programs and $601 million annually in support of treatment strategies . Therefore, periodic praziquantel administration would represent a very small add-on cost to the PEPFAR budget, and yet would have the dual benefits of making dramatic improvements in the reproductive health of women living in rural Africa, likely reducing HIV/AIDS transmission. Shown in Table 2 are the prevalence rates of both HIV/AIDS and schistosomiasis in the 15 countries where PEPFAR operates. At the minimum, we strongly advocate for the introduction of low-cost praziquantel MDA in the PEPFAR countries of Mozambique, Tanzania, and Zambia by using PEPFAR funds in support of SCI activities through a Global Network for NTDs –. This represents a $0.32 solution that could have enormous benefits for young African women and a huge potential beneficial impact on Africa's AIDS epidemic.
- 1. Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J (2006) Schistosomiasis and water resources development: Systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 6(7): 411–425. doi:10.1016/S1473-3099(06)70521-7.
- 2. Hotez PJ, Bethony JM, Oliveira SC, Brindley PJ, Loukas A (2008) Multivalent anthelminthic vaccine to prevent hookworm and schistosomiasis. Expert Rev Vaccines 7(6): 745–752. doi:10.1586/147605188.8.131.525.
- 3. King CH, Dangerfield-Cha M (2008) The unacknowledged impact of chronic schistosomiasis. Chronic Illn 4(1): 65–79. doi:10.1177/1742395307084407.
- 4. Fenwick A (2006) Waterborne infectious diseases–could they be consigned to history? Science 313(5790): 1077–1081. doi:10.1126/science.1127184.
- 5. van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, et al. (2003) Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 86(2–3): 125–139.
- 6. Poggensee G, Feldmeier H, Krantz I (1999) Schistosomiasis of the female genital tract: Public health aspects. Parasitol Today 15(9): 378–381.
- 7. Kjetland EF, Ndhlovu PD, Mduluza T, Gomo E, Gwanzura L, et al. (2005) Simple clinical manifestations of genital schistosoma haematobium infection in rural Zimbabwean women. Am J Trop Med Hyg 72(3): 311–319.
- 8. Gelfand M, Ross WF (1953) The distribution of schistosome ova in the genito-urinary tract in subjects of bilharziasis. Trans R Soc Trop Med Hyg 47(3): 218–220.
- 9. Gelfand M, Ross MD, Blair DM, Weber MC (1971) Distribution and extent of schistosomiasis in female pelvic organs, with special reference to the genital tract, as determined at autopsy. Am J Trop Med Hyg 20(6): 846–849.
- 10. Feldmeier H, Poggensee G, Krantz I, Helling-Giese G (1995) Female genital schistosomiasis. new challenges from a gender perspective. Trop Geogr Med 47: 2 SupplS2–S15.
- 11. Swai B, Poggensee G, Mtweve S, Krantz I (2006) Female genital schistosomiasis as an evidence of a neglected cause for reproductive ill-health: A retrospective histopathological study from Tanzania. BMC Infect Dis 6: 134. doi:10.1186/1471-2334-6-134.
- 12. Kjetland EF, Kurewa EN, Ndhlovu PD, Midzi N, Gwanzura L, 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): 1509–1517. doi:10.1111/j.1365-3156.2008.02161.x.
- 13. Feldmeier H, Krantz I, Poggensee G (1994) Female genital schistosomiasis as a risk-factor for the transmission of HIV. Int J STD AIDS 5(5): 368–372.
- 14. Kjetland EF, Ndhlovu PD, Gomo E, Mduluza T, Midzi N, et al. (2006) Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS 20(4): 593–600. doi:10.1097/01.aids.0000210614.45212.0a.
- 15. Ndhlovu PD, Mduluza T, Kjetland EF, Midzi N, Nyanga L, et al. (2007) Prevalence of urinary schistosomiasis and HIV in females living in a rural community of Zimbabwe: Does age matter? Trans R Soc Trop Med Hyg 101(5): 433–438. doi:10.1016/j.trstmh.2006.08.008.
- 16. Serwadda D, Wawer MJ, Musgrave SD, Sewankambo NK, Kaplan JE, et al. (1992) HIV risk factors in three geographic strata of rural Rakai district, Uganda. AIDS 6(9): 983–989.
- 17. Rebbapragada A, Kaul R (2007) More than their sum in your parts: The mechanisms that underpin the mutually advantageous relationship between HIV and sexually transmitted infections. Drug Discov Today Dis Mech 4: 237–246.
- 18. White RG, Orroth KK, Glynn JR, Freeman EE, Bakker R, et al. (2008) Treating curable sexually transmitted infections to prevent HIV in Africa: Still an effective control strategy? J Acquir Immune Defic Syndr 47(3): 346–353. doi:10.1097/QAI.0b013e318160d56a.
- 19. Orroth KK, Gavyole A, Todd J, Mosha F, Ross D, et al. (2000) Syndromic treatment of sexually transmitted diseases reduces the proportion of incident HIV infections attributable to these diseases in rural Tanzania. AIDS 14(10): 1429–1437.
- 20. Schistosomiasis Control Initiative (2008) Schistosomiasis Control Initiative: working towards a world without worms. Available: http://www.sci-ntds.org/. Accessed 4 May 2009.
- 21. Toure S, Zhang Y, Bosque-Oliva E, Ky C, Ouedraogo A, et al. (2008) Two-year impact of single praziquantel treatment on infection in the national control programme on schistosomiasis in Burkina Faso. Bull World Health Organ 86(10): 780–787, A.
- 22. Koukounari A, Gabrielli AF, Toure S, Bosque-Oliva E, Zhang Y, et al. (2007) Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso. J Infect Dis 196(5): 659–669. doi:10.1086/520515.
- 23. Garba A, Toure S, Dembele R, Bosque-Oliva E, Fenwick A (2006) Implementation of national schistosomiasis control programmes in West Africa. Trends Parasitol 22(7): 322–326. doi:10.1016/j.pt.2006.04.007.
- 24. World Health Organization (2006) Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs in control interventions: A manual for health professionals and programme managers. Geneva: WHO Press.
- 25. Kjetland EF, Mduluza T, Ndhlovu PD, Gomo E, Gwanzura L, et al. (2006) Genital schistosomiasis in women: a clinical 12-month in vivo study following treatment with praziquantel. Trans R Soc Trop Med Hyg 100(8): 740–752. doi:10.1016/j.trstmh.2005.09.010.
- 26. Richter J, Poggensee G, Kjetland EF, Helling-Giese G, Chitsulo L, et al. (1996) Reversibility of lower reproductive tract abnormalities in women with schistosoma haematobium infection after treatment with praziquantel–an interim report. Acta Trop 62(4): 289–301.
- 27. Kjetland EF, Ndhlovu PD, Kurewa EN, Midzi N, Gomo E, et al. (2008) Prevention of gynecologic contact bleeding and genital sandy patches by childhood anti-schistosomal treatment. Am J Trop Med Hyg 79(1): 79–83.
- 28. Feldmeier H, Daccal RC, Martins MJ, Soares V, Martins R (1998) Genital manifestations of schistosomiasis mansoni in women: important but neglected. Mem Inst Oswaldo Cruz 93: Suppl 1127–133.
- 29. McManus DP, Loukas A (2008) Current status of vaccines for schistosomiasis. Clin Microbiol Rev 21(1): 225–242. doi:10.1128/CMR.00046-07.
- 30. UNAIDS (2008) Status of the global HIV epidemic: 2008 report on the global AIDS epidemic. Chapter 2. Available: http://data.unaids.org/pub/GlobalReport/2008/jc1510_2008_global_report_pp29_62_en.pdf. Accessed 4 May 2009.
- 31. Population Reference Bureau (2007) World population highlights: key findings from PRB's 2007 world population data sheet. Population Bulletin 62(3): 1–12. Available: http://www.prb.org/pdf07/62.3Highlights.pdf. Accessed 4 May 2009.
- 32. Leutscher PD, Pedersen M, Raharisolo C, Jensen JS, Hoffmann S, et al. (2005) Increased prevalence of leukocytes and elevated cytokine levels in semen from schistosoma haematobium-infected individuals. J Infect Dis 191(10): 1639–1647. doi:10.1086/429334.
- 33. Leutscher PD, Reimert CM, Christensen NO, Vennervald BJ (2000) Male genital schistosomiasis (MGS)–a neglected risk factor for HIV transmission in sub-Saharan Africa? [abstract number LbPeC7079]. International Conference on AIDS; 9–14 July 2000; Durban, South Africa 13: 53.
- 34. Cohen MS (2004) HIV and sexually transmitted diseases: lethal synergy. Top HIV Med 12(4): 104–107.
- 35. Dyer JR, Eron JJ, Hoffman IF, Kazembe P, Vernazza PL, et al. (1998) Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. J Infect Dis 177(1): 224–227.
- 36. Gabrielli AF, Toure S, Sellin B, Sellin E, Ky C, et al. (2006) A combined school- and community-based campaign targeting all school-age children of Burkina Faso against schistosomiasis and soil-transmitted helminthiasis: performance, financial costs and implications for sustainability. Acta Trop 99(2–3): 234–242. doi:10.1016/j.actatropica.2006.08.008.
- 37. PEPFAR (2008) The power of partnerships: the U.S. President's emergency plan for AIDS relief. 2008 annual report to congress - highlights. Available: http://www.pepfar.gov/documents/organization/101150.pdf. Accessed 4 May 2009.
- 38. Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, et al. (2007) Control of neglected tropical diseases. N Engl J Med 357(10): 1018–1027. doi:10.1056/NEJMra064142.
- 39. Hotez PJ, Fenwick A, Savioli L, Molyneux DH (2009) Rescuing the bottom billion through control of neglected tropical diseases. Lancet 373(9674): 1570–1575. doi:10.1016/S0140-6736(09)60233-6.
- 40. The Sabin Vaccine Institute (2008) Global Network for Tropical Diseases. Available: http://www.globalnetwork.org/. Accessed 4 May 2009.
- 41. WHO Expert Committee on the Control of Schistosomiasis (1993) The control of schistosomiasis. Second report of the WHO Expert Committee. WHO Technical Report Series 830. Image WHO 92721. Geneva: WHO. Available: http://whqlibdoc.who.int/trs/WHO_TRS_830.pdf. Accessed 5 May 2009.
- 42. UNAIDS (2008) Status of the global HIV epidemic: 2008 report on the global AIDS epidemic. Annex 1: HIV and AIDS estimates and data, 2007 and 2001. Available: http://data.unaids.org/pub/GlobalReport/2008/jc1510_2008_global_report_pp211_234_en.pdf. Accessed 4 May 2009.