Schistosomiasis, a water-borne flatworm parasitic infection, is endemic to many countries mainly in Africa (90% of cases) but also in Asia, South America, and the Caribbean. It is estimated to affect more than 200 million people with deaths estimated between 24,0671 and 200,000 globally yearly2 and has the highest disease burden among the World Health Organization recognized neglected tropical diseases.3,4 People are infected most commonly in childhood through skin contact with contaminated water, and depending on the species, the adult worms settle in different parts of the venous system where they live on average for 5–7 years. Pathological lesions resulting from inflammatory reactions to Schistosoma egg deposition in the tissues by female adult worms are known to be one of the major causes of chronic liver disease, portal hypertension, and bladder cancer in sub-Saharan Africa.
Schistosomiasis also affects the female genital tract (fallopian tubes, uterus, cervix, vagina, and vulva). Termed female genital schistosomiasis (FGS), it is usually caused by the species S. haematobium but also by other species including S. mansoni. Clinical features include hypertrophic and ulcerative lesions of the vulva, vagina, and cervix, as well as grainy sandy patches, abnormal blood vessels, and rubbery papules on the cervix or vaginal wall. Estimates suggest there may be 20 million cases of FGS worldwide,5,6 with a prevalence in women ranging from 33% to 75% in some African endemic countries.7–11 The diagnosis is challenging, requiring a gynecological examination by a trained clinician, and FGS can be mistaken for other pathologies such as cervical cancer or sexually transmitted infections (STIs).
The medication used to treat schistosomiasis, praziquantel (PZQ), is cheap, available, and effective in early infections12–14 but likely ineffective once chronic calcified lesions have developed.15 The best strategy to prevent FGS is to treat schistosomiasis rapidly after infection occurs. The World Health Organization recommends annual treatment with praziquantel for school-aged children in highly endemic areas to treat schistosomiasis12,16,17—an intervention that is relatively affordable, at about 40 US cents per person.18
Over the years, several studies have indicated an association between HIV prevalence and FGS. Schistosoma haematobium and HIV prevalences correlate in sub-Saharan Africa,19 and in this region, a study across 43 countries found that each S. haematobium infection per 100 individuals was associated with a 2.9% (95% CI: 0.2% to 5.8%) increase in HIV prevalence.20 In Zimbabwe, women with FGS had a higher prevalence of HIV than those without FGS (33% compared to 26%, P = 0.05), with an even stronger association in women older than 35 years (37.5% compared to 16.8%, P < 0.001).21 In Mozambique, a study showed an association between high rates of schistosome exposure and increased rates of HIV infection in women.22 Two case–control studies have also shown an up to 4 times increased odds of HIV infection in people with urogenital schistosomiasis.23,24 The association between FGS and HIV seems clearer than the association between HIV and S. mansoni or S. haematobium infection in general. For example, some studies found increased odds of becoming HIV-infected if coinfected with S. mansoni compared with women who were not coinfected,25,26 while other case–control studies did not find any association.21,27–29
These studies suggest that schistosomiasis may put women at a higher risk of acquiring HIV. FGS may lead to an increased susceptibility to HIV infection through damage to the mucosal barrier of the cervix and vagina by lesions.11 In addition, susceptibility to HIV may increase through local30–32 and systemic33 immune modulation induced by the immunological reactions to egg deposition. This may explain the high rates of HIV in young women living in highly endemic rural areas such as along Lake Victoria in Tanzania34 and KwaZulu-Natal.35 Therefore, it is plausible that PZQ treatment programs aimed at the prevention, or if proved effective, treatment of FGS, could reduce HIV infection, especially in younger women.36–39
The effect of HIV on the frequency and severity of FGS has not been well described. It is not known, for example, if HIV-infected women are at an increased risk of becoming infected with schistosomes through reduced immunity and thus are at an increased risk of developing FGS. This possibility is supported by data from Tanzania showing that the intensity of S. mansoni infection was higher in HIV-positive women.26 However, if FGS does develop in HIV-infected women, it may be associated with less severe disease forms because many of the pathogenic effects of schistosome infection are immune mediated, and therefore potentially less severe if one is immune suppressed. It has also been shown that urinary excretion of S. haematobium eggs is decreased or equivalent in HIV-positive women.28,40–42 In addition, a reported sequelae of FGS is infertility, and it is possible that this risk is increased in HIV-infected women if their risk of FGS is increased.43–46
Another potential clinical concern is a further increase in the rate of cervical cancer in HIV-positive women, already at an increased risk of this malignancy due to HIV. The chronic inflammation associated with schistosome infection is known to cause bladder and liver cancer, and there are reports of an association with cervical cancer either as a direct effect of the schistosomiasis or by influencing persistence of high-risk subtypes of human papillomavirus (HPV).47,48
The effects of FGS on those infected with HIV are also not well understood. In a case–control study from Tanzania, those with schistosomiasis who recently acquired HIV had higher HIV viral loads compared with those who did not have schistosomiasis.25 Furthermore, a study from Zimbabwe showed that treatment of schistosomiasis was associated with lower HIV viral loads and increased CD4 cell counts.49 Therefore, schistosome infection, which leads to chronic immune activation, may increase HIV viral load50 and, thus, the rate of HIV disease progression. On the other hand, a recent study from Tanzania showed that those with evidence of schistosome infection at the time of HIV seroconversion had an 82% reduction in the risk of their CD4 count falling to < 350 cells/mm3 and/or death.51 In addition, a further study from Tanzania found lower HIV viral loads in those with schistosome coinfection if the time of HIV infection was taken into account.52 These studies suggest some protection against HIV disease progression by schistosome coinfection.
Schistosomiasis may also significantly increase the risk of HIV transmission to sexual partners and from mother to child either due to increased viral load53 or the presence of increased virus-carrying inflammatory cells in semen and vaginal fluids. A modeling study suggested that for every 100 HIV-infected people, each suffering one episode of schistosome infection, there were 8.5 (2.7%–97.5%: 0.2–38.6) excess onward HIV-1 transmission events attributable to schistosome coinfection.54
Importantly, it is not known if there is an effect on mortality in HIV-infected women affected by FGS. However, it is plausible that it may be increased through genitourinary related sepsis from inflamed and ulcerated mucosa. It is known that severe bacterial sepsis is a frequent cause of mortality in HIV-infected patients, especially when immune suppression is severe.55 Mortality rates are also increased in HIV-infected people with other illnesses associated with the breakdown of protective surfaces such as skin in patients with Buruli ulcer.56 If a true increase in mortality risk was found, it would demand increased attention to the prevention, screening, and treatment of FGS in HIV populations.
There may also be significant treatment effects to consider for coinfected patients. First, it is possible that the effectiveness of FGS treatment with PZQ, which is already in question,15 may be further reduced compared to non–HIV-infected women, either due to immune suppression from HIV infection, or through interactions with antiretroviral drugs to treat HIV, as PZQ is metabolized by the cytochrome P450 group including CYP 3A4 and CYP2C19.57 This metabolism pathway may result in increased treatment failure or recurrence rates.58 PZQ doses may need to be increased or prolonged, but these issues have not been adequately studied. It has also been reported that schistosome coinfection is associated with a reduced immunological response to ART.59 Furthermore, it is possible that ART initiation may lead to immune reconstitution inflammatory syndrome associated with FGS.60,61 If severe, the resulting tissue damage could lead to increased long-term FGS complications, including infertility, and this could justify screening for FGS before ART initiation.
FGS can be diagnosed clinically through identification of the pathognomonic lesions associated with S. haematobium infection in the female genital tract—mucosal grainy sandy patches linked to egg granulomas.11,62 However, this requires gynecological examination equipment and trained clinicians. Diagnosis can also be made by visualization of eggs in lesions, but this requires access to histopathology services, which are uncommon in most endemic countries, and unless excluding malignancy, biopsying lesions is best avoided, as the biopsy site may temporarily increase HIV infection risk. FGS lesions have the potential to be misdiagnosed as cancer without histopathology, potentially leading to unnecessary cancer surgery.63 Research, therefore, needs to be undertaken to develop better diagnostic tools for FGS, especially focused on point of care. An example would be health clinic diagnosis using self-administered vaginal swabs, as a positive Schistosoma-specific PCR in vaginal lavage fluid can detect genital lesions,64 although the sensitivity for detection with current tools is low.65 Perhaps, multiplex-based polymerase chain reaction technology could be applied to combine the detection of Schistosoma DNA in gynecological samples with the detection of STIs such as HPV, herpes simplex virus (HSV), chlamydia, gonorrhoea, and syphilis.
Currently screening for FGS is uncommonly performed in HIV-infected women in schistosomiasis-endemic areas. This is likely related to a number of factors including the lack of awareness and understanding of the significance of FGS in HIV-coinfected women, a lack of capacity in HIV services to perform adequate gynecological examinations, unclear cost-benefit, a lack of training of staff in how to diagnose FGS, and the absence of an easy to use point-of-care diagnostic test.
For programs wanting to address the burden of FGS and at the same time cervical cancer screening, the HIV-infected population is an appropriate group to include as a prioritized population because they seem to have a higher burden of both diseases than the non–HIV-infected population—therefore, targeting HIV-positive women will likely allow access to large numbers of women with these diseases. In addition, they are also likely to have a greater risk of adverse clinical outcomes from FGS than in non–HIV-infected women meaning addressing this issue is particularly urgent in this population. However, there is a need to increase awareness among clinicians and program managers about the importance of FGS in this population, and strategies need to be designed to incorporate FGS screening, prevention, and treatment into the care of HIV-positive women (Table 1). Models of care need to be explored to ensure this is performed efficiently and appropriately. Options could include combining them with HPV prevention and cervical cancer screening or STI services, either introduced into HIV clinics, or established in female-specific health services. Operational research needs to be undertaken to pilot and assess the feasibility and effectiveness of the different models of care.
The paucity of data regarding the impact of FGS and HIV coinfection points to an urgent need for clinical research to better understand the extent and significance of these concerns. Summarized in Table 2, we propose a research agenda that aims to address many of these important information gaps and stimulate interest and support. Answering these questions would help to inform the development of approaches for the management of FGS/HIV coinfection, which are currently lacking. In combination with the proposed research agenda, more emphasis needs to be put into increasing the knowledge and awareness of communities, clinicians, program managers, and local, regional, and national programs around the important issues relating to FGS/HIV coinfection. Support from funding agencies will be needed to make the resources available required to turn the research agenda into reality.
In conclusion, the likely increased prevalence of HIV in women infected with FGS means that FGS is an important health problem for HIV-positive women in schistosomiasis-endemic areas. FGS may have significant effects on those infected with HIV including more rapid disease progression, increased HIV transmission to others, and potentially increased mortality (Table 3). Furthermore, FGS may make young women more susceptible to HIV and be significantly impacting the HIV epidemic in sub-Saharan Africa. In addition, it is possible that HIV may have a significant effect on FGS outcomes such as disease severity, risk of cervical cancer and infertility, and response rates to PZQ treatment. Therefore, there is an urgent need for research (clinical and operational) around FGS/HIV coinfection to answer the significant gaps in current knowledge. There is also an important need to increase awareness about the issues and provide guidance for clinicians and program managers caring for HIV/FGS-coinfected women.
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