Two hundred million people in 76 countries have schistosomiasis and 85% of these are on the African continent . Women with urinary Schistosoma haematobium may have lesions on the uterine cervix, in the vagina and on the vulva [2–6]. Furthermore women may have genital schistosomiasis, even without urinary schistosomiasis [7–9]. Genital sandy patches, often accompanied by concomitant blood vessel friability and inflammation, are reportedly pathognomonic for S. haematobium infection, and have been found in up to 46% of the women in high-endemic areas [6,7,9–11].
Women comprise 57% of the HIV-infected population in Africa . Several studies on HIV prevalence have shown an unexplained gender quotient disfavouring rural women [12,13], with 1.3–6.4 HIV-positive women to every man. Furthermore, in rural women the HIV prevalences peak at younger ages, suggesting that risk factors in rural and urban populations may be different [13–15].
Sexually transmitted genital ulcers may provide points of entry for viral transmission [14,16–19]. In epidemiological studies sexually transmitted diseases (STDs) have been associated with increased risk of HIV transmission. No study has scrutinized the possible association between genital schistosomiasis and HIV.
In Africa the highest HIV prevalence rates are found in urban and semi-urban areas . Schistosoma haematobium is transmitted in freshwater bodies and is thus usually a rural phenomenon. The two diseases meet in migrating populations, travellers, commuting spouses and roadside villages , moreover there are now reports of rural HIV epidemics in Africa [12,15,21]. This study sought to assess if there is an association between genital S. haematobium infection and HIV in women in rural Zimbabwe.
MATERIALS AND METHODS
Inclusion and exclusion criteria
A cross-sectional study was conducted in north-western Zimbabwe. All women aged 20–49 years were invited to take part in the study [7,22]. From the area directly around the clinic and at three pick-up points 83% (294/353) attended, but only 33% (233/706) attended from the surrounding areas. As has been described previously women from the pick-up points did not differ from women from the surrounding areas with respect to symptoms or diseases. Virgins, pregnant, postmenopausal and menstruating women were excluded. No schistosomiasis control programme had been done on the adult population.
Inclusion in the study took place after individual informed oral consent. Permission was granted by the provincial and district medical directors, the village headman and at village meetings. Ethical approval was given by the Medical Research Council of Zimbabwe and by the ethical committee of the Special Programme for Research and Training in Tropical Diseases Research, UNDP/WB/WHO. Patients and partners were treated in accordance with the standard Zimbabwean syndromic approach and referred when necessary .
A nurse questioned the women in Shona (the local language) for current and past urogenital symptoms and obstetric history. Clinical investigations were done by one clinician (E.F.K.) as has been described previously . Briefly, at the time the clinician knew neither the HIV result nor the result of S. haematobium examination in urine. Genital surfaces were examined using a photocolposcope after which papanicolaou (Pap) smears were done in all consenting women. Upon suspicion and if the patient agreed, specimens for STD or cancer diagnosis were taken .
Homogenous yellow sandy patches were sandy looking areas with no distinct grains using 15-times magnification [5,7]. Grainy sandy patches portrayed oblong (approximately 0.05 mm by 0.2 mm) grains situated in the mucosa. Neo-vascularization was defined as pathological convoluted (cork-screw), reticular, circular and/or branched, uneven-calibre blood vessels visible (15-times magnification) on the mucosal surface. Contact bleeding was defined as fresh blood originating from the mucosal surface. Body mass index (BMI), used as a surrogate marker for CD4 cell count, was calculated by dividing weight (kg) by height (m)2 [24,25].
Urine samples were examined for S. haematobium ova [7,26]. A single terminal-spined ovum gave a positive diagnosis in Pap smears, wet mounts or biopsies of genital tissue . Wet mounts were taken from consenting women who showed debris or friable, loose and bleeding tissue. As lesions may offer an entry port for HIV, and many women in the area may not be able to decide whether to have intercourse , biopsies were only done in consenting women on clinical indication. Stool was processed by the Kato Katz technique .
Other specimens and laboratory tests
As described in detail previously, examinations for STDs and HIV were carried out last, and only when there was sample material remaining after other examinations [7,22,30]. Women were tested for a median of seven STDs (range, 1–8, selected results below): Serologic tests were run for HIV (29%, 153/523), trichomonas and herpes simplex virus type 2 (HSV-2). HSV-2 was found in 65% (307/476). Current syphilis was determined by the presence of an ulcer and seroconversion. Past syphilis (6%, 30/481) was determined by two serological tests. Cultures were run for Haemophilus ducreyi. Polymerase chain reactions (PCR) were run for H. ducreyi and human papillomavirus (HPV, 33%, 81/236). Trichomoniasis was also tested by microscopic examination, as was candidiasis and Neisseriae gonorrhoeae. Bacterial vaginosis was diagnosed using Nugent's criteria. PCR was run for N. gonorrhoeae and Chlamydia trachomatis (Chlamydia). Pap smears were investigated for cell atypia. Herpes simplex virus type 1 and donovaniasis were not tested due to high and negligible prevalence, respectively.
Chi-squared, Fisher's exact test (for numbers below 5) and odds ratio (OR) with 95% confidence interval (95% CI) were used when comparing prevalence in two groups of subjects. Mann–Whitney U-test was used to compare BMI or age in two groups. In order to study simultaneously the impact of several variables, logistic regression analysis was applied with a 5% significance level; variables were included if the P-value from crude association was less than 0.2 and if the Spearman rank correlation coefficient was below 0.7. Where there were less than 10 cases, the variable was not included in regression analysis. Pap smear was the only laboratory test for S. haematobium ova taken irrespective of findings and was therefore chosen for analysis against other variables . The statistical analysis was computed using Statistical Package for the Social Sciences (SPSS), version 11 (SPSS Inc., Chicago, Illinois, USA).
Baseline schistosomal data have been reported in detail previously [7,22,30]. Briefly 46% (243/527) were found to have genital sandy patches, 44% (231/527) had neo-vascularization, and 23% (122/527) had contact bleeding. Median age was 30 years for HIV-positive, and 36 years for HIV-negative women (P = 0.003). Women between the ages of 25 and 29 years had the highest HIV prevalence (45%). BMI was significantly associated with HIV seropositivity (age adjusted OR, 0.89; 95% CI, 0.8–0.9; P = 0.002).
Genital S. haematobium was the strongest predictor for neo-vascularization, the two types of genital sandy patches, and contact bleeding in multivariate analysis, adjusted for sexually transmitted diseases . Only later did we realize that we should have adjusted for HIV status and age as well. Table 1 shows that adjustment for HIV, age, and length of stay in the area did not have a modifying effect on the association between the lesions and S. haematobium ova. Moreover, in HIV-positive women, BMI did not have modifying effect on the association between these findings and S. haematobium ova; and did not influence the size of the lesions (data not shown).
Length of stay in the area and HIV results was known in 520 women. Further results represent the 479 women who had stayed more than 3 years in the area. HIV was found in 41% (29/70) of women with laboratory-proven genital schistosomiasis as opposed to 26% HIV-positive women (96/375) in the schistosomal ova negative group (OR, 2.1; 95% CI, 1.2–3.5; P = 0.008). Table 2 shows that HIV was significantly associated with homogenous yellow, but not with grainy sandy patches. In the HIV-positive women there was no association between BMI and the listed findings in Table 2 (data not shown, small subgroups). Adjustment for age did not have a modifying effect on the association between the HIV and S. haematobium-related findings in Table 2.
Genital schistosomiasis as a possible cause of infertility will be discussed in detail later (manuscript in preparation). Infertility was significantly associated with S. haematobium in Pap smears, and also when adjusted for age (adjusted OR, 4.2; 95% CI, 1.3–13.9; P = 0.020) and is included in the analysis below. There was no association between S. haematobium and divorce or number of sexual partners (data not shown).
Multivariate analysis of genital schistosomiasis and other predictors for HIV
Table 3 shows that S. haematobium ova in Pap smears were found more frequently in women with HIV. Less than half (42%, 200/479) were tested for HPV, there were less than 10 cases of unskilled paid labour, and there was only one case who had both S. haematobium and past syphilis; thus these variables were excluded from the multivariate model. HIV seropositivity was not significantly with Chlamydia, atypical cells, bacterial vaginosis, candidiasis, or trichomoniasis.
Homogenous yellow sandy patches and urinary schistosomiasis were not included in the multivariate analysis as risk factors for HIV because they were in the same causal pathway as S. haematobium ova found in Pap smears (Table 1). However, when tested in the same multivariate analysis (instead of Pap smears), homogenous yellow sandy patches remained a significant predictor for HIV (adjusted OR, 1.7; 95% CI, 1.04–2.8; P = 0.044). Urinary S. haematobium ova excretion however, was not significantly associated with HIV (adjusted OR, 1.4; 95% CI, 0.8–2.2; P = 0.23). Schistosoma mansoni infection, other STDs, divorce, religion, and tribe did not influence the associations.
Genital schistosomiasis and HIV seroconversion
Twelve months after baseline seven of the 224 re-investigated HIV-negative women had become HIV positive (incidence 3.1%); six of them had been treated with praziquantel at baseline. The median age was 28 years for seroconverters, and 38 for HIV-negative women (P = 0.056), six were married and one was divorced. All seven women had S. haematobium-related findings before seroconversion as opposed to 65% (142/217) of women who remained HIV negative (P = 0.098). Sandy patches were found in five of the seven women before seroconversion. The two women who did not have any genital schistosomal findings, had urinary schistosomiasis. All seroconverted women had a rural childhood and current regular water body contact. There were no significant differences for the STDs between the seroconverters and the 217 women who did not become HIV positive. Two women were found to be seropositive for HSV-2. However at baseline or at 3 months, none of the seroconverted women had vesicles, ulcers, erosions, fissures, vaginal discharge, leukoplakia or tumours. Baseline laboratory analyses of the seroconverted showed no current or past syphilis, HPV, atypical cells, gonorrhoea, bacterial vaginosis, candidiasis, or trichomoniasis in smears.
Newcomers to the area
Forty-one women had stayed 3 years, or less in the area. They were more often single (P = 0.068) and infertile (P = 0.073), and the median age was 23 years as opposed to 36 years in the rest (P < 0.001). They were more often farm labourers (P = 0.013), had more Chlamydia (P < 0.006), trichomoniasis (P = 0.015) and current syphilis (P = 0.10) than the rest of the women. Moreover newcomers were more often from an urban area (P = 0.003) and had less childhood water body contact (P = 0.003) than the women who had stayed for a longer time in the study area. Homogenous yellow sandy patches and S. haematobium ova were found in 12 and one cases, respectively; none were associated with HIV seropositivity (P = 0.17 and P = 1.0, respectively, numbers were small).
Death, HIV and genital schistosomiasis
Twelve of 527 people had passed away 12 months after the baseline investigation. Although the cause of death was not known, 11 of these had been HIV positive at baseline (OR for HIV seropositivity in the dead, 26; 95% CI, 3.3–203; P = 0.002). Seven of the deceased had an S. haematobium-related finding at baseline (P = 0.67). The median age was 33 years for deceased and 35 years for live women. Of the women who had passed away five had urinary S. haematobium ova excretion at baseline and five had homogenous yellow sandy patches. Only one had grainy sandy patches, and only one of the deceased had S. haematobium ova (by biopsy); four of them had been biopsied.
Women with S. haematobium ova in Pap smears had a three-fold risk of having HIV in this rural Zimbabwean population. The association remained highly significant after controlling for established risk factors [15,18,21]. All seven women in this rural area, who became HIV positive had signs of S. haematobium infection at baseline. Homogenous yellow sandy patches were also significantly associated with HIV in multivariate analysis. As has been reported previously women in the age group 25–29 years had the highest HIV infection prevalence . Furthermore the study confirmed HSV-2, past syphilis and HPV were also significantly associated with HIV [15,18,30,31]. The study confirms that excretion or presence of S. haematobium ova in urine is not exacerbated in HIV-positive women [32–34]. Although the associations are significant, some confidence intervals are wide and there has been multiple statistical testing; results must therefore be interpreted with caution.
Does HIV have an effect on the presence of ova in Pap smears?
The Pap smear test method is an insensitive test method for S. haematobium ova, reflected in the wide confidence interval in its correlation with HIV [7,35]. Low CD4 cell count has been suggested to increase susceptibility to schistosomal re-infection after treatment . It is not known if low CD4 cell count exacerbates genital schistosomiasis or increases susceptibility to primary acquisition of schistosomiasis. However, newcomers did not have more S. haematobium-related findings than permanent residents. Furthermore HIV neither influenced the association between S. haematobium ova and the sandy patches, neo-vascularization or contact bleeding, nor was there an association, in the HIV-positive women, between BMI (as a surrogate marker for CD4 cell count [24,25]) and clinical or laboratory-proven genital schistosomiasis. CD4 cell counts were regrettably unknown in this study. Most women had to walk a distance to the clinic or to a vehicle, we therefore cannot preclude that women with AIDS are under-represented although a number of women reported having had recurrent herpes zoster and oral thrush, and although geographical subgroups of women were similar with respect to reproductive tract diseases . Eleven women with HIV passed away during the study period and it is likely that this group had lower CD4 cell counts than the HIV-negative women. However, the deceased neither had more positive Pap smears, nor more homogenous yellow sandy patches than the HIV-negative women. Treatment for urinary schistosomiasis has been found equally effective in HIV-positive and HIV-negative individuals . Moreover, other studies have shown that schistosomal ova excretion rates are lower, not higher in HIV-positive patients, or comparable in HIV-positive and HIV-negative individuals [32–34,38,39]. Schistosomal disease such as liver fibrosis is reportedly not exacerbated in HIV-positive individuals . We therefore find it likely that the significantly higher prevalence of genital schistosomiasis, in HIV-positive individuals, is caused by persistent schistosomal disease from before HIV infection , rather than HIV catalysis of genital ova excretion to the mucosal surface.
It is not possible to determine cause and effect of HIV in a cross-sectional study . HIV infection has occurred, at an unknown point in time, possibly in a different phase and hypothetically in the absence of schistosomal disease. In adult women, however, there is no difference in genital schistosomiasis in the different age groups [7,9]. It is therefore likely that most local rural women already had schistosomiasis at the time of HIV transmission [7,9,41].
Genital schistosomiasis as a cause of promiscuous behaviour
Previous papers have suggested that genital schistosomiasis is the cause of infertility [8,10]. In addition it has been suggested that women may be less attractive sexual partners due to events such as dyspareunia or post-coital bleeding . Schistosoma-positive and negative groups showed comparable divorce rates and numbers of sexual partners. The partner HIV status was not known and a woman's schistosomal disease may have been severe, but she would not have been at risk of HIV if her partner were HIV negative. Women in this area claimed that infertility led husbands to have out-of-wedlock sexual relationships. However, the effect of infertility on HIV transmission has been controlled for in this paper and the comparable divorce and partner rates in women with and without genital schistosomiasis make it unlikely that husband HIV status would have a confounding effect in our study population although we cannot completely preclude it.
Transmission of HIV to women
There is a considerable degree of mucosal change such as sandy patches, contact bleeding and proliferated blood vessels associated with S. haematobium ova deposition in the female reproductive organs [7,11,42,43]. Surrounding each ovum or cluster of ova there may be Langerhans cells, eosinophils, neutrophils, plasma cells, fibroblasts, macrophages and T cells with schistosoma-induced higher density of CCR5 and CXCR4 HIV-receptors on the cells [41,42,44–46]. Feldmeier et al. have hypothesized that HIV in semen may attain easy access through the friable and eroded epithelium or through broken vessels, during coitus, creating direct points of contact between the HIV virus and the receptive cells of the woman .
Transmission of HIV to men
Furthermore, HIV has been demonstrated in genital ulcer exudates [40,48,49] and this may hold true for schistosomal lesion exudates as well. Women with genital schistosomiasis may pose an additional risk of HIV transmission to their male sexual partners. Genital HIV-RNA excretion has been shown to decrease after treatment of other reproductive tract diseases [19,50,51]. However no study has investigated the effect of vaginal HIV viral load after treatment of female genital schistosomiasis, and no study has investigated the transmission of HIV from ‘schistosomal women’ to men.
Genital sandy patches, was the commonest current genital lesion in this population and was found in almost half of the women, 29% had homogenous yellow sandy patches [7,22]. Hence S. haematobium may be hypothesized to predominate as a cause of mucosal susceptibility in certain geographic areas. In S. haematobium endemic areas HIV may have spread with genital schistosomiasis, rather than STDs, as an essential risk factor for heterosexual transmission [7,38,47].
The economic burden of the HIV/ AIDS epidemic has made it difficult for many countries to invest in schistosomiasis control . This study indicates that schistosomiasis control – possibly starting in the young girls  – may perhaps be an important auxiliary in the current prevention programmes for HIV. The possibility of reduced HIV transmission in schistosomiasis endemic areas adds new intervention points in the battle against HIV on the behavioural aspects and on the development of sanitary infrastructures. Prospective studies however, are needed to confirm whether genital S. haematobium infection indeed poses a risk factor for HIV transmission to women. In addition, the effect of female genital schistosomiasis, as a risk factor for HIV transmission to men, needs to be explored.
The authors are grateful for the financial support received. Technical, medical, statistical or cultural assistance were provided by the Provincial Medical Director and Supervisor, Dr L. Charimari, Mupfure community and the councillor and staff at Madziwa, Harare Central and Mt. Darwin Hospitals, personnel from Blair Research Laboratory, Dr T. Magwali and Professor B. Myrvang. We are indebted to the Medical Research Council of Zimbabwe, staff and headmistress of Mupfure Secondary School, and the following indispensable people: sisters J. Chikoore, E. N. Kurewa and late sister P. Dungare, village health workers, environmental health technicians, and in particular N. Taremeredzwa, C. Mukahiwa, W. Mashange, R. Manyaira, and T. Mushipe for prolonged hard work under very difficult circumstances.
Sponsorship: Financial support was granted by UNDP/ World Bank/ WHO Special Programme for Research and Training in Tropical Diseases, Danish Bilharziosis Laboratory, Norwegian Research Council, NORAD and Ullevaal University Hospital: Research Forum, Department of Infectious Diseases and Centre for Imported and Tropical Diseases.
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