Prevalence and incidence of genital warts and cervical Human Papillomavirus infections in Nigerian women

Genital warts are common manifestations of genital Human Papillomavirus (HPV) infections [1]. They are commonly associated with HPV6 and HPV11 [2]. However, many other HPV types have also been isolated in genital warts, including HPV 2, 40, 42, 43 and 54 [3, 4]. Although there is rising prevalence and incidence of genital warts in the general population in Europe and the United States, countries such as Australia and England with high HPV vaccination coverage have reported a decline in the burden of genital warts among young women [1, 5‐8]. In contrast, little is known about genital warts in Sub-Saharan Africa (SSA) [9]. Most studies on genital warts in SSA have been conducted in high risk populations such as people attending sexually transmitted diseases’ (STD) clinics or commercial sex workers [9]. Other studies were conducted among women receiving antenatal care [9].

Genital warts can present with four morphologic features – condylomata acuminata, smooth or flat papular lesions, or keratotic warts. Apart from their appearance, they are often symptomless except in some cases of vulvar warts which may cause dyspareunia and discomfort; penile warts and pruritus; vaginal warts and vaginal discharge, bleeding, obstruction of the birth canal, and neonatal infection which may lead to juvenile onset recurrent papillomatosis; perianal and intra-anal warts that cause pain, bleeding on defecation and pruritus [10‐14]. Genital warts can have profound effects on patients’ quality of life [15]. They may regress spontaneously or remain quiescent for extended periods. They can be refractory to treatment with high recurrence rates leading to substantial health care costs [16]. In 2004, the estimated economic burden of genital warts exceeded $220 million in the US, [17] and $64 million in Spain [18]. Data on economic costs are not available for SSA countries.

Studies show that vaccination with the quadrivalent and nonavalent HPV vaccine, which offers protection against HPV 6 and 11, can reduce the incidence of genital warts [19]. This has renewed interest in estimating and monitoring the burden of anogenital warts as an early indicator of the impact of HPV vaccination programs. In Nigeria, there are isolated, small-sized, pilot HPV vaccination projects but no systematic, national or regional programs [20]. Therefore, estimating the pre-vaccination burden of genital warts would be of practical utility for future monitoring and evaluation projects.

In this study, we describe the prevalence, incidence, associated risk factors and cervical HPV types associated with genital warts in Nigerian women.

Of the 1020 women enrolled, 58 were excluded due to missing HIV and HPV data (41 missing HIV results, 13 missing baseline HPV results, 4 missing both HIV and HPV) results leaving 962 women available for prevalent genital warts analyses. Most participants (72%, 692/962) completed follow-up visits. Of these 692 women, we excluded 62 participants whose HPV results were missing at follow-up leaving 630 women for genital wart incidence analysis. Sixteen of these women had prevalent genital warts at the enrolment visit. Therefore, they were no longer at risk for incident genital warts and were subsequently excluded leaving 614 women. Among these 614 women, we imputed person time at risk for 4% (22/614) of participants who were missing follow-up visit date. All instances of missing data were in women without incident genital warts. Sensitivity analysis, comparing results from models with and without imputed data did not show any significant differences. We present results from models with the imputed data in order to reduce loss of information that would arise from listwise deletion of cases.

We identified HIV infection as a risk factor for prevalent genital warts and higher number of sex partners in the past year as a risk factor for incident genital warts in this study. Cervical HPV11, but not HPV6 infection was associated with prevalent genital warts.

Previous studies have shown that HIV positive women are more likely to be infected with HPV, have multiple HPV infections, [25] and have slower clearance compared with HIV negative women [26]. Clearance of HPV infection is mediated by a cell-mediated immune response, and the cellular response against genital warts includes an antigen specific CD4+ Th1 response [27]. Therefore, the increased risk of genital warts in HIV positive women is likely due to the reduced ability of the immune system to control HPV infections, as well the shared risk factors for transmission of HIV and HPV infections.

Given the ubiquity of HPV infections, the number of sexual partners in the past year is a corollary of exposure to new HPV infections from new sexual partners. Women with a higher number of sexual partners in the preceding year are more likely to have been exposed to new HPV infections from new sexual partners than women who report fewer number of sexual partners [28]. Genital warts have a short incubation period, with about 65% of people exposed to partners with genital warts, developing lesions within 1–8 months [29]. Therefore, the three-fold increased risk of incident genital warts with each additional new partner in the preceding year observed in our study likely reflects the clinical manifestations of newly acquired HPV infections.

Prevalence of HPV6 was 4% (1/27) in women with genital warts compared to the overall prevalence of 1% (10/962) in the study population, while prevalence of HPV11 was 15% (4/27) in women with genital warts compared to the overall prevalence of 2% (15/962) in the study population [22]. In age adjusted models, HPV11, but not HPV6, was significantly associated with prevalent genital warts. The prevalence of cervical HPV6 infection among women with prevalent genital warts in our study are lower than that from other studies in Burkina Faso (6%) [30], South Africa (5%) [30], Germany (67%) [31], United States (17%) [4], and England (33%) [32]. These differences may reflect the relative contributions of non-HPV 6/11 infections to the burden of genital warts, and differences in the age distribution of the study populations. Due to the recurring nature of genital wart infections and the transient nature of most cervical HPV infections, inferences based on HPV detection at time of genital wart diagnosis need to be interpreted with caution. Intermittent detection of persistent HPV infection may be due to episodic fluctuation in viral load levels including below the detection limit of many HPV DNA assays [33]. HPV infections may also go through a phase of latency in the basal cells of the cervical epithelium during which period the virus may be undetectable [3].

The prevalence of genital warts among HIV negative women in our study is lower than that found in HIV negative, pregnant women in Malawi where prevalence was approximately 2% [9]. This is consistent with results from previous studies which show that HPV prevalence tend to be higher among pregnant compared to age-matched non pregnant women as a result of temporary immunosuppression and increased steroid hormones during pregnancy [34]. The prevalence of genital warts in HIV positive women in our study is similar to that in a recent study of HIV positive women in South Africa (6%) but slightly lower than that in Burkina Faso (8%) [30]. Geographic variations in any HPV prevalence, cultural environment, sexual behavior, HPV viral characteristics and host susceptibility may explain these findings. In a meta-analysis assessing the burden of any HPV infection in women with normal cytological findings, standardized by country specific population sizes, any HPV prevalence was higher in Eastern Africa (34%) compared to Western Africa, which includes Nigeria (20%) [35]. Similarly, the incidence and prevalence of other HPV associated diseases such as cervical cancer is higher in Eastern Africa compared to Western Africa [35].

We observed a peak prevalence of genital warts in women aged 20–29 years followed by a decline till about 40–49 years old where there was a second but smaller peak. This result is consistent with our previous findings on prevalent low risk HPV infection in this study population and the epidemiology of several other STIs from other populations where the highest peaks are observed in young people soon after sexual debut, with a secondary peak in middle age in some populations [22, 36]. Possible explanations for the bimodal pattern include the reactivation of latent HPV infections in later life due to waning of immunity, acquisition of new HPV infections due to new sexual partners and possibly cohort effects [37].

The incidence rates of 515 in HIV negative and 1370 per 100,000 person-years in HIV positive women in our study are higher than that from European and North American studies [5]. In a systematic review of population based incidence rates using data from medical chart reviews and retrospective administrative databases in European and North American populations, Patel et al. reported incidence rates of genital warts per 100,000 person-years ranging from 76 in Germany to 430 in Italy [5]. Incidence of genital warts based on clinical pelvic examinations tend to be higher than that obtained from medical chart reviews or administrative databases because patients may be unwilling or unable to present to health care facilities [5]. Additionally, medical records and administrative databases may be incomplete and the quality of information provided by different health care workers may vary significantly.

Few studies of the incidence of genital warts have been conducted in SSA and these have been in high risk populations such as HIV negative commercial sex workers in Burkina Faso where the incidence was 1100 per 100,000 person-years, [9] and in women younger than 40 years, attending an STD clinic in Nigeria with incidence of 2700 per 100,000 person-years [9]. A recent study found genital wart incident rates of 2470 and 2330 per 100,000 person years in HIV positive women in Burkina Faso and South Africa respectively [30]. These rates are higher than what we observed in HIV positive women in our study. Factors related to differences between the study populations and  differences in HIV epidemiology may account for these findings.

We found that women younger than 30 years old or HIV negative were more likely to be lost to follow up in our study. Considering that the prevalence of genital warts was higher in women less than 30 years old in this study, it is possible we underestimated the incidence of genital warts as a result. As incidence estimates were stratified by HIV status, the increased likelihood of being lost to follow up among HIV negative women, is more likely to influence estimates for HIV negative but not HIV positive women. We previously published a detailed study of predictors of attrition in this cohort and identified age and HIV status as important risk factors [38].

We found that HIV positive women were significantly more likely to report condom use than HIV negative women. This finding may reflect recent efforts by the President’s Emergency Plan for AIDS Relief (PEPFAR) program to promote condom use among sexually active HIV positive individuals to reduce risk of HIV and other sexually transmitted infections (STI) [39]. It is plausible that there are differences in the psychological and recall processes for self reported sexual history among HIV negative and HIV positive women. HIV positive women may feel a sense of personal responsibility in preventing the transmission of HIV and other STIs to sexual partners and therefore may over report condom use, which they may perceive as a more socially desirable response. This is supported by our previous study showing less reliability in reporting sexual behaviour among HIV positive compared to HIV negative women in this study population [21].

To our knowledge, this is the first longitudinal study to describe the prevalence and incidence of genital warts among HIV negative and HIV positive women who are neither pregnant nor considered to be at increased risk for other STDs in West Africa. Due to the recurring nature of genital warts, newly detected cases of genital warts may truly be incident cases or may be recurrent episodes. In our study, we collected self-reported history of previous genital warts and excluded these cases from incidence analyses. However, it is possible that there may be some residual confounding as a result of inaccuracies in the self-reported history.

HPV detection was based on cells obtained from the cervix which may not be representative of the causative HPV types in the genital warts. Previous studies have reported varying degrees of type specific concordance between cervical HPV and HPV isolated from genital warts [4, 31]. In these studies, agreements for HPV6 detected in genital swabs and cervical swabs among young women with genital warts ranged from 16% in a US study, [4] to 71% in a German study [31]. Therefore, it is likely that the prevalence estimates of HPV types in our study underestimate the true prevalence of the different HPV types in genital warts. Despite this limitation, our results provide some information on the HPV type distribution among Nigerian women with genital warts. Further studies, that directly sample gential warts are needed to better understand genital warts epidemiology in Nigeria.

Other limitations of our study include small sample size, the small number of incident genital warts despite the relatively large follow-up person time and the absence of HIV parameters such as viral load and CD4+ count. Therefore, our effect estimates for incident genital warts may be unstable. In our study design, we purposively enroled HIV negative and HIV positive women. Therefore, the prevalence of HIV in our study population does not represent HIV prevalence in the Nigerian female population. Hence, we provide prevalence and incidence estimates separately for HIV negative and HIV positive populations.

Genital warts diagnosis in our study was based on visual identification with bright light. Without histological confirmation, it is possible that some other genital conditions such as seborrheic keratoses, dysplastic and benign nevi, molluscum contagiosum and neoplastic lesions may have been misclassified as genital warts [13]. However, biopsy is not routinely recommended for genital warts diagnosis, and the nurses in our study were trained to rule out these other genital conditions and refer lesions suspicious of neoplasia.

Our study provides important information on the epidemiology of genital warts among women in Nigeria. The results can be used for monitoring and modelling effectiveness of the public health impact of future HPV vaccination programs in Nigeria. Our findings of a high burden of genital warts and the association between cervical HPV11 and genital warts support the use of either the quadrivalent or nonavalent vaccine for genital wart prevention in future HPV vaccination programs in Nigeria.