Human Papillomavirus is the most common sexually transmitted infection worldwide Trottier and Franco, 2006, with a estimated global prevalence among women of 10.4% (de Sanjose et al., 2007). HPV prevalence among African women is disproportionately high, ranging from 22.1% to 46.0% (Clifford et al., 2005a; de Sanjose et al., 2007; Smith et al., 2008). In a study of genital HPV prevalence among heterosexual men on 5 continents, Vardas and colleagues found the prevalence of any HPV type at 21.0% (18.7% penis, 13.1% scrotum, 7.9% perineal / perianal region) (Vardas et al., 2011). In excess of 100 HPV genotypes have been identified, with about 40 infecting the mucosal epithelium. These HPV genotypes are divided into high-risk and low-risk genotypes, according to their association with cervical lesions. The high risk HPV (hrHPV) types are more frequently found in premalignant or malignant lesions and are associated with cancers of the cervix, vulva, vagina, anus, and penis (Baldwin et al., 2004; Castellsague, 2008; Castellsague et al., 2002; Cogliano et al., 2005; Gravitt et al., 2000; Gustavsson et al., 2009; WHO-IARC, 2007; WHO, 2007b).
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An underlying association between cervical cancer and hrHPV has been well established (Bosch et al., 1995; Castellsague et al., 2002; Koutsky et al., 1992; Lehtinen et al., 2001; Morris, 2007; Rozendaal et al., 2000), as demonstrated by the estimated worldwide prevalence of hrHPV in cervical carcinomas of 99.7% (Walboomers et al., 1999). Cervical cancer is the most widespread cancer affecting women in developing countries and more than 70% of cases of cervical cancer occurring in this region have been attributed to hrHPV genotypes 16 and 18 (de Sanjose et al., 2007; Munoz et al., 2004; Schiffman et al., 2007). Therefore, any intervention reducing the acquisition or transmission of HPV will also significantly reduce the burden of disease, especially in developing countries (Castellsague et al., 2002).
Ninety percent of genital warts (GWs), also called condylomata acuminate is caused by low-risk HPV (lrHPV) genotypes 6 and 11 (Garland et al., 2009). LrHPV prevalence in women has been estimated at 13.6% in Sub-Saharan Africa (Clifford et al., 2005a), Comparatively little is known about the epidemiology and natural history of lrHPV infection and GWs in sub-Saharan Africa. LrHPV prevalence shows considerable regional variation, such as 11% in the Gambia , 28% in Tanzania and can range from 1.2% to 30.0% depending on geographical region, target population, and sexual behaviour (Smith et al., 2008). Although treatment helps to eliminate the virus, GWs generally not painful, but they do itch and with frequent new lesions or recurrences causing in patient distress (Garland et al., 2009; Lacey, 2005). GWs can cause a decline in health-related quality of life (Woodhall et al., 2008). The psychological burden of GWs have the largest impact on quality of life compared with other clinical forms of HPV, mainly due to impact on sexuality, self-image, and partner transmission (Pirotta et al., 2009).
Multiple hrHPV and lrHPV infections may have important clinical and epidemiological implications. Infection with multiple HPV genotypes has been associated with anogenital warts (Brown et al., 1999; Chan et al., 2009; Nielson et al., 2009), the acquisition of new HPV type and HPV infection persistence (Kjaer et al., 2005), dysplasia (Fife et al., 2001), cervical intraepithelial neoplasia severity (Bello et al., 2009; Spinillo et al., 2009), cytological abnormalities in anal epithelium (Damay et al., 2010b), and HIV co-infection (Banura et al., 2008; Muller, Chirwa, and Lewis, 2009; Vajdic et al., 2009). Therefore, the investigation of lrHPV infection and the number of lrHPV genotypes detected in urethral swabs is key since being infected with one or multiple genotypes may result in a different clinical outcome.
Incidence and HPV type distribution in men with GWs was 2.35 cases per 1000 person-years, the highest incidence among men aged 18-30 years (3.43 cases per 1000 person-years), with HPV 6 (43.8%), HPV 11 (10.7%), and HPV 16 (9.8%) the genotypes most commonly detected in GWs (Anic et al., 2011). In a study of men who have sex with men (MSM) infected with HIV, 74.6% had anal HPV infection, 68.7% had hr HPV infection, and 56.7% had multiple infections. Most frequent HPV types identified were HPV 44/55 (19.4%), HPV 53 (19.4%), HPV 16 (16.4%), HPV 39 (16.4%), and HPV 42 (14.9%) (Damay et al., 2010a). In a South African cohort of heterosexual men, the prevalence of anogenital HPV among study participants was 78%. In 81%, HPV 6, 11, 16 and 18 were prevalent as either single or combined infections. HPV types 6 and/or 11 were significantly higher among GW patients (p<0.001). HIV seropositivity was significantly associated with multiple HPV infections (OR=3.98, 95% CI 1.58 to 10.03) (Muller, Chirwa, and Lewis, 2009).
Since men are carriers of HPV and the main route of transmission to women is through sexual contact with infected men, it would be of benefit to reduce the HPV prevalence, not only in women, but in men as well. Recent observational studies have suggested that HPV prevalence was reduced among circumcised men compared to uncircumcised men (Baldwin et al., 2004; Castellsague et al., 2007; Castellsague et al., 2002; Giuliano et al., 2009; Hernandez et al., 2008b; Vaccarella et al., 2006) whereas other studies failed to find an association (Nielson et al., 2007b; Shin et al., 2004). However, two recent male circumcision (MC) trials have demonstrated a lower hrHPV prevalence and incidence among circumcised men by 32% to 35%. The authors argue that while male circumcision is primarily a male concern, one trial also reported benefits derived by female partners of circumcised men (Wawer et al., 2011). This protective effect of MC against acquisition could be explained by the role of the foreskin on HPV transmission. Viral access to the basal keratinocytes in the cornified epithelium of the circumcised penis is limited. There is no a difference between the keratinisation of the glans penis of circumcised men and uncircumcised men, but the mucosal epithelium of the inner prepuce is not keratinised which makes it more susceptible to microtrauma injury during intercourse (vaginal, anal and oral sex). It is postulated that poor genital hygiene, inflammatory effect of accumulated smegma, can also assist in the harbouring of HPV infection (Gray et al., 2009). Consequently, the same protective effect of MC can be expected on lrHPV prevalence, but to date, very little is known about this association.
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The objective of this study was to analyze the effect of medical male circumcision (MMC) on the prevalence of hrHPV and lrHPV infection by considering both hrHPV and lrHPV prevalence and the number of hrHPV and lrHPV genotypes detected among young men. The secondary objective was to identify other risk factors for hr HPV or lrHPV infection.
Data used were collected during the MMC randomized controlled trial (RCT) conducted in Orange Farm (South Africa), which demonstrated a partially protective effect of male circumcision on the acquisition of HIV (Auvert et al., 2005).
An independent and partial protective effect of MC was demonstrated on the prevalence of hrHPV and lrHPV. This effect on hrHPV was shown on the prevalence and not incidence because of the available biological samples in this MC trial. When the analysis was adjusted for possible confounding factors, such as sexual behaviour and condom use, the outcome remained unchanged. Given the results of the propensity analysis, the randomization and the absence of obvious differences between groups in N. gonorrhea prevalence or sexual behavioural characteristics, the difference in hrHPV prevalence between the 2 groups is likely attributable to MC. Therefore, the difference observed is probably the consequence of dissimilarity in hrHPV incidence between circumcised and uncircumcised men. In this study hrHPV prevalence is likely a proxy for hrHPV incidence, as HPV prevalence rises as a function of age among young men (Okesola and Fawole, 2000).
HPV-type co-infections can have an impact of HPV vaccination and disease in men due to potential HPV type competition followed by type replacement. It is important to conduct studies on multiple HPV infections, HPV distribution, associations between HPV types in multiple infections among men and type competition in men. Type competition may result from unknown biological kinetics, whereby infection with one HPV type inhibits the acquisition or facilitates persistence of other HPV types (Rositch et al., 2012).
No effect of MC on some hrHPV genotypes, such as 16 and 33 could be established. The apparent disparity in the effect of MC for different genotypes can be the result of true variation or random variation. This should be further investigated, for example, by comparing the results of the present study with those of other MMC trials conducted in other African countries (Bailey et al., 2007; Gray et al., 2007).
The protective effect of MC demonstrated in this study, corresponds in magnitude to what could have been expected from observational studies. Castellsague and colleagues (Castellsague et al., 2007) found in their meta-analysis an odds ratio of 0.56 (95% CI, 0.39-0.82), whereas Baldwin (Baldwin et al., 2004) reported an adjusted relative risk of 0.44 (95% CI, 0.23-0.81). Hernandez (Hernandez et al., 2008b) determined that uncircumcised men had an increased risk of nearly a 2-fold of oncogenic HPV infections (relative risk, 1.96 [95% CI, 1.02-3.75]). This study presents clear evidence that MC lowers the risk of heterosexual hrHPV acquisition among men.
HrHPV remains a major public health concern because of its contributory association with malignancies, especially cervical cancer in women. These findings show why MC has long been thought to be protective against cervical cancer (Morris, 2007). MC reduces the risk of hrHPV infection among men and as a result reduces the exposure of women to hrHPV. Consequently, the risk of cervical cancer is lowered because of the causal link between hrHPV and cervical cancer among women (Bosch et al., 1995; Castellsague et al., 2002; Koutsky et al., 1992; Lehtinen et al., 2001; Morris, 2007; Rozendaal et al., 2000; Wawer et al., 2011).
Three randomized controlled trials have shown that MC has a partial protective effect on the acquisition of HIV by males in Africa (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007). In each case, the trial was terminated as the results were conclusive and it was considered unethical not to offer MC to the control groups in advance of the planned trial end date. The effect of MC on HPV reinforces the recommendation of the World Health Organization and the Joint United Nations Programme on HIV/AIDS for the implementation of MC programs in countries with a high prevalence of HIV infection, a low prevalence of MC, and a high acceptance of MC (UN, 2007). While the cost of HPV vaccine remains a problem in Africa, the protective effect of MC may be an alternative to HPV vaccines in terms of genotype coverage and target-group age range.
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There was a strong independent association found between lrHPV urethral infection and MC. lrHPV infection was analyzed as a prevalence rate and in terms of number of lrHPV detected in urethral swabs, because it was assumed that being infected with one genotype was different from being infected with two or more genotypes (Chan et al., 2009; Muller, Chirwa, and Lewis, 2009; Nielson et al., 2009). Results showed that the risk of being infected with one lrHPV genotype (PMR) and with at least one genotype (PRR) consistently decreased among men from the intervention group. They did not differ significantly from control group participants in terms of sexual behaviour, apart from reporting more frequently at the 21-month visit having had at least one sexual partnership in the previous12 months.
Few observational studies have observed this association but results remained inconsistent (Baldwin et al., 2004; Giuliano et al., 2009; Muller, Chirwa, and Lewis, 2009; Nielson et al., 2007b; Svare et al., 2002). Only one of these studies found statistically significant association of circumcision status with the prevalence of lrHPV infection (Giuliano et al., 2009). However, Tobian and colleagues (Tobian et al., 2009) have published similar results, analyzing data collected in another African population and using a different HPV swabbing site. A 34% reduction in lrHPV prevalence among circumcised men was reported. For this reason, it can be concluded that the protective effect of MC on hrHPV infection can be generalized to lrHPV genotypes as well.
In accordance with observational studies, this work highlighted some other risk factors of lrHPV, such as the number of lifetime sexual partners (Giuliano et al., 2009; Hernandez et al., 2008a; Nielson et al., 2007b; Shin et al., 2004; Vaccarella et al., 2006) and being older than 21 years old (Kjaer et al., 2005), although the role of age may vary (Giuliano et al., 2009; Nielson et al., 2007b; Vaccarella et al., 2006). The data also presented evidence that supports the protective role of condom use on hrHPV and lrHPV infections (Baldwin et al., 2004; Kjaer et al., 2005; Nielson et al., 2007b; Vaccarella et al., 2006).
Possible mechanisms by which circumcised men are less likely to be infected with HPV could be explained by a reduced acquisition of new infection or an increased clearance of pre-existing infection, because the absence of foreskin may reduce the risk of auto-reinfection at the urethral site (Gray et al., 2009).
This study has some limitations. First, biological samples were not collected throughout the follow-up period, so the hrHPV and lrHPV status at inclusion are not known. The reduced effect of MC on HPV infection could be not rigorously demonstrated due to the lack of data on HPV status at baseline. This information would have allowed a comparison of HPV incidence as a function of MC status and HPV prevalence between intervention groups at inclusion. As some participants were already infected by HPV at inclusion, the effect on prevalence measured undervalued the true effect of MC. However, MC was randomly assigned, and controlling for the propensity score did not affect the results. Second, participants were not blinded to the intervention and this may have led to sexual behaviour change and bias. Finally, hrHPV and lrHPV were detected in urethral swab samples, a method that is likely to miss infections (Giuliano et al., 2007). The prevalence of HPV infections in this cohort is likely underestimated, because the rate of detection in the urethra is significantly lower than that in the glans, corona sulcus, or penis shaft (Aguilar et al., 2006; Giuliano et al., 2007). This underestimation would be equally distributed among the two groups of randomization. However, there is no risk of non-differential misclassification, as there were no difference when the urethral HPV prevalences before and after circumcision in a subsample of participants were compared. This underestimation would have no effect on PRRs and PMRs. Despite this loss of power, this study demonstrated a significant protective effect of MC against HPV infection. A critique of the laboratory methodology is that due to the initial screening for 13 hrHPV types only, followed by reflex genotype testing on the positives, some HPV (especially lrHPV) genotypes might have been missed.
Human papillomavirus genotypes that infect the genital track in humans are divided on the basis of their oncogenic potential into "high-risk" (hrHPV) and "low-risk" (lrHPV) genotypes (Castellsague, 2008). lrHPVs are most commonly associated with lesions such as genital warts that are non-malignant (Monk and Tewari, 2007), whereas hrHPV are found in the majority of premalignant or malignant lesions of the genitals and are associated with cancers of the cervix, vulva, vagina, anus, penis, head and neck (Baldwin et al., 2004; Castellsague, 2008; Monk and Tewari, 2007; Morris, 2007; WHO, 2007b).
The prevalence of genital HPV among both sub-Saharan African males and females is high. Cervical cancer is 99% attributable to hrHPV (Walboomers et al., 1999). Cervical is the leading cause of cancer mortality among women in Southern African women (Castellsague, 2008). Cervical cancer is a recognized AIDS-defining illness and there is a strong correlation between HIV and invasive cervical cancer (Castro, 1992). In Africa, both infections contribute significantly to the burden of morbidity and mortality; therefore it is of great public health importance to conduct research to highlight the epidemiologic and aetiologic association of HIV and HPV. Recent published epidemiological data show that the probability of HIV transmission in African countries is amplified by HPV (Auvert et al., 2011; Mbulawa et al., 2009; Veldhuijzen et al., 2012). There are several mechanistic explanations why HPV and other STIs can aid HIV uptake: 1) it can increase the viral burden in the genital tract; 2) it can increase the concentration of HIV in genital secretions and increase viral diversity; 3) it may play a role in mucosal disruption and inflammation to facilitate HIV acquisition (Cohen, 2006)
The focus of most studies exploring the link between HIV and genital HPV was on the effects that HIV infection has on the prevalence, incidence, and the distribution of HPV genotypes. HIV-positive status is found to be strongly associated with higher HPV prevalence in both sexes (Castellsague, 2008; Giuliano et al., 2008c; Ng'andwe et al., 2007; Ng'ayo et al., 2008; Partridge and Koutsky, 2006; Safaeian et al., 2008b), higher hrHPV prevalence (Aynaud et al., 1998; Giuliano et al., 2008c; Mayaud et al., 2001; Ng'andwe et al., 2007; Partridge and Koutsky, 2006; Safaeian et al., 2008b), higher HPV incidence (Safaeian et al., 2008a), higher prevalence of infections with multiple HPV genotypes (Aynaud et al., 1998; Giuliano et al., 2008c; Ng'andwe et al., 2007; Ng'ayo et al., 2008; Partridge and Koutsky, 2006; Safaeian et al., 2008a), and higher frequency of HPV lesions in multiple locations (Aynaud et al., 1998).
The inconsistency in both the clinical progression and transmission of HIV infection has driven a search for cofactors influencing replication of the virus. Host immune and genetic factors and replication kinetics influence the progression of HIV disease. Co-infections between diverse exogenously and sexually acquired infectious agents and HIV have emerged to influence the rate of HIV replication and transmission (Cohen, 2006). Genital herpes simplex virus type 2 (HSV-2) is highly prevalent worldwide and an increasingly important cause of genital ulcer disease (Klug et al., 2009). Increased HSV-2 prevalence in developing countries contributes to an increase in the proportion of GUD and attributes to HIV and HSV-2 asymptomatic shedding within the genital tract (Mahiane et al., 2009; Paz-Bailey et al., 2007). This observed synergistic association between HIV and HSV-2 can be used as a model for investigating the co-pathogenic existence between HIV and HPV. HPV and HSV-2 share similarities as for both, dormancy or persistence are key factors in management and diagnosis, both cause lesions that can aid uptake of HIV and prevalence for both viruses can be reduced by MC (Mahiane et al., 2009; Tobian et al., 2009)
The objectives of this study were: 1) to explore the association of hrHPV and lrHPV with HIV incidence in men, and 2) to evaluate HPV as a risk factor or confounder for HIV acquisition in a young male cohort from South Africa, a group which is presumably at high risk for STIs such as HPV and HIV.
Longitudinal data were used and collected in Orange Farm (South Africa), an area of high HIV prevalence (DOH, 2008) during a male circumcision randomized controlled trial, which demonstrated a reducing effect of male circumcision on the acquisition of HIV (Auvert et al., 2005).
Data from this trial demonstrated an important association of oncogenic HPV with HIV incidence among young African men. However, the data did not show any association of nononcogenic HPV with HIV incidence.
This study has main 5 limitations. First, as with any observational study, no causal relationship between HPV and HIV could be concluded from the findings. Second, although urethral sampling has been shown to be unaffected by circumcision status (Auvert et al., 2009; Weaver et al., 2004), it has the shortcoming of underestimating the presence of genital HPV (Aguilar et al., 2006; Giuliano et al., 2007). This underestimation is not expected to change the positive association with HIV incidence, but it could be argued that the strength of this association may vary with swabbing sites. hrHPV was the most prevalent sexually transmitted infections in this cohort despite this underestimation. Third, the collection of genital swabs for HPV testing was done at the last follow-up visit, which is on average several months after HIV infection. It is therefore possible that, among the subsets of participants who contracted hrHPV during follow-up, some got infected with HPV after HIV acquisition. This will tend to dilute the strength of the association between HPV and HIV. Fourth, the Roche Linear Array genotyping assay used for screening in this study, detects mainly. This needs to be considered in the comparison hrHPV and lrHPV prevalence. Lastly, HPV lesion detection was not performed in this study.
Several nonexclusive and plausible explanations could account for these findings. First, both sexually transmitted viruses, HIV and HPV share the same transmission route and behavioural risk factors. However, after controlling for these sexual behavioural variables, this association remains strong. Second, the results could be partly due to HIV infection facilitating HPV acquisition or HPV reactivation from the basal cell layer in the epithelium due to a compromised immune system. This explanation is unlikely as the participants in this study were recently infected with HIV and in all probability still had healthy immune systems. Thirdly, it could be argued that female partners co-infected with HIV and HPV- may have shed hrHPV more easily than HIV-negative women. HPV lesions are more likely to be dysplasic when the immune system is depressed (Steben and Duarte-Franco, 2007) and latent HPV infection can reactivated in immune compromised individuals (Aubin et al., 2007; Aynaud et al., 1998; Strickler et al., 2005). The average age of the female partners of the study participants was 3 years older than the median age of sexual debut reported in the same community, which is about 17 (Pettifor et al., 2005). This makes this last explanation improbable: female partners who had their sexual debut on average 3 years earlier, making it unlikely that they already had a compromised immune system due to HIV infection. Fourth, the findings could indicate that hrHPV, but not lrHPV, facilitates HIV acquisition.
There are several points in favour of the latter explanation: 1) there is strong evidence of a association between HIV and HPV acquisition, as shown in various cross-sectional studies (Ng'andwe et al., 2007; Ng'ayo et al., 2008; Safaeian et al., 2008b); 2) two other longitudinal studies have shown that HPV facilitates HIV acquisition among MSM in the United States (Chin-Hong et al., 2009) and among Zimbabwian women (Smith-McCune, 2009), with the latter demonstrating a differential effect between hrHPV and lrHPV on HIV acquisition; 3) hrHPVs facilitating HIV acquisition is biologically plausible. The likelihood of hrHPV increasing the susceptibility to HIV infection was first suggested in 2002 (Clarke and Chetty, 2002). The arguments are that (a) hrHPV infection of basal cell epithelia could activate cell-mediated immune responses through the recruitment of macrophages and T lymphocytes (Coleman et al., 1994; Nicol et al., 2005; Stanley, 2009), these are HIV target cells and may facilitate HIV uptake; (b) cytokines could be stimulated by genital HPV (Gage et al., 2000; Nicol et al., 2005), which can facilitate HIV transcription and replication; and (c) HPV infection can lead to persisting inflammation and immune system activation (Behbahani et al., 2007). hrHPV is more likely to result in a persistent infection (versus lrHPV) (Brown et al., 2005; Franco et al., 1999; Rowhani-Rahbar et al., 2007), escalating the probability of HIV acquisition if there is really HPV-induced immune activation.
This study provides additional evidence of the strong interaction between HPV and HIV; however it does not give a definite explanation of the association of HPV and HIV incidence. There is a need for further studies to investigate this association, using, for example, data from other longitudinal male circumcision trials (Bailey et al., 2007; Gray et al., 2007) or the data collected during the COL-1492 trial (Marais et al., 2008), conducted on South African female sex workers. Testing the hypothesis that hrHPV facilitates HIV acquisition is complex as it entails the demonstration of a causal association. The validation of this hypothesis could require testing the potential protective effect of available HPV vaccines on HIV acquisition.