Abstract

Background. Persistent infection with human papillomavirus (HPV) is associated with the development and progression of HPV-related disease, including cervical intraepithelial neoplasia (CIN) and invasive cervical cancer.

Methods. We examined the impact of human immunodeficiency virus (HIV) status and type on the clearance of HPV infection among 614 Senegalese women enrolled in a longitudinal study of HPV and CIN. Women were examined every 4 months for HPV DNA. Clearance was defined as 2 consecutive negative HPV DNA test results.

Results. Cox proportional hazard regression with time-dependent covariates indicated that HIV-positive women were less likely to clear HPV infection (adjusted hazard ratio [HR], 0.31 [95% confidence interval {CI}, 0.21–0.45]) than HIV-negative women. Among HIV-positive women, those with CD4 cell counts <200 or from 200 to 500 cells/µL showed a 71% (adjusted HR, 0.29 [95% CI, 0.11–0.76]) and 32% (adjusted HR, 0.68 [95% CI, 0.31–1.48]) reduction in the likelihood of HPV clearance, respectively, compared with those with CD4 cell counts >500 cells/µL. HIV-2 infection was associated with an increased likelihood of HPV clearance (adjusted HR, 2.46 [95% CI, 1.17–5.16]), compared with that for HIV-1 infection.

Conclusions. HIV infection reduces the likelihood of HPV clearance. Among HIV-positive women, immunosuppression, as measured by CD4 cell count, reduces the likelihood of HPV clearance, and HIV type appears to be associated with HPV clearance.

Persistent infection with human papillomavirus (HPV) is associated with the development and progression of HPV-related disease in the genital tract. Previous studies have shown that individuals infected with HIV show an increased duration of genital HPV infection [1–11]. The higher prevalence of genital warts and cervical neoplasia among HIV-positive individuals may be in part a reflection of the increased durability of HPV infection. The impact of HIV infection on the natural history of HPV infection is not yet fully understood; however, it is thought that HIV-induced immunosuppression can lead to an inability to control the expression of HPV, resulting in an increased risk of persistent infection. Some have also speculated that HIV infection may increase the oncogenicity of high-risk HPV types and possibly the activity of low-risk HPV types [12].

Most cases of HIV infection are due to HIV-1; however, HIV-2 represents a noticeable proportion of all HIV infections in some countries, such as West African nations, India, Brazil, and Portugal [13]. Although similar in many ways, there are important differences between HIV-1 and HIV-2, such as reduced pathogenicity and enhanced immune control of HIV-2 infection relative to HIV-1 infection [13, 14]. There is a dearth of information on the impact of HIV type (HIV-1 and HIV-2) on the clearance of HPV infection. That HIV-2 is associated with less severe immunosuppression than HIV-1 may have an effect on the clearance of HPV infection.

In the present study, conducted in Senegal, West Africa, we sought to assess the impact of HIV status and type on the clearance of HPV infection. Furthermore, we examined the role played by CD4 cell count and HIV load as markers of immunosuppression and their effect on the clearance of HPV infection among HIV-positive women.

Subjects, Materials, and Methods

Study population, specimen collection, and procedures. Study population, collection of specimens, and study procedures have been described in detail elsewhere [15]. In brief, between 1 October 1994 and 1 January 1998, all women older than 15 years (n = 5392) presenting to the University of Dakar infectious disease clinic (n = 4349 [80.7%]) and commercial sex workers attending 1 of 2 sexually transmitted disease (STD) clinics in either Dakar (n = 773 [14.3%]) or M'Bour (n = 270 [5.0%]) were offered serologic testing for HIV-1 and HIV-2 and cytological screening for cervical HPV DNA and abnor-mal cells. Women returned 4 weeks later for their results; women found to be infected with HIV or high-risk HPV types were invited to participate in a longitudinal study, with visits occurring every 4 months to assess the risk of developing cervical lesions. Of 1348 eligible women, 939 (69.7%) enrolled, including 614 women who were HPV positive at their baseline visit and had at least 2 consecutive follow-up visits and, thus, were included in the final analyses in this study. At each visit, enrolled women underwent a detailed interview regarding sexual behavior and medical history; in addition, blood was ob-tained for HIV serological testing, CD4 cell count determi-nation, and quantitation of plasma HIV RNA. HPV DNA detection and typing were done by polymerase chain reaction (PCR) with HPV L1 consensus primers, HPV type–specific oligonucleotide probes, and a generic probe, as described elsewhere [16]. Before 1 April 1998, HPV DNA detection was done by PCR with the consensus primers MY09 and MY11, which were specific for a highly conserved region in the L1 open reading frame. Positive samples were then reamplified to assess the presence of 12 HPV types, using primer groups for low-risk (combined 6 and 11) and high-risk (16; 18; combined 31, 33, 35, and 39; combined 45 and 56; and combined 51 and 52) HPV types. New probes became available beginning on 1 April 1998, and a PCR-based reverse-line strip testing method (Roche Molecular Systems) with probes for low-risk (6, 11, 40, 42, 53, 54, 57, 66, and 84) and high-risk (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, 59, 68, 73, 82, and 83) HPV types was used for HPV detection and typing.

Quantitative and qualitative assays for HIV RNA were performed as described elsewhere [17]. The qualitative assay was performed on all available samples that were negative by the quantitative assays. The quantitative and qualitative HIV-1 RNA assays detect as few as 80 and 40 HIV-1 RNA copies/mL, respectively, with reproducible sensitivities of 400 and 200 HIV-1 RNA copies/mL, respectively. The HIV-2 quantitative and qualitative assays detect as few as 40 and 20 HIV-2 RNA copies/mL, respectively, with reproducible sensitivities of 200 and 100 HIV-2 RNA copies/mL.

Written informed consent was obtained from all enrolled women. The present study was conducted according to procedures approved by the institutional review boards of the University of Washington and the University of Dakar.

Statistical methods. The analyses were limited to women who were infected with HPV at their baseline visit. A sample was considered to be HPV negative if HPV was not detected by any of the methods used. Untyped HPVs were considered to be either those HPV types that were included in the reverse-line strip test but not the 12-type mixture used before 1 April 1998 or unclassified HPV types. To reduce the likelihood of misclassification introduced by false-negative results, clearance was defined as 2 consecutive HPV-negative test results.

The Kaplan-Meier method was used to provide estimates of the cumulative incidence of the end point of interest—clearance of HPV infection—by HIV status and type. Cox proportional hazard regression models with time-dependent covariates were used to assess the effect of HIV status and type on time to clearance of HPV infection, adjusting for confounding factors. Age, parity, type of contraception, current cigarette smoking, being a commercial sex worker, acquiring a new sexual partner during the previous 4 months, HPV type (high risk vs. low risk or untyped), and multiple (>1) HPV infections were included as potential confounding factors. To assess the effect of CD4 cell count and HIV load on the clearance of HPV infection among HIV-positive women, separate models adjusting for the aforementioned potential confounding factors were used. A priori, CD4 cell counts were stratified into 3 groups (>500, 200–500, and <200 cells/µL), and HIV load (quantified as plasma HIV RNA copies per milliliter) was evaluated per order-of-magnitude increase.

Finally, a composite Cox proportional hazard regression model was used to assess the impact of HIV type on time to clearance of HPV infection, after adjustment for the afore-mentioned confounding factors and accounting for CD4 cell count. Acquiring a new sexual partner during the past 4 months and CD4 cell count were included as time-dependent covariates in the models. Data for women who did not clear their HPV infection by the end of the follow-up or who were lost to follow-up were analyzed as censored observations.

Because the HPV DNA testing methods used throughout the duration of the study allowed us to have access to type-specific data on HPV-16 and HPV-18, we also compared the clearance of these 2 types between HIV-positive and HIV-negative women.

Analyses were performed using SAS (version 9.1; SAS Institute) and Stata (version 9.2; StataCorp). All statistical tests were 2-sided, and the significance level was set at α = .05.

Results

The mean and median ages of the 614 participants were 31.4 and 30 years, respectively; ages ranged from 17 to 56 years. Of the study subjects, 63.5% were University of Dakar infectious disease clinic outpatients, and the remaining 36.5% were commercial sex workers attending 1 of 2 STD clinics. Of these 614 women, 418 (68.1%) were HIV negative, 133 (21.7%) were HIV-1 positive, 43 (7.0%) were HIV-2 positive, and 20 (3.2%) were dually infected with HIV-1 and HIV-2 (table 1). In comparison with HIV-negative women, HIV-positive women were significantly more likely to be older; to be divorced, separated, or widowed; to not use contraception; to have lower CD4 cell counts; and to have multiple HPV infections at baseline. The majority (58.1%) of the HIV-negative women were infected with high-risk HPV types; this was because the HIV-negative women with high-risk HPV infections were oversampled in the original study to constitute a group of women at high risk for developing high-grade squamous intraepithelial lesions. Among HIV-positive women, those infected with HIV-1 were significantly more likely to be younger, to not use contraception, and to have lower CD4 cell counts than were those infected with HIV-2 or dually infected with HIV-1 and HIV-2. Women infected with HIV-2 were significantly less likely to have been born out of Senegal, to be infected with high-risk HPV types, and to be infected with multiple HPV types at baseline than were women infected with HIV-1 or dually infected with HIV-1 and HIV-2. None of the HIV-positive women were receiving antiretroviral therapy.

Table 1

Demographic and laboratory characteristics of the study population, by HIV status and type at the baseline visit.

Table 1

Demographic and laboratory characteristics of the study population, by HIV status and type at the baseline visit.

Overall, participants had a mean of 5 follow-up visits (maximum, 18 follow-up visits), a mean follow-up duration of 2.1 years (maximum follow-up duration, 5.8 years), and a median follow-up duration of 1.2 years. Figure 1 provides Kaplan-Meier curves illustrating the proportion of women who cleared their HPV (any HPV, HPV-16, and HPV-18) infection at each point of time over the follow-up period, by HIV status. As seen in figure 1A, HIV-positive women were less likely to clear their HPV infection than were HIV-negative women (P < .0001, log-rank test). There were 100 and 66 women infected with HPV-16 and HPV-18 at baseline, respectively. In HPV type–specific analyses (figures 1B and 1C), HIV-positive women were less likely to clear HPV-16 (P = .05, log-rank test) and HPV-18 (P = .03, log-rank test) infections than were HIV-negative women. Figure 2 shows the Kaplan-Meier curve illustrating the proportion of HIV-positive women who cleared their HPV infection at each time point over the follow-up period, by HIV type. Women infected with HIV-2 were more likely to clear their HPV infection than were women infected with HIV-1 (P = .01, log-rank test).

Figure 1

Cumulative incidence of human papillomavirus (HPV) clearance, by HIV status. A, Any HPV infection. B, HPV-16 infection. C, HPV-18 infection.

Figure 1

Cumulative incidence of human papillomavirus (HPV) clearance, by HIV status. A, Any HPV infection. B, HPV-16 infection. C, HPV-18 infection.

Figure 2

Cumulative incidence of human papillomavirus (HPV) clearance among HIV-positive women, by HIV type.

Figure 2

Cumulative incidence of human papillomavirus (HPV) clearance among HIV-positive women, by HIV type.

In univariate regression analyses (table 2), several characteristics were significantly inversely associated with HPV clearance; these included HIV-positive status, infection with a high-risk HPV type, infection with multiple HPV types, use of condoms, current cigarette smoking, and being a commercial sex worker. In multivariate analysis, after adjustment for all variables shown in table 2, only HIV-positive status, infection with a high-risk HPV type, and being a commercial sex worker remained independently inversely associated with HPV clearance. HIV-positive women showed a significant (69%) reduction (adjusted hazard ratio {HR}, 0.31 [95% confidence interval {CI}, 0.21–0.45]) in the likelihood of clearing their HPV infection, compared with HIV-negative women. Of note, after adjustment for CD4 cell count (data not shown in the table), this association was attenuated but remained significant (adjusted HR, 0.48 [95% CI, 0.31–0.74]). In separate HPV type–specific analyses, HIV-positive women were less likely to clear HPV-16 (HR, 0.57 [95% CI, 0.32–1.02]) and HPV-18 (HR, 0.42 [95% CI, 0.19–0.95]) infections than were HIV-negative women.

Table 2

Unadjusted and adjusted associations between characteristics of the study population and clearance of human papillomavirus (HPV) infection.

Table 2

Unadjusted and adjusted associations between characteristics of the study population and clearance of human papillomavirus (HPV) infection.

The women infected with high-risk HPV types showed a significant (29%) reduction (adjusted HR, 0.71 [95% CI, 0.53–0.93]) in likelihood of clearing their HPV infection, compared with the women infected with low-risk HPV types or untyped HPV. The strength of the association between HIV status and HPV clearance did not significantly differ between the women infected with high-risk HPV types (adjusted HR, 0.23 [95% CI, 0.13–0.41]) and the women infected with low-risk HPV types or untyped HPV (adjusted HR, 0.37 [95% CI, 0.23–0.61]) (P = .18). Finally, commercial sex workers showed a significant (42%) reduction (adjusted HR, 0.58 [95% CI, 0.36–0.91]) in the likelihood of clearing their HPV infection, compared with the women who were not commercial sex workers.

Among HIV-positive women (table 3), infection with HIV-2 was associated with an ∼2.5-fold increase in the likelihood of HPV clearance, compared with infection with HIV-1 (adjusted HR, 2.46 [95% CI, 1.17–5.16]). HIV-positive women with a CD4 cell count <200 and from 200 to 500 cells/µL showed a 71% (adjusted HR, 0.29 [95% CI, 0.11–0.76]) and 32% (adjusted HR, 0.68 [95% CI, 0.31–1.48]) reduction in the likelihood of HPV clearance, respectively, compared with HIV-positive women with a CD4 cell count >500 cells/µL. In addition, among HIV-positive women, HIV load was inversely associated with the likelihood of HPV clearance (adjusted HR for each order-of-magnitude increase in plasma HIV RNA copies per milliliter, 0.77 [95% CI, 0.64–0.91]). Finally, the association between HIV type and HPV clearance was further ad-justed for CD4 cell count. This adjustment attenuated the association; the women infected with HIV-2 no longer showed a significant increase in the likelihood of HPV clearance, compared with the women infected with HIV-1 (adjusted HR, 1.87 [95% CI, 0.83–4.21]). The adjusted HRs for CD4 cell count were slightly attenuated after adjustment for HIV type: CD4 cell count <200 and from 200 to 500 cells/µL showed a 64% (adjusted HR, 0.36 [95% CI, 0.13–0.98]) and 24% (adjusted HR, 0.76 [95% CI, 0.34–1.72]) reduction in the likelihood of HPV clearance, respectively, compared with the HIV-positive women with a CD4 cell count >500 cells/µL.

Table 3

Unadjusted and adjusted associations between HIV type, CD4 cell count, and HIV load and clearance of human papillomavirus (HPV) infection among HIV-positive women.

Table 3

Unadjusted and adjusted associations between HIV type, CD4 cell count, and HIV load and clearance of human papillomavirus (HPV) infection among HIV-positive women.

Discussion

Our analyses demonstrated that the HIV-positive women were less likely to clear their HPV infection than were the HIV-negative women. Among the HIV-positive women, those infected with HIV-2 were more likely to clear their HPV infection than were those infected with HIV-1; this association was significantly attenuated after taking into account the effect of CD4 cell count on the clearance of HPV infection.

Our results showed a 69% reduction (HR, 0.31) in the likelihood of HPV clearance among HIV-positive women, compared with that among HIV-negative women. This magnitude of reduction is similar to the results of some previous studies. For example, as part of a multicenter study coordinated by the Italian National Institute of Health, Branca et al. [5] reported that HIV-positive women were less likely to clear their HPV infection than were HIV-negative women (odds ratio, 0.33). Also, in the population-based longitudinal ALIVE (AIDS Link to Intravenous Drug Experience) study, Ahdieh et al. [1] reported that, compared with that among HIV-negative women, the relative incidence of HPV clearance was 29% and 10% among HIV-positive women with a CD4 cell count of ≥200 and <200 cells/µL, respectively.

The increased persistence of HPV infection in immunosuppressed individuals illustrates the critical role played by the cell-mediated immune response in the resolution and control of HPV infection [18]. It is believed that the overall evidence from allograft recipients, persons with inherited immunodeficiencies, and HIV-positive individuals suggests that the absolute deficit in CD4 cell count plays an important role in HPV-induced disease [19]. We found that the severity of the impairment of cell-mediated immunity, as measured by CD4 cell count, was a significant determinant of HPV clearance among HIV-positive women. This was consistent with the results of previous studies [1, 2, 4, 7]. CD4 cell counts of all women in the present study, regardless of their HIV status, were measured; therefore, we had the opportunity to assess the impact of CD4 cell count on the clearance of HPV infection among both HIV-negative and HIV-positive women. Interestingly, after adjustment for CD4 cell count, HIV-positive women were still significantly less likely to clear their HPV infection than were HIV-negative women. There are at least 2 potential explanations for such an observation. First, incomplete adjustment for CD4 cell count (treated as a categorical variable with 3 aforementioned categories) in the model may have resulted in residual confounding. Of note, when we treated CD4 cell count as a continuous variable (both as a single linear term and also with the quadratic term) in the model, HIV-positive women still showed a significantly lower likelihood of HPV clearance than did HIV-negative women. Second, CD4 cell count may not fully explain the difference in the likelihood of HPV clearance between HIV-positive and HIV-negative women. It has been suggested that HIV may interact with HPV in ways not limited to a decline in CD4 cell count [4]. For instance, alteration of the cytokine response to HPV infection in the cervical mucus of HIV-positive women has been suggested as one of the possible mechanisms by which HIV can alter the natural history of HPV infection [20].

Consistent with the results of HERS (US HIV Epidemiology Research Study) [21], we did not find evidence that HIV status and HPV type (i.e., high risk vs. low risk) may modify each other's impact on HPV clearance. Koshiol et al. [21] provided evidence that the association between HPV type (high risk vs. low risk) and HPV clearance did not differ significantly on the basis of subject HIV status in a population with access to an-tiretroviral therapy. Similarly, HIV-positive women in our study, none of whom had access to antiretroviral therapy, showed significant reductions in the likelihood of HPV clearance compared with HIV-negative women, whether they were infected with high-risk or low-risk HPV types, and the extent of these reductions did not differ significantly by HPV type.

The present study setting, Senegal, West Africa, provided us with a unique opportunity to examine the effect of HIV-2 infection on the clearance of HPV infection, separately from that of HIV-1 infection. HIV-2 is generally less pathogenic than HIV-1; in effect, it appears to be an attenuated form of HIV-1 [13]. Individuals infected with HIV-2 usually have a long period of clinical latency (10 years or more), resulting in a mortality rate estimated to be two-thirds lower than that for HIV-1 [14, 22]. This may be due to the lower virulence, lower rate of CD4 cell count decline, lower plasma viral load, and better overall immune control of replication associated with HIV-2 relative to HIV-1 [23, 24]. Therefore, because of the central role played by cell-mediated immunity in the clearance of HPV infection, it is conceivable that women infected with HIV-2 clear their HPV infection more rapidly than do women infected with HIV-1. In fact, we observed that, after accounting for CD4 cell count, women infected with HIV-2 were no longer significantly more likely to clear their HPV infection than were women infected with HIV-1. In line with differences in pathogenesis and immunology between HIV-1 and HIV-2, CD4 cell count may be on the causal pathway of the relationship between HIV type and HPV clearance.

The present study is subject to some limitations. First, we used prevalent cases of HPV infection to assess HPV clearance. Ideally, we would have wanted to identify incident cases of HPV infection and follow them over time to assess HPV clearance. However, we were limited by sample size (n = 90) and the length of follow-up time. Second, the HPV testing method was not consistent throughout the study period; we did not have access to newer type-specific PCR probes before 1 April 1998. However, there is no evidence that HIV status may have affected the sensitivity of these 2 test strategies, and, thus, any potential HPV misclassification due to the testing strategy is likely to be nondifferential to result in attenuated observed associations. Unfortunately, the combined measurement of HPV types 6 and 11; 31, 33, 35 and 39; 45 and 56; and 51 and 52 did not allow us to assess type-specific clearance of infection with these types. Furthermore, although we did have access to type-specific tests for HPV-16 and HPV-18 throughout the study, we were limited by a small sample size for each of these infections; therefore, we were not able to assess the impact of HIV status on the clearance of HPV-16 or HPV-18 infection after taking into account several potential confounders of this association. Third, untyped HPV infections were categorized with low-risk types in our analyses, and some of these infections could have been with high-risk HPV types. However, when we categorized untyped HPVs and high-risk types in the same group (data not shown), our results did not show an appreciable difference. Because we treated HPV type (high risk vs. low risk) as a potential confounding factor of the associations between HIV status and HPV clearance and between HIV type and HPV clearance, some level of residual confounding may be present in the results because of misclassification of the confounding factor. Finally, although we took several potential confounders into account, it is still possible that HIV-positive and HIV-negative women differ in some other aspects that have a bearing on HPV clearance. For example, information on other sexually transmitted infections was not available. It has been suggested that Chlamydia trachomatis infection may play a role in HPV persistence [25, 26]. Because we were not able to adjust for such other potential confounders, some level of uncontrolled confounding may be present in the results.

In the present study, both CD4 cell count and HIV load were separately associated with the clearance of HPV infection among HIV-positive women. Antiretroviral therapy reconstitutes the immune system, resulting in an increased CD4 cell count and decreased HIV load [4]. Therefore, HIV-positive women who receive antiretroviral therapy may be able to clear HPV infection more rapidly than women who do not receive antiretroviral therapy. Supporting evidence for this assertion, however, is lacking, with some studies showing no significant impact of antiretroviral therapy on the clearance of HPV infection [27–29]. Studies assessing the potential long-term impact of antiretroviral therapy on persistence of HPV infection are needed. Finally, to our knowledge, this study provides the first assessment of the impact of HIV type on clearance of HPV infection. Further exploration of the potential differences between HIV-1 and HIV-2 with respect to the alteration of the natural history of HPV infection is needed; such effort could result in a better understanding of the role played by the immune response in the clearance of HPV infection.

Acknowledgments

We thank Deana Rich, Elise Reay-Ellers, and Macoumba Touré for their invaluable coordination of study procedures in Senegal; Mame Dieumbe Mbengue-Ly, Marie Pierre Sy, and Pierre Ndiaye for patient care; Jane Kuypers, Diouana Ba, and Haby Agne for their leadership in the laboratory; Fatou Faye-Diop for data entry; and Alison Starling for questionnaire development and data management. Finally, we thank the women who participated in this longitudinal study.

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Potential conflicts of interest: none reported.
Presented in part: Second North American Congress of Epidemiology, Seattle, 21–24 June 2006 (abstract 288-S).
Financial support: National Institutes of Health (grants CA 62801 and 97275).