This cervical cancer study in Johannesburg, South Africa is, to our knowledge, the largest to date among HIV-seropositive women in Africa. Half of 1,010 HIV-seropositve women had cervical lesions, with cervical abnormalities prevalence increasing with lower CD4 immune status. High observed prevalence of ASCUS or greater is similar to that observed in 397 HIV-seropositive women from Cape Town, South Africa (54%) [30
], yet somewhat lower than among 150 HIV-seropositive women from Zambia (76%) [30
]. Overall observed prevalence of LSIL (24%) and HSIL (18%) was also higher than among HIV-seropositive women in the United States (15.4 and 7.9%, respectively), a European cohort (21.0 and 2.8%, respectively) [32
] or Zimbabwe (9.7 and 3.4%) [34
In this study from Johannesburg, 42% of HIV-seropositive women had CD4 counts < 200 cells/mm3
. Our results of HSIL prevalence of 18% are not as high as that observed in Zambia (33%) among a smaller number of HIV-seropositive women who also had low median CD4 counts of 165/mm3
]. Observed prevalence, however, was higher than among women with unknown HIV serostatus screened in the Free State province, South Africa (LSIL of 18% and HSIL of 8%) [35
]. The high prevalence of cervical neoplasia in our study could be partially explained by more advanced stages of HIV immunosuppression among female participants when compared to previous studies from the United States and Europe [32
]. In addition, the lack of cervical cancer screening is also a likely cause of this phenomenon since cervical cancer in non-HIV-infected women is higher in South Africa than the United States. Of note, one-fifth of HSIL cases were 30 years of age or younger. Given these results, cervical cancer screening should be considered in HIV-seropositive women upon diagnosis rather than being delayed until 30 years of age [36
The number of different types of any HPV or oncogenic HPV DNA types among HIV-seropositive women was smaller with increasing severity of cervical neoplasia (i.e. HIV-seropositive women with HSIL appear to have fewer HPV types than those with LSIL). These findings are consistent with data among largely HIV-seronegative women [4
], indicative of the relatively fewer number of HPV types that may be etiologically important for the development of HSIL vs. lower grades of cervical neoplasia in HIV-seropositive women. Our results, however, are limited to HPV DNA detection within cervical exfoliated cells, rather than biopsy specimens. Although cytological results were presented in current analyses, as used in current clinical practice, histological confirmation of study outcomes may have lead to the reclassification of some clinical endpoints. Of the 182 cases of HSIL or greater, 83 had available pathology results. Most HSIL cases were histologically confirmed as CIN-2 (30%) or CIN-3 (47%), whereas slightly less than one quarter (23%) were classified as CIN-1 by histology. Measures of association between risk factors and grades of cervical neoplasia presented, respectively, in Tables and , were similar, however, when CIN, rather than SIL, classifications were used.
HPV 16 was the most common HPV type in HIV-seropositive women with HSIL (41.7%) in the present study, with HPV 18 being relatively rare (2.8%). These results are similar to a review of African data among largely HIV-seronegative women where HPV 16 and/or 18 prevalence was 45% in HSIL [4
], Among 77 HIV-seropositive women with HSIL from Zambia [31
], HPV 52 was the most common type, followed by HPV types 58. A previous review indicated that HSIL cases among HIV-seropositive women may have a lower proportion of HPV-16 positivity than HIV-seronegative HSIL cases [17
]. Given recent data from Kenya indicating that HPV 16 prevalence was similar in HIV-seropositive and HIV-seronegative ICC cases [8
], further data on HPV oncogenic types in HSIL and ICC cases are needed among a larger number of HIV-seropositive HSIL and ICC cases from Africa.
Combined HPV 16 and/or 18 prevalence among HIV-seropositive women in South Africa was 42% HSIL and 53% in LSIL, respectively. Thus, as with HIV-seronegative women, a notable proportion of HSIL and LSIL cases in HIV-seropositive women could be potentially prevented by the vaccination of female adolescents prior to first sexual intercourse. Not withstanding, a non-negligible proportion of HSIL and LSIL cases will not be prevented by HPV prophylactic vaccination, highlighting that cervical cancer screening remains paramount for optimal cervical cancer prevention. Further, approximately half of HSIL cases among HIV-seropositive women in this study harbored other high-risk HPV types 33, 56 and 66 (~47%). This is important to consider for the development of future therapeutic vaccines that are urgently needed in regions with a high burden of ICC.
Among HIV-seropositive women from Johannesburg, lower CD4 counts were consistently associated with a higher risk of cervical lesions (ASCUS, LSIL and HSIL or greater). Our results are consistent with previous screening studies of HIV-seropositive women [37
]. It is not surprising that HIV-seropositive women with greater immunosuppression are at a higher risk of cervical disease. Consistently, lower CD4 counts (<500 cells/mm3
) have been associated with a higher probability of progression to higher cervical disease grades [32
The relatively broader distribution of HPV types among HIV-seropositive women with lower CD4 counts suggests reactivation of latent HPV viral infections [38
]. Our results are similar to previous studies indicating that HIV-seropositive women with CD4 counts < 200/mm3
have a higher prevalence of any HPV or oncogenic HPV types [11
] when compared to those with CD4 counts > 500/mm3
. Of interest, HPV 16 prevalence in our study increased with greater immune suppression, declining from 38% among women with CD4 counts < 200 cells/mm3
to 6% for CD4 counts > 500 cells/mm3
. As a sensitivity analysis, we limited analyses to HIV-seropositive women with normal cytology and found similar results. Albeit based on relatively smaller sample sizes, these results suggest that within the African content that HPV 16 may not be better at evading host immune responses than other HPV types, as previously suggested [6
]. Strickler et al. showed a relatively weaker association of type 16 with decreasing CD4 counts than other HPV types [9
] among HIV-seropositive women from the United States consistently, Koshiol et al. found that the persistence of HPV 16 among HIV-seropositive women did not appear to be associated with CD4 counts [6
]. These results from South Africa, although based on relatively small sizes, suggest that HPV 16 prevalence may be affected by the level of CD4 immune suppression. As previously hypothesized, the relationship of HPV 16 infection with the immune suppression in our population may differ from European and US HIV-infected women, potentially due to higher levels of immunosuppression in the underlying population within the African context [9
]. Further data are needed to investigate the prevalence and persistence of HPV 16 and other high-risk HPV types, stratified by the level of CD4 count, in HIV-seropositive women in both African and relatively more developed populations.
Another interesting finding in this study was that HIV-seropositive women who used condoms had a lower risk of HSIL than non-users (table ): PR = 0.7 95% CI (0.5–0.9). A study of HIV-seronegative women (n
= 82) also found a lower risk of cervical neoplasia among women who reported consistent condom use compared with those who did not [41
]. There is also evidence in HIV-seronegative women that the consistent use of condoms was associated with a higher clearance rate of HPV and of cervical neoplasia [42
]. In our present study, a protective effect was not found with ASCUS or LSIL with condom use.
Given the cross-sectional design, the current study can not reliably address the temporal effect of HAART on HPV persistence or the progression of cervical neoplasia. The multivariate analysis did not find any association between HAART use and any grade of cervical neoplasia, and is in agreement with previous research [14
]. One study among 328 US women found no difference in cervical disease prevalence between HIV-seropositive women treated and untreated with either mono- or combination therapy (non-HAART) over study follow-up [14
]. An Italian study of 163 HIV-seropositive women also found no beneficial effect of HAART therapy on the risk of incident SIL, or on the progression rate of cervical lesions after adjusting for CD4 cell count [23
]. Given inconsistent associations between HAART use and the risk of cervical neoplasia, the effect of HAART therapy on cervical neoplasia is still being debated. Although potent anti-HIV regimens are effective for the restoration of patient’s immune system by increasing CD4 counts, limited data suggest that HAART use may not affect HPV viral persistence [21
]. Further prospective studies in this cohort will be done to evaluate whether HAART has any role in modifying the progression of cervical dysplasia in these HIV-seropositive women. Further studies are also needed to determine whether the earlier initiation of HAART at higher CD4 counts than is currently recommended for clinical practice will useful for the prevention of high-grade cervical lesions among HIV-seropositive women.
One limitation of this study is the lack of HIV viral load data and analysis as a measure of HIV disease status. HIV baseline viral loads before the initiation of HAART are generally not done in the South African government HIV treatment clinics [27
]. Another possible bias in the study is that very ill women were excluded from the study. These women might have had lower CD4
counts; therefore, we may actually be underestimating the prevalence of high-grade lesions that would have been found if these women had not been excluded. However, we do not think that this was a significant selection bias, given that women with CD4
counts < 200 represents 43% of our study population.
Given that many African HIV-seropositive women are living longer in the era of HAART, they now face longer-term HIV-related complications including invasive cervical cancer. The wide-spread introduction of currently available prophylactic HPV vaccines would reduce, but not eliminate, a large proportion of high-grade cervical lesions. Thus, strengthening and expanding cervical cancer screening program in settings where HIV prevalence is high remains imperative.