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HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India: 12-month follow-up

HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India:... International Journal of Women’s Health Dovepress open access to scientific and medical research Open access Full Text article O r I g I nal r esearc H HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India: 12-month follow-up 1,2 Petros Isaakidis Background: HIV-infected women are at a higher risk of cervical intraepithelial neoplasia (CIN) and cancer than women in the general population, partly due to a high prevalence of persis- sharmila Pimple tent human papillomavirus (HPV) infection. The aim of the study was to assess the burden of HPV Bhanumati Varghese 1 infection, cervical abnormalities, and cervical cancer among a cohort of HIV-infected women samsuddin Khan as part of a routine screening in an urban overpopulated slum setting in Mumbai, India. Homa Mansoor Methods: From May 2010 to October 2010, Médecins Sans Frontières and Tata Memorial Joanna ladomirska Hospital Mumbai offered routine annual Pap smears and HPV DNA testing of women attending n eelakumari sharma an antiretroviral therapy (ART) clinic and a 12-month follow-up. Women with abnormal test esdras Da silva results were offered cervical biopsy and treatment, including treatment for sexually transmitted carol Metcalf infections (STIs). severine caluwaerts Results: Ninety-five women were screened. Median age was 38 years (IQR: 33–41); median Petra alders nadir CD4-count 143 cells/µL (IQR: 79–270); and median time on ART 23 months (IQR:10–41). evangelia e n tzani HPV DNA was detected in 30/94 women (32%), and 18/94 (19%) showed either low-grade or Tony reid high-grade squamous intraepithelial lesions (LSIL/HSIL) on Pap smear. Overall, .50% had 1 cervical inflammatory reactions including STIs. Of the 43 women with a cervical biopsy, eight Médecins sans Frontières, Mumbai, India; c linical and Molecular (8.4%) had CIN-1, five (5.3%) CIN-2, and two (2.1%) carcinoma in situ. All but one had HPV epidemiology Unit, Department of DNA detected (risk ratio: 11, 95% confidence interval: 3.3–34). By October 2011, 56 women Hygiene and epidemiology, University had completed the 12-month follow-up and had been rescreened. No new cases of HPV infec- of Ioannina s chool of Medicine, Ioannina, greece; Preventive tion/LSIL/HSIL were detected. Oncology Department, Tata Memorial Conclusion: The high prevalence of HPV infection, STIs, and cervical lesions among women Hospital, Mumbai, India; Médecins attending an ART clinic demonstrates a need for routine screening. Simple, one-stop screening sans Frontières, Brussels, Belgium strategies are needed. The optimal screening interval, especially when resources are limited, needs to be determined. Keywords: HIV/AIDS, HPV, women’s health, cervical cancer, operational research, India Introduction About half a million cases of cervical cancer occur annually worldwide, 80% of which occur in low-resource countries. In India, cervical cancer ranks as the most frequent cancer among women, especially among those between 15 and 45 years of age. Human papillomavirus (HPV) is a major risk factor for cervical cancer since as much as 83% correspondence: Petros Isaakidis of invasive cervical cancers are associated with human papillomavirus 16 or 18, and Médecins sans Frontières, chandni about 8% of women in the general population are estimated to harbor cervical HPV Bungalow, Union Park, Off carter road, Khar (W), Mumbai 400 052, India infection at a given time. Tel +91 9930 534211 HIV-infected women in various settings were found to have higher rates of persis- email msfocb-asia-epidemio@brussels. msf.org tent HPV infection, more abnormal Pap tests, more cervical intraepithelial neoplasia submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 487–494 Dovepress © 2013 Isaakidis et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IJWH.S47710 permission from Dove Medical Press Ltd, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Ltd. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Isaakidis et al Dovepress (CIN) lesions, and aggressive cervical cancer, compared with to October 2010. HIV-infected women aged 25–65 years with 3–6 the general population, and these numbers are increasing. intact uterus and with no past history of cervical neoplasia and The high rate of cervical disease reported in HIV-infected who gave consent were recruited. Women coinfected with women and the extended life expectancy due to better access multidrug-resistant tuberculosis at the early stages of treat- to antiretroviral therapy (ART) have led to recommendations ment were offered the screening at a later stage, depending for aggressive screening and prompt treatment of cervical on their condition. Women that refused consent were further lesions; yet, the most appropriate strategy to screen HIV- excluded from the study. infected women, particularly in resource-constrained settings, 7–9 remains unclear. Moreover, the existing evidence on the Pap test, HPV detection, and cervical impact of ART on the incidence and evolution of CIN is still biopsy unclear, thus reinforcing the recommendation of systematic All the women participating in the study were tested for cer- 3,6 screening of all HIV-infected women, even those on ART. vical cytology and HPV and underwent colposcopy with or Overall, the evidence assessing the extent and magnitude of without biopsy. HPV testing by Hybrid capture II was done HPV infection and the burden of cervical abnormalities and by cervical sampling brush (Digene cervical sampler, Qiagen, cancer among HIV-infected women is sparse and remains Venlo, the Netherlands). HPV DNA status for high-risk HPV largely undocumented. types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) The aim of this study was to assess the burden of HPV was determined with the use of the second-generation HC II infection, cervical abnormalities, and cervical cancer among probe B, microtiter assay (Digene). Colposcopy was carried a cohort of HIV-infected women as part of a routine screen- out by trained doctors for all participants irrespective of their ing in an urban, overpopulated slum setting in Mumbai, screening test result. Colposcopy-guided punch biopsies were India. Specific objectives included: to measure the overall obtained from subjects with abnormal findings on colpos - yield of HPV infection, cervical abnormalities, and cervical copy. Biopsy specimens were processed and reported using cancer; to report on the treatment outcomes among women the CIN system. True disease status was den fi ed as CIN-2 and with treated abnormalities; and to identify factors associated worse lesions. CD4 T-cell counts (BD, Franklin Lakes, NJ, with cervical abnormalities, especially factors related to the USA) were obtained from the participant’s medical record. HIV infection (CD4 count, ART, etc). To our knowledge, Nadir CD4 T-cell count was defined as the lowest level of this is one of the first reports on cervical abnormalities in immunosuppression recorded for a specific patient. HIV-infected patients in India. Treatment protocol and follow-up Methods Women with any grade of CIN were called back for cryo- study design therapy or loop electrosurgical excision procedure (LEEP), This was a prospective cohort of HIV-infected patients fol- as appropriate. Women with suspected invasive cancer lowed up from February 2010 to October 2011. were referred to the Tata Memorial Hospital for further management. All treated women were followed-up for up setting and study population to 1 year for colposcopy evaluation in order to determine Médecins Sans Frontières (MSF) has been operating a cure rates. specialized HIV clinic in Mumbai, India since 2006, pro- viding treatment free of charge to patients referred by ART Data collection and statistical methods centers from the greater Mumbai area and by community Information on HIV and ART of all patients was prospectively non-governmental organizations. Patients are referred to collected in specic fi ally designed patient l fi es and routinely the clinic because of coinfections (especially multidrug- entered in a database. For the HPV and cervical cancer screen- resistant tuberculosis and hepatitis B or C) and because they ing, clinical and laboratory information were recorded in the require antiretroviral agents or regimens not readily available same patient files but entered in a different database. A unique through the national ART program. Most of the patients are identic fi ation code was assigned to each patient and was used slum dwellers. in both databases. Patient characteristics were described A universal cervical cancer screening was organized, in using medians, interquartile ranges (IQRs), and percentages, collaboration with the Preventive Oncology Department of as appropriate. We estimated the burden of cervical abnor- the Tata Memorial Hospital, Mumbai, India, from February malities at the screening and follow-up using proportions. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women Table 1 sociodemographic characteristics of the Mumbai HIV- In order to identify predictors for cervical pathologies, infected female cohort univariate and multivariate analyses were performed using Characteristic (N) n (%) Median (IQR) logistic regression and generalized linear models. Multivariate age (years) (95) 38 (33–41) models considered all variables with P , 0.1 on univariate  ,30 12 (12.6) models and used a backward elimination approach for n fi al   30–39 48 (50.5) selection. There was no overt violation of the proportionality 35 (36.8)  $40 assumption. Statistical analyses were performed using SPSS 143 (79–270) nadir cD4 count (cells/ µl) (95) (v 16.0; IBM Corporation, Armonk, NY, USA) and Stata 35 (36.8)  #100 26 (27.4)   101–200 (version 11; StataCorp LP, College Station, TX, USA).   201–350 16 (16.8) 18 (19.0)  .350 ethics Time on arT (months) (95) 23 (10–41) The tests, follow-up of abnormalities, and treatment 25 (26.3)   0–11 23 (24.2)   12–23 options were explained to patients, and their written con- 18 (19.0)   24–35 sent requested. The study met the MSF’s Ethics Review 29 (30.5)  $36 Board-approved criteria for analysis of routinely collected education (95) program data. 24 (25.3)   Illiterate   Primary 19 (20.0)   secondary 40 (42.1) Results 12 (12.6)   Tertiary Baseline patient characteristics Monthly income (UsD) (95) 60 (40–100) 34 (35.8)  ,50 and HIV status 33 (34.7)   50–99 Of the 390 HIV-infected women registered in the HIV clinic 28 (29.5)  $100 from 2006, the 99 adult women who attended the clinic gravidity (94) 1 (1–2) from October to May 2010 were considered for inclusion in 10 (10.6)   0 the study. Three women denied screening and one teenager 42 (44.7)   1  $2 42 (44.7) reported no history of sexual activity and was excluded from Married/currently living with partner (95) the study; thus, 95 women were screened during the first   Yes 48 (50.6) screening. The median age was 38 (IQR: 33–41), and 51% 47 (49.4)   no of the women were aged between 30 and 39 years (Table 1). ever smoked/chewed tobacco (95) Approximately half of the women were married or living with 19 (20)   Yes 76 (80)   no a partner at the time of the study; a large proportion of widows ever used drugs/alcohol (95) and separated women was recorded in this cohort (46%). Most 2 (2.1)   Yes women had attained at least primary education, while 13% 93 (97.9)   no had received higher education. Eighty percent had either never Use of hormonal contraceptives (94) smoked or were not current smokers, while 98% of the cohort 1 (1.1)   Yes   no 93 (98.9) had never used drugs or alcohol. A large majority (98.9%) of Abbreviations: arT, antiretroviral therapy; IQr, interquartile range; UsD, Us the women were not making use of any type of hormonal con- dollar. traceptive method. Forty-v fi e percent of the women had had two or more pregnancies during their lifetime. Thirty-seven retrieved. HPV infection was detected in 30 (32%) of the percent had a nadir CD4 T-cell count of ,100 cells/µL. All 94 women with an available result. patients were on ART at the time of the screening; the median Overall, 43 women, almost half of the participants, had time on ART was 23 months (IQR: 10–41). cervical inflammatory reactions. Forty-one percent had inflammation of the cervix, including STIs, but not intra - Baseline HPV infection status, cytology epithelial lesions. Cervical cytology was abnormal in 18 and pathology results, and treatment of 94 women (19%). Low-grade squamous intraepithelial The majority (98%) of this cohort of HIV-infected women had lesions (LSIL) and high-grade squamous intraepithelial never had a gynecological examination before the screening lesions (HSIL) were detected in 14% and 5% of the partici- was offered. For one woman, a Pap smear test result was not pants, respectively. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Isaakidis et al Dovepress The women with cervical inflammatory reactions were chemotherapy as per the recommended treatment guidelines. referred for colposcopy with a guided cervical biopsy by This patient, at the 18-month follow-up, had to switch to the examining physician during the first round of screening. second-line ART due to virological failure after 3 years on Biopsy was abnormal in 16% women: eight (8%) had CIN-1, r fi st-line ART. The patient was, however, in excellent general five (5%) CIN-2, and two (2%) women were diagnosed with condition and she was not immunologically compromised at carcinoma in situ. the time of the ART switch. Five patients underwent LEEP during the first screening round; four women with CIN-2 and one with CIN-1. Eight 12-month follow-up women received cryotherapy: one woman with CIN-2 and Figure 1 shows the flow of patients in the two screening seven women with CIN-1. One woman with cervical cancer rounds and reasons for not screening. Sixteen women died in a car accident before any treatment was started. were not eligible for rescreening as they hadn’t completed The second woman diagnosed with cervical cancer was 12 months of follow-up at the time of the analysis. By successfully operated on and received radiotherapy and October 2011, 56 (59%) women had completed at least HIV-infected women eligible for first screening N = 99 Women not screened: Not accepted = 3 Excluded = 1 Women screened (1st round) N = 95 Women diagnosed with cancer: Died = 1 Treated = 1 HIV-infected women eligible for 12-month follow-up N = 93 Women not screened: 12 months not completed = 16 Transferred out = 14 Not accepted = 4 Died = 2 Lost to follow-up = 1 Women screened (2nd round) N = 56 Figure 1 Flowchart of cervical cancer screening in a cohort of HIV-infected women at baseline and 12-month follow-up. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women 12 months of follow-up and had been rescreened. No new multivariate models, no sociodemographic or clinical fac- cases of HPV infection, LSIL, or HSIL were detected on tor was found to be significantly associated with cervical rescreening. Of the 15 women who were found HPV-positive neoplasia (Table 2). in the first screening and pursued a second screening, nine tested negative in the second screening while the remain- Discussion ing six remained HPV-positive in the second screening at In the present study, we estimated the prevalence and 12 months. 12-month incidence of cervical abnormalities and assessed factors associated with cervical neoplasia among HIV- Factors associated with HPV infection infected women enrolled in care in an HIV clinic in Mumbai, India who attended a screening program. The vast majority and cIn of women had never previously been screened for cervical In the bivariate regression analysis, no factor was nominally abnormalities. We found that one-third of the women tested significantly associated with an increased risk for HPV positive for HPV; more than half had inflammation of the infection. In multivariate models, and adjusting for all fac- cervix, including STIs; and as many as 17% of the women tors, nadir CD4, time on treatment, and parity were associated screened had abnormal Pap smear results. Prevalence of with HPV infection (Table 2). CIN was similarly high, at approximately 16%. Finally, we All but one of the eleven women (91%) with CIN found no new cases of HPV infection, LSIL, HSIL, CIN, or cancer were infected with HPV. Similarly, the two or cancer among women rescreened 12 months after their participants with invasive cervical cancer were infected initial screening. with HPV. In the bivariate models, and despite the lack of Studies among the general population in resource-limited power, HPV infection was significantly associated with countries have shown high prevalence of cervical neoplasia. cervical neoplasia (RR: 11, 95% CI: 3.3–34). In further However, little is known about the prevalence and incidence of cervical abnormalities and HPV infection among HIV- Table 2 Factors associated with HPV infection and cervical infected women. Interestingly, our study findings are in abnormalities (n = 93) accordance with a very recent study in which the investiga- Factor n (%) HPV High- and low- OR grade squamous tors observed similar rates of HPV infection and cervical (P-value) intraepithelial pathology. Moreover, in studies among HIV-infected women lesions in Sao Paolo, Rio De Janeiro, and Belo Horizonte, Brazil, OR (P-value) 13%, 24%, and 24% had a diagnosis of squamous intra- age (years) 11–13 epithelial lesions, respectively. In studies in Cambodia,  ,35 29 (30.5) 66 (69.5) 0.46 (0.203) 0.68 (0.613)  $35 Thailand, and People’s Republic of China, the prevalence nadir cD4 (cells/ µl) of HSIL/LSIL among women attending HIV clinics was 61 (64.2) 3.73 (0.025)* 1.04 (0.954)  #200 8,14,15 17%, 16%, and 8%, respectively. Studies conducted in  .200 34 (35.8) Zambia and Kenya reported higher prevalences, 33% and Months on arT 16,17 25 (26.3) 3.57 (0.027)* 1.27 (0.743) 27%, respectively, among HIV-infected women Finally,  ,12 70 (73.7)  $12 in our study, and bearing in mind the available published Previous pregnancies evidence, we report an intermediate HPV prevalence among 52 (54.7)   0 or 1 HIV-infected women.  $2 42 (44.2) 3.32 (0.035)* 0.88 (0.859) It is well established that HPV infection is a contributor to Income (UsD/month) 34 (35.8) 1.33 (0.580) 0.90 (0.882)  ,50 cervical cancer and that it progresses to squamous intraepi- 61 (64.2)  $50 thelial neoplasia more frequently and rapidly in HIV-infected level of education women than in the general population. Our main study find - 43 (45.3) 1.29 (0.611) 1.05 (0.934)   Primary or less ings indicate that HPV infection was frequent in this cohort   secondary or more 52 (54.7) of patients and significantly associated with squamous intra - HPV at baseline 64 (67.4) –   not detected epithelial lesions, suggesting that this population follows an 30 (31.6) –   Detected 19.69 (,0.001)* epidemiological pattern in common with other HPV-infected Notes: *P , 0.05; 94 patients were included. women, who remain at high risk for cervical neoplasia; as Abbreviations: arT, antiretroviral therapy; HPV, human papillomavirus; Or, odds ratio. such, aggressive screening and management are justified submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Isaakidis et al Dovepress for HIV/ HPV co-infected women. We offered colposcopy and the number of lifetime sexual partners. However, India plus biopsy to all women with clinical findings suggestive is a conservative society in which extramarital sex is taboo, of neoplasia as well as to all women with abnormal Pap especially for women, and we would expect a rather homo- smears. This practice proved very effective for the confirma - genous sample in these regards. tion of cervical abnormalities, and guided prompt treatment. Worth discussing is that we found no new cases of Nevertheless, the estimated uptake of Pap tests in India is HPV infection or squamous intraepithelial lesion in the discouragingly low, at 2.6%; the situation is no better in urban 12-month follow-up in this cohort of patients. While we centers, where uptake is only slightly higher, at 4.9%. Our strongly believe that screening and management of cer- experience from Mumbai, a major metropolitan center with vical abnormalities and cancer in HIV-infected women access to HPV DNA testing and quality-controlled cytol- should be recurrent and aggressive, we also acknowledge ogy and pathology showed that the very availability of such that, when resources are limited, the type and frequency of services is not enough to guarantee increased access. Major screening needs to be carefully determined. United States constraints include the capacity of the existing facilities and cervical cancer screening guidelines for HIV-uninfected lack of awareness in both the general population and among women 30 years or older were recently revised, with the health care providers. Our findings suggest that, in settings suggested interval between Pap tests increasing from 3 to with limited access to care, women with a history of HPV 5 years for those with normal cervical cytology results and 22,23 should be prioritized, especially if HIV-infected. negative oncogenic HPV. It is not clear if an interval of Modeling for factors potentially associated with squamous 3 or 5 or more years between screenings could be used in intraepithelial lesions in HIV-infected women, we found that HIV-infected women who are HPV-negative and cytologi- immunosuppression, as measured by nadir CD4 count, was cally normal. Meanwhile, as HPV testing is not available not significantly associated with squamous intraepithelial in most resource-constrained settings, we advocate for lesion prevalence. Similarly, time on ART was not found to annual screening and prompt management of cervical have a statistically significant protective effect in the occur - abnormalities. Implementation of a cytology-based screen- rence of squamous intraepithelial lesions in this population. ing strategy in rural or resource-limited settings may be The absence of significant associations could be explained challenging. In previous MSF experience in Cambodia, by the lack of power to detect these associations. Neverthe- “screening for cervical cancer using the conventional less, the degree of immunosuppression is expected to have Pap test proved just as difficult for HIV-positive women, an effect on the incidence and progression of squamous already enrolled in care, as for women of the general intraepithelial lesions among HIV-infected women as it has population.” 13–17 been shown in several observational studies. To date, The single-visit screen-and-treat approach, using visual evidence on an independent association between ART and inspection with acetic acid (VIA) and cryotherapy, has been the natural history of HPV infection or the risk of squamous shown to be effective and acceptable among women in intraepithelial lesions and cervical cancer is contradictory resource-constrained settings. However, it is still not well 18–21 and inconclusive. It is likely that the increased survival known whether this approach, is effective and safe for HIV- 24,25 of these women due to ART may lead to higher incidence and infected women. Studies from Zambia have shown that mortality from cervical pathologies and cancer. linking cervical cancer prevention and treatment services There are a number of limitations to this study. First, we (including LEEP) with HIV care and treatment is feasible 26,27 fully acknowledge that this is a small study; however, we and safe. Sankaranarayanan et al, in 2009, demonstrated argue that the setting in which the study took place poses in a cluster-randomized study in rural India that a “single challenges in gathering large sample sizes, and even study- round of HPV testing was associated with a significant ing small datasets provides valuable information. Second, reduction in the numbers of advanced cervical cancers we acknowledge that only 60% of the women were followed and deaths from cervical cancer.” The HIV status of the up after 12 months. The actual loss to follow-up, death rate, women enrolled in that study, however, was not discussed and refusals were relatively low. A significant number of in the study report. women were transferred out from the program and a relatively Recently, in a large observational study in, USA, it was large number of women were yet to complete 12 months of found that there were no differences in the 5-year cumula- follow-up at the time of the analysis. Moreover, we were tive incidence of HSIL and CIN-2 between HIV-infected and not able to collect data on the age of first sexual intercourse -uninfected women. The authors, however, concluded that submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women 6. De Vuyst H, Franceschi S. Human papillomavirus vaccines in further evidence is needed, including randomized evidence, HIV-positive men and women. Curr Opin Oncol. 2007;19(5): before expanding the current recommendations for testing 470–475. all HIV-infected women for HPV. In resource-limited set- 7. Comprehensive Cervical Cancer Control: A Guide to Essential Practice. Geneva: World Health Organization; 2006. tings, operational research is also needed to demonstrate 8. Raguenaud ME, Isaakidis P, Ping C, Reid T. 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HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India: 12-month follow-up

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© 2013 Isaakidis et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License.
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International Journal of Women’s Health Dovepress open access to scientific and medical research Open access Full Text article O r I g I nal r esearc H HPV infection, cervical abnormalities, and cancer in HIV-infected women in Mumbai, India: 12-month follow-up 1,2 Petros Isaakidis Background: HIV-infected women are at a higher risk of cervical intraepithelial neoplasia (CIN) and cancer than women in the general population, partly due to a high prevalence of persis- sharmila Pimple tent human papillomavirus (HPV) infection. The aim of the study was to assess the burden of HPV Bhanumati Varghese 1 infection, cervical abnormalities, and cervical cancer among a cohort of HIV-infected women samsuddin Khan as part of a routine screening in an urban overpopulated slum setting in Mumbai, India. Homa Mansoor Methods: From May 2010 to October 2010, Médecins Sans Frontières and Tata Memorial Joanna ladomirska Hospital Mumbai offered routine annual Pap smears and HPV DNA testing of women attending n eelakumari sharma an antiretroviral therapy (ART) clinic and a 12-month follow-up. Women with abnormal test esdras Da silva results were offered cervical biopsy and treatment, including treatment for sexually transmitted carol Metcalf infections (STIs). severine caluwaerts Results: Ninety-five women were screened. Median age was 38 years (IQR: 33–41); median Petra alders nadir CD4-count 143 cells/µL (IQR: 79–270); and median time on ART 23 months (IQR:10–41). evangelia e n tzani HPV DNA was detected in 30/94 women (32%), and 18/94 (19%) showed either low-grade or Tony reid high-grade squamous intraepithelial lesions (LSIL/HSIL) on Pap smear. Overall, .50% had 1 cervical inflammatory reactions including STIs. Of the 43 women with a cervical biopsy, eight Médecins sans Frontières, Mumbai, India; c linical and Molecular (8.4%) had CIN-1, five (5.3%) CIN-2, and two (2.1%) carcinoma in situ. All but one had HPV epidemiology Unit, Department of DNA detected (risk ratio: 11, 95% confidence interval: 3.3–34). By October 2011, 56 women Hygiene and epidemiology, University had completed the 12-month follow-up and had been rescreened. No new cases of HPV infec- of Ioannina s chool of Medicine, Ioannina, greece; Preventive tion/LSIL/HSIL were detected. Oncology Department, Tata Memorial Conclusion: The high prevalence of HPV infection, STIs, and cervical lesions among women Hospital, Mumbai, India; Médecins attending an ART clinic demonstrates a need for routine screening. Simple, one-stop screening sans Frontières, Brussels, Belgium strategies are needed. The optimal screening interval, especially when resources are limited, needs to be determined. Keywords: HIV/AIDS, HPV, women’s health, cervical cancer, operational research, India Introduction About half a million cases of cervical cancer occur annually worldwide, 80% of which occur in low-resource countries. In India, cervical cancer ranks as the most frequent cancer among women, especially among those between 15 and 45 years of age. Human papillomavirus (HPV) is a major risk factor for cervical cancer since as much as 83% correspondence: Petros Isaakidis of invasive cervical cancers are associated with human papillomavirus 16 or 18, and Médecins sans Frontières, chandni about 8% of women in the general population are estimated to harbor cervical HPV Bungalow, Union Park, Off carter road, Khar (W), Mumbai 400 052, India infection at a given time. Tel +91 9930 534211 HIV-infected women in various settings were found to have higher rates of persis- email msfocb-asia-epidemio@brussels. msf.org tent HPV infection, more abnormal Pap tests, more cervical intraepithelial neoplasia submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 487–494 Dovepress © 2013 Isaakidis et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IJWH.S47710 permission from Dove Medical Press Ltd, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Ltd. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Isaakidis et al Dovepress (CIN) lesions, and aggressive cervical cancer, compared with to October 2010. HIV-infected women aged 25–65 years with 3–6 the general population, and these numbers are increasing. intact uterus and with no past history of cervical neoplasia and The high rate of cervical disease reported in HIV-infected who gave consent were recruited. Women coinfected with women and the extended life expectancy due to better access multidrug-resistant tuberculosis at the early stages of treat- to antiretroviral therapy (ART) have led to recommendations ment were offered the screening at a later stage, depending for aggressive screening and prompt treatment of cervical on their condition. Women that refused consent were further lesions; yet, the most appropriate strategy to screen HIV- excluded from the study. infected women, particularly in resource-constrained settings, 7–9 remains unclear. Moreover, the existing evidence on the Pap test, HPV detection, and cervical impact of ART on the incidence and evolution of CIN is still biopsy unclear, thus reinforcing the recommendation of systematic All the women participating in the study were tested for cer- 3,6 screening of all HIV-infected women, even those on ART. vical cytology and HPV and underwent colposcopy with or Overall, the evidence assessing the extent and magnitude of without biopsy. HPV testing by Hybrid capture II was done HPV infection and the burden of cervical abnormalities and by cervical sampling brush (Digene cervical sampler, Qiagen, cancer among HIV-infected women is sparse and remains Venlo, the Netherlands). HPV DNA status for high-risk HPV largely undocumented. types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) The aim of this study was to assess the burden of HPV was determined with the use of the second-generation HC II infection, cervical abnormalities, and cervical cancer among probe B, microtiter assay (Digene). Colposcopy was carried a cohort of HIV-infected women as part of a routine screen- out by trained doctors for all participants irrespective of their ing in an urban, overpopulated slum setting in Mumbai, screening test result. Colposcopy-guided punch biopsies were India. Specific objectives included: to measure the overall obtained from subjects with abnormal findings on colpos - yield of HPV infection, cervical abnormalities, and cervical copy. Biopsy specimens were processed and reported using cancer; to report on the treatment outcomes among women the CIN system. True disease status was den fi ed as CIN-2 and with treated abnormalities; and to identify factors associated worse lesions. CD4 T-cell counts (BD, Franklin Lakes, NJ, with cervical abnormalities, especially factors related to the USA) were obtained from the participant’s medical record. HIV infection (CD4 count, ART, etc). To our knowledge, Nadir CD4 T-cell count was defined as the lowest level of this is one of the first reports on cervical abnormalities in immunosuppression recorded for a specific patient. HIV-infected patients in India. Treatment protocol and follow-up Methods Women with any grade of CIN were called back for cryo- study design therapy or loop electrosurgical excision procedure (LEEP), This was a prospective cohort of HIV-infected patients fol- as appropriate. Women with suspected invasive cancer lowed up from February 2010 to October 2011. were referred to the Tata Memorial Hospital for further management. All treated women were followed-up for up setting and study population to 1 year for colposcopy evaluation in order to determine Médecins Sans Frontières (MSF) has been operating a cure rates. specialized HIV clinic in Mumbai, India since 2006, pro- viding treatment free of charge to patients referred by ART Data collection and statistical methods centers from the greater Mumbai area and by community Information on HIV and ART of all patients was prospectively non-governmental organizations. Patients are referred to collected in specic fi ally designed patient l fi es and routinely the clinic because of coinfections (especially multidrug- entered in a database. For the HPV and cervical cancer screen- resistant tuberculosis and hepatitis B or C) and because they ing, clinical and laboratory information were recorded in the require antiretroviral agents or regimens not readily available same patient files but entered in a different database. A unique through the national ART program. Most of the patients are identic fi ation code was assigned to each patient and was used slum dwellers. in both databases. Patient characteristics were described A universal cervical cancer screening was organized, in using medians, interquartile ranges (IQRs), and percentages, collaboration with the Preventive Oncology Department of as appropriate. We estimated the burden of cervical abnor- the Tata Memorial Hospital, Mumbai, India, from February malities at the screening and follow-up using proportions. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women Table 1 sociodemographic characteristics of the Mumbai HIV- In order to identify predictors for cervical pathologies, infected female cohort univariate and multivariate analyses were performed using Characteristic (N) n (%) Median (IQR) logistic regression and generalized linear models. Multivariate age (years) (95) 38 (33–41) models considered all variables with P , 0.1 on univariate  ,30 12 (12.6) models and used a backward elimination approach for n fi al   30–39 48 (50.5) selection. There was no overt violation of the proportionality 35 (36.8)  $40 assumption. Statistical analyses were performed using SPSS 143 (79–270) nadir cD4 count (cells/ µl) (95) (v 16.0; IBM Corporation, Armonk, NY, USA) and Stata 35 (36.8)  #100 26 (27.4)   101–200 (version 11; StataCorp LP, College Station, TX, USA).   201–350 16 (16.8) 18 (19.0)  .350 ethics Time on arT (months) (95) 23 (10–41) The tests, follow-up of abnormalities, and treatment 25 (26.3)   0–11 23 (24.2)   12–23 options were explained to patients, and their written con- 18 (19.0)   24–35 sent requested. The study met the MSF’s Ethics Review 29 (30.5)  $36 Board-approved criteria for analysis of routinely collected education (95) program data. 24 (25.3)   Illiterate   Primary 19 (20.0)   secondary 40 (42.1) Results 12 (12.6)   Tertiary Baseline patient characteristics Monthly income (UsD) (95) 60 (40–100) 34 (35.8)  ,50 and HIV status 33 (34.7)   50–99 Of the 390 HIV-infected women registered in the HIV clinic 28 (29.5)  $100 from 2006, the 99 adult women who attended the clinic gravidity (94) 1 (1–2) from October to May 2010 were considered for inclusion in 10 (10.6)   0 the study. Three women denied screening and one teenager 42 (44.7)   1  $2 42 (44.7) reported no history of sexual activity and was excluded from Married/currently living with partner (95) the study; thus, 95 women were screened during the first   Yes 48 (50.6) screening. The median age was 38 (IQR: 33–41), and 51% 47 (49.4)   no of the women were aged between 30 and 39 years (Table 1). ever smoked/chewed tobacco (95) Approximately half of the women were married or living with 19 (20)   Yes 76 (80)   no a partner at the time of the study; a large proportion of widows ever used drugs/alcohol (95) and separated women was recorded in this cohort (46%). Most 2 (2.1)   Yes women had attained at least primary education, while 13% 93 (97.9)   no had received higher education. Eighty percent had either never Use of hormonal contraceptives (94) smoked or were not current smokers, while 98% of the cohort 1 (1.1)   Yes   no 93 (98.9) had never used drugs or alcohol. A large majority (98.9%) of Abbreviations: arT, antiretroviral therapy; IQr, interquartile range; UsD, Us the women were not making use of any type of hormonal con- dollar. traceptive method. Forty-v fi e percent of the women had had two or more pregnancies during their lifetime. Thirty-seven retrieved. HPV infection was detected in 30 (32%) of the percent had a nadir CD4 T-cell count of ,100 cells/µL. All 94 women with an available result. patients were on ART at the time of the screening; the median Overall, 43 women, almost half of the participants, had time on ART was 23 months (IQR: 10–41). cervical inflammatory reactions. Forty-one percent had inflammation of the cervix, including STIs, but not intra - Baseline HPV infection status, cytology epithelial lesions. Cervical cytology was abnormal in 18 and pathology results, and treatment of 94 women (19%). Low-grade squamous intraepithelial The majority (98%) of this cohort of HIV-infected women had lesions (LSIL) and high-grade squamous intraepithelial never had a gynecological examination before the screening lesions (HSIL) were detected in 14% and 5% of the partici- was offered. For one woman, a Pap smear test result was not pants, respectively. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Isaakidis et al Dovepress The women with cervical inflammatory reactions were chemotherapy as per the recommended treatment guidelines. referred for colposcopy with a guided cervical biopsy by This patient, at the 18-month follow-up, had to switch to the examining physician during the first round of screening. second-line ART due to virological failure after 3 years on Biopsy was abnormal in 16% women: eight (8%) had CIN-1, r fi st-line ART. The patient was, however, in excellent general five (5%) CIN-2, and two (2%) women were diagnosed with condition and she was not immunologically compromised at carcinoma in situ. the time of the ART switch. Five patients underwent LEEP during the first screening round; four women with CIN-2 and one with CIN-1. Eight 12-month follow-up women received cryotherapy: one woman with CIN-2 and Figure 1 shows the flow of patients in the two screening seven women with CIN-1. One woman with cervical cancer rounds and reasons for not screening. Sixteen women died in a car accident before any treatment was started. were not eligible for rescreening as they hadn’t completed The second woman diagnosed with cervical cancer was 12 months of follow-up at the time of the analysis. By successfully operated on and received radiotherapy and October 2011, 56 (59%) women had completed at least HIV-infected women eligible for first screening N = 99 Women not screened: Not accepted = 3 Excluded = 1 Women screened (1st round) N = 95 Women diagnosed with cancer: Died = 1 Treated = 1 HIV-infected women eligible for 12-month follow-up N = 93 Women not screened: 12 months not completed = 16 Transferred out = 14 Not accepted = 4 Died = 2 Lost to follow-up = 1 Women screened (2nd round) N = 56 Figure 1 Flowchart of cervical cancer screening in a cohort of HIV-infected women at baseline and 12-month follow-up. submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women 12 months of follow-up and had been rescreened. No new multivariate models, no sociodemographic or clinical fac- cases of HPV infection, LSIL, or HSIL were detected on tor was found to be significantly associated with cervical rescreening. Of the 15 women who were found HPV-positive neoplasia (Table 2). in the first screening and pursued a second screening, nine tested negative in the second screening while the remain- Discussion ing six remained HPV-positive in the second screening at In the present study, we estimated the prevalence and 12 months. 12-month incidence of cervical abnormalities and assessed factors associated with cervical neoplasia among HIV- Factors associated with HPV infection infected women enrolled in care in an HIV clinic in Mumbai, India who attended a screening program. The vast majority and cIn of women had never previously been screened for cervical In the bivariate regression analysis, no factor was nominally abnormalities. We found that one-third of the women tested significantly associated with an increased risk for HPV positive for HPV; more than half had inflammation of the infection. In multivariate models, and adjusting for all fac- cervix, including STIs; and as many as 17% of the women tors, nadir CD4, time on treatment, and parity were associated screened had abnormal Pap smear results. Prevalence of with HPV infection (Table 2). CIN was similarly high, at approximately 16%. Finally, we All but one of the eleven women (91%) with CIN found no new cases of HPV infection, LSIL, HSIL, CIN, or cancer were infected with HPV. Similarly, the two or cancer among women rescreened 12 months after their participants with invasive cervical cancer were infected initial screening. with HPV. In the bivariate models, and despite the lack of Studies among the general population in resource-limited power, HPV infection was significantly associated with countries have shown high prevalence of cervical neoplasia. cervical neoplasia (RR: 11, 95% CI: 3.3–34). In further However, little is known about the prevalence and incidence of cervical abnormalities and HPV infection among HIV- Table 2 Factors associated with HPV infection and cervical infected women. Interestingly, our study findings are in abnormalities (n = 93) accordance with a very recent study in which the investiga- Factor n (%) HPV High- and low- OR grade squamous tors observed similar rates of HPV infection and cervical (P-value) intraepithelial pathology. Moreover, in studies among HIV-infected women lesions in Sao Paolo, Rio De Janeiro, and Belo Horizonte, Brazil, OR (P-value) 13%, 24%, and 24% had a diagnosis of squamous intra- age (years) 11–13 epithelial lesions, respectively. In studies in Cambodia,  ,35 29 (30.5) 66 (69.5) 0.46 (0.203) 0.68 (0.613)  $35 Thailand, and People’s Republic of China, the prevalence nadir cD4 (cells/ µl) of HSIL/LSIL among women attending HIV clinics was 61 (64.2) 3.73 (0.025)* 1.04 (0.954)  #200 8,14,15 17%, 16%, and 8%, respectively. Studies conducted in  .200 34 (35.8) Zambia and Kenya reported higher prevalences, 33% and Months on arT 16,17 25 (26.3) 3.57 (0.027)* 1.27 (0.743) 27%, respectively, among HIV-infected women Finally,  ,12 70 (73.7)  $12 in our study, and bearing in mind the available published Previous pregnancies evidence, we report an intermediate HPV prevalence among 52 (54.7)   0 or 1 HIV-infected women.  $2 42 (44.2) 3.32 (0.035)* 0.88 (0.859) It is well established that HPV infection is a contributor to Income (UsD/month) 34 (35.8) 1.33 (0.580) 0.90 (0.882)  ,50 cervical cancer and that it progresses to squamous intraepi- 61 (64.2)  $50 thelial neoplasia more frequently and rapidly in HIV-infected level of education women than in the general population. Our main study find - 43 (45.3) 1.29 (0.611) 1.05 (0.934)   Primary or less ings indicate that HPV infection was frequent in this cohort   secondary or more 52 (54.7) of patients and significantly associated with squamous intra - HPV at baseline 64 (67.4) –   not detected epithelial lesions, suggesting that this population follows an 30 (31.6) –   Detected 19.69 (,0.001)* epidemiological pattern in common with other HPV-infected Notes: *P , 0.05; 94 patients were included. women, who remain at high risk for cervical neoplasia; as Abbreviations: arT, antiretroviral therapy; HPV, human papillomavirus; Or, odds ratio. such, aggressive screening and management are justified submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Isaakidis et al Dovepress for HIV/ HPV co-infected women. We offered colposcopy and the number of lifetime sexual partners. However, India plus biopsy to all women with clinical findings suggestive is a conservative society in which extramarital sex is taboo, of neoplasia as well as to all women with abnormal Pap especially for women, and we would expect a rather homo- smears. This practice proved very effective for the confirma - genous sample in these regards. tion of cervical abnormalities, and guided prompt treatment. Worth discussing is that we found no new cases of Nevertheless, the estimated uptake of Pap tests in India is HPV infection or squamous intraepithelial lesion in the discouragingly low, at 2.6%; the situation is no better in urban 12-month follow-up in this cohort of patients. While we centers, where uptake is only slightly higher, at 4.9%. Our strongly believe that screening and management of cer- experience from Mumbai, a major metropolitan center with vical abnormalities and cancer in HIV-infected women access to HPV DNA testing and quality-controlled cytol- should be recurrent and aggressive, we also acknowledge ogy and pathology showed that the very availability of such that, when resources are limited, the type and frequency of services is not enough to guarantee increased access. Major screening needs to be carefully determined. United States constraints include the capacity of the existing facilities and cervical cancer screening guidelines for HIV-uninfected lack of awareness in both the general population and among women 30 years or older were recently revised, with the health care providers. Our findings suggest that, in settings suggested interval between Pap tests increasing from 3 to with limited access to care, women with a history of HPV 5 years for those with normal cervical cytology results and 22,23 should be prioritized, especially if HIV-infected. negative oncogenic HPV. It is not clear if an interval of Modeling for factors potentially associated with squamous 3 or 5 or more years between screenings could be used in intraepithelial lesions in HIV-infected women, we found that HIV-infected women who are HPV-negative and cytologi- immunosuppression, as measured by nadir CD4 count, was cally normal. Meanwhile, as HPV testing is not available not significantly associated with squamous intraepithelial in most resource-constrained settings, we advocate for lesion prevalence. Similarly, time on ART was not found to annual screening and prompt management of cervical have a statistically significant protective effect in the occur - abnormalities. Implementation of a cytology-based screen- rence of squamous intraepithelial lesions in this population. ing strategy in rural or resource-limited settings may be The absence of significant associations could be explained challenging. In previous MSF experience in Cambodia, by the lack of power to detect these associations. Neverthe- “screening for cervical cancer using the conventional less, the degree of immunosuppression is expected to have Pap test proved just as difficult for HIV-positive women, an effect on the incidence and progression of squamous already enrolled in care, as for women of the general intraepithelial lesions among HIV-infected women as it has population.” 13–17 been shown in several observational studies. To date, The single-visit screen-and-treat approach, using visual evidence on an independent association between ART and inspection with acetic acid (VIA) and cryotherapy, has been the natural history of HPV infection or the risk of squamous shown to be effective and acceptable among women in intraepithelial lesions and cervical cancer is contradictory resource-constrained settings. However, it is still not well 18–21 and inconclusive. It is likely that the increased survival known whether this approach, is effective and safe for HIV- 24,25 of these women due to ART may lead to higher incidence and infected women. Studies from Zambia have shown that mortality from cervical pathologies and cancer. linking cervical cancer prevention and treatment services There are a number of limitations to this study. First, we (including LEEP) with HIV care and treatment is feasible 26,27 fully acknowledge that this is a small study; however, we and safe. Sankaranarayanan et al, in 2009, demonstrated argue that the setting in which the study took place poses in a cluster-randomized study in rural India that a “single challenges in gathering large sample sizes, and even study- round of HPV testing was associated with a significant ing small datasets provides valuable information. Second, reduction in the numbers of advanced cervical cancers we acknowledge that only 60% of the women were followed and deaths from cervical cancer.” The HIV status of the up after 12 months. The actual loss to follow-up, death rate, women enrolled in that study, however, was not discussed and refusals were relatively low. A significant number of in the study report. women were transferred out from the program and a relatively Recently, in a large observational study in, USA, it was large number of women were yet to complete 12 months of found that there were no differences in the 5-year cumula- follow-up at the time of the analysis. Moreover, we were tive incidence of HSIL and CIN-2 between HIV-infected and not able to collect data on the age of first sexual intercourse -uninfected women. The authors, however, concluded that submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress Dovepress cervical neoplasia in HIV-infected Indian women 6. De Vuyst H, Franceschi S. Human papillomavirus vaccines in further evidence is needed, including randomized evidence, HIV-positive men and women. Curr Opin Oncol. 2007;19(5): before expanding the current recommendations for testing 470–475. all HIV-infected women for HPV. In resource-limited set- 7. Comprehensive Cervical Cancer Control: A Guide to Essential Practice. Geneva: World Health Organization; 2006. tings, operational research is also needed to demonstrate 8. Raguenaud ME, Isaakidis P, Ping C, Reid T. 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International Journal of Women’s Health Dovepress Publish your work in this journal The International Journal of Women’s Health is an international, peer- a very quick and fair peer-review system, which is all easy to use. reviewed open-access journal publishing original research, reports, Visit http://www.dovepress.com/testimonials.php to read real quotes editorials, reviews and commentaries on all aspects of women’s from published authors. healthcare including gynecology, obstetrics, and breast cancer. The manuscript management system is completely online and includes Submit your manuscript here: http://www.dovepress.com/international-journal-of-womens-health-journal submit your manuscript | www.dovepress.com International Journal of Women’s Health 2013:5 Dovepress

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International Journal of Women's HealthPubmed Central

Published: Aug 13, 2013

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