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Incidence of cervical disease associated to HPV in human immunodeficiency infected women under highly active antiretroviral therapy

Incidence of cervical disease associated to HPV in human immunodeficiency infected women under... Background: Women infected with human immunodeficiency virus (HIV) may be at higher risk of developing cervical cancer than non infected women. In a pilot study, we assessed the relationships among cervical cytology abnormalities associated to Human Papillomavirus (HPV), HIV infection and Highly Active Antiretroviral Therapy (HAART) on the development of Squamous Intraepithelial lesions (SILs). Out of the 70 HIV infected women from Douala -Cameroon (Central Africa) that we included in the study, half (35) were under HAART. After obtaining information related to their lifestyle and sexual behaviour, cervicovaginal samples for Pap smears and venous blood for CD4 count were collected and further divided into two groups based upon the presence or absence of cervical cytology abnormalities i.e. those with normal cervical cytology and those with low and high Squamous Intraepithelial lesions (LSIL, HSIL). Results: Assessment was done according to current antiretroviral regimens available nationwide and CD4 count. It was revealed that 44.3% of HIV-infected women had normal cytology. The overall prevalence of LSIL and HSIL associated to HPV in the studied groups was 24.3% (17/70) and 31.4% (22/70) respectively. Among the 22 HSIL-positive women, 63.6% (14/22) were not on antiretroviral therapy, while 36.4% (8/22) were under HAART. HIV infected women under HAART with positive HSIL, showed a median CD4+ T cell count of 253.7 +/- 31.7 higher than those without therapy (164.7 +/- 26.1). The incidence of HSIL related to HPV infection within the study group independently of HAART initiation was high. Conclusion: These results suggest the need for extension and expansion of the current study in order to evaluate the incidence of HPV infection and cervical cancer among HIV-infected and non HIV- infected women in Cameroon. Page 1 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Within eight (08) month, patients aged between 21–56 Background Genital infection by human papillomavirus (HPV) is one years, were recruited in a day care centre at Bonassama of the most common sexually transmitted infections, hospital in Douala for HIV therapy. All were included in a known to be the cause of cervical cancer [1-3]. Although pilot study on clinical and behavioural characteristics HPV is known to be strongly associated with the develop- associated with HIV infection. The study was carried out ment of cervical cancer, most HPV infections in young according to the guidelines for human experimental mod- women are transient [4]. Women with persistent infection els in clinical research as stated by the ministry of public appear to have a higher risk of developing significant cer- Health of Cameroon. vical cancer [2,5]. The burden of this infection on public health is compounded by the recognized causal relations Inclusion criteria between genital HPV infection and cervical dysplasia or Enrolled women were single or married; non-pregnant; cervical cancer [6,7]. Although factors that influence per- aged 21 years old and above and HIV infected, initiated or sistence of HPV are not yet well understood, several stud- not with HAART. Patients were divided in two groups: ies suggest that alterations in cell mediated immune group one consisted of women who were diagnosed HIV responses play a major role in persistence of HPV. The positive and were not yet eligible for antiretroviral ther- higher rates of HPV infection, high-grade squamous apy. Patients in this group were considered untreated only intraepithelial lesion (HSIL), and cervical cancer among at the beginning of the study. The second group com- immunosuppressed individuals, specifically HIV-infected prised HIV-infected women receiving HAART, who were women, underscore the importance of control of immune enrolled on the basis of a three months' minimum length response in HPV infection. Studies on adult women have of treatment. Patients in this group had different thera- consistently shown that the prevalence of HPV infection peutic protocols spread over different periods of treat- and HSIL are higher among HIV infected women and that ment. From the list of patients eligible for the study, these differences are exaggerated among women with subjects were randomly chosen in a systematic manner. lower CD4+ cell counts [8-10]. Several recent prospective The objective of the study was explained to patients and studies have documented that the rate of persistence of verbal consent was sought from each of them. HPV among HIV-infected women is higher than that Collection of Specimens among non HIV-infected women [11,12]. Specific types of HPV are associated with cervical cancer, but whether At the screening visit, venous blood was collected for CD4 these high-risk types have natural histories that are differ- analysis, and pap smears performed for early detection of ent from those of other types not associated with cervical cervical carcinoma as previously described [17]. Subjects cancer is unknown [13,14]. The modification of the viral underwent a general physical examination and completed markers may be the crucial factor of disequilibrium in the a short standardized interview, including questions per- interaction between virus and host: an increased replicat- taining to medical history, sexual behaviour, history of ing capacity of the virus versus a reduced control mecha- STIs, age of first sexual intercourse, pregnancy, parity and nism of the immune system. In this context it's evident abortion. that in HIV-infected women, both viral and host factors conspire, as these patients have an impaired immune sys- Histological analysis tem usually more exposed to HPV infection. Some studies Pap smears were interpreted and classified according to the Bethesda System as negative, atypical squamous cells have also considered the impact on cervical pathology on HIV disease care, mainly represented by the introduction of unknown significance, LSIL, HSIL, or invasive cervical of highly active antiretroviral therapy (HAART), which cancer [18,19]. Conventional Pap smears were used and through the substantial recovery of immune function has slides were read by a pathologist. Blood samples were significantly changed the scenario regarding HIV-related obtained for flow cytometry CD4+ T cell counts using pathologies such as opportunistic infections and cancers AIDS Clinical Trials Group standardized flow-cytometry [15,16]. The objectives of this study were to compare rates protocols as described elsewhere [20]. of cervical abnormalities related to HPV infection among Statistical analysis HIV-infected women with and without HAART initiation and to examine immunological and behavioural risk fac- Data obtained were verified for consistency, coded, and tors associated with persistence of HPV. computerized. Throughout the text, values are given as mean ± s.d. Percentages were calculated from the overall Subjects and methods number of cases. Raw data were compared using Fisher's Study population exact-test (StatXact 2.05 software). Appropriate probabili- A total of 70 HIV-infected women were enrolled in the ties were calculated [21] and size variation with Mann- study after informed consent and divided into two groups: Whitney rank sum test as the normality test failed (Sigma 35 under HAART and 35 not initiated with HAART. Stat 2.03 software). Page 2 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 probably due to the number patients assigned to each Results Subjects characteristics parameter. Seventy HIV infected women were randomly recruited using systemic random sampling from the outpatients at HAART and incidence of cervical abnormalities the day care centre of Bonassama hospital in Douala. Table 2 presents histological analyses of studied samples. Table 1 summarizes the socio-demographic information The Pap smear test results revealed the following within as well as information on reproductive and sexual charac- the study groups: those with normal cervical cytology teristics of the study groups. Sampling was done according (44.3%) and those with abnormal Pap smear; LSIL to: age with a mean age of 35.5 ± 1.9 years and 35.1 ± 1.3 (24.3%), and HSIL (31.4%) respectively. The cervical years; age of first vaginal sex with a mean age of 16.9 ± 5 abnormalities differences were statistically significant for years and 17.2 ± 0.5 years; number of pregnancies with a the two study groups when comparing the total frequency mean number of 3.7 ± 0.5 and 3.9 ± 0.4; parity with a abnormalities (48.6% vs. 62.9%, P = 0.034) for treated mean number of 2.6 ± 0.5 and 2.6 ± 0.4; abortion with a and untreated groups respectively. Table 3 represents the mean number of 1.2 ± 0.2 respectively for women under frequency of distribution of cervical cytology results in the HAART and women not initiated with HAART. Significant treated and untreated groups according to the duration of differences were observed between these groups at base- therapy. Cervical abnormalities are high in the absence of line in terms of ages of patients: when comparing the therapy: 47.1% and 63.6% for LSIL and HSIL respectively. mean age of patients above 40 years (52.3 ± 2.3% (9) vs. The difference in the distribution of the cytological picture 44.9 ± 1.2% (10), P = 0.007) and when comparing the among LSIL and HSIL cases was statistically none signifi- mean parity of more than 4 (9.8 ± 0.7% (4) vs. 5.9 ± 0.5% cant (P > 0.05). Table 4 represents the Incidence of cervi- (8), P = 0.006) for treated and untreated group respec- cal cytology results in the HAART treatment group tively. The significant difference observed between treated according to the duration of therapy. Normal cervical and untreated groups in terms of mean age and parity is cytology increase with the duration of therapy: 5.7% to 34.3% within the period of treatment 1–5 month and Table 1: Selected baseline characteristics of HIV infected women as study subjects. Under HAART No HAART Groups n% Mean ± SE n % Mean ± SE p value A. Age (years) <30 12 34.3 26.4 ± 0.7 10 28.6 26.4 ± 0.9 0.988 ns 30 – 40 14 40.0 32.4 ± 0.8 15 42.8 34.3 ± 0.9 0.115 ns >40 9 25.7 52.3 ± 2.3 10 28.6 44.9 ± 1.2 0.007 * Total 35 - 35.5 ± 1.9 35 - 35.1 ± 1.3 0.872 ns B. Age at first vaginal sex (years) ≤ 16 18 51.4 14.6 ± 0.3 15 42.9 14.5 ± 0.3 0.874 ns >16 17 48.6 19.3 ± 0.7 20 57.1 19.3 ± 0.4 0.956 ns Total 35 - 16.9 ± 0.5 35 - 17.2 ± 0.5 0.643 ns C. Pregnancy 0 2 5.7 0.0 ± 0.0 0 0.0 0.0 ± 0.0 - 1 – 4 23 65.7 2.3 ± 0.3 22 62.9 2.3 ± 0.2 0.971 ns 5 – 9 7 20.0 6.1 ± 0.6 11 31.4 5.9 ± 0.4 0.750 ns >10 3 8.6 11.0 ± 0.6 2 5.71 10.5 ± 0.5 0.800 ns# Total 35 - 3.7 ± 0.5 35 - 3.9 ± 0.4 0.737 ns D. Parity 0 7 20.0 0.0 ± 0.0 5 14.3 0.0 ± 0.0 - 1 – 4 24 68.6 2.1 ± 0.3 22 62.8 2.0 ± 0.2 0.711 ns >4 4 11.4 9.8 ± 0.7 8 22.8 5.9 ± 0.5 0.006 * Total 35 - 2.6 ± 0.5 35 - 2.6 ± 0.4 0.964 ns E. Abortion 0 13 37.1 0.0 ± 0.0 12 34.3 0.0 ± 0.0 - 1 – 2 15 42.9 1.2 ± 0.1 17 48.6 1.4 ± 0.1 0.353 ns >2 7 20.0 3.4 ± 0.2 6 17.1 3.3 ± 0.3 0.628 ns Total 35 - 1.2 ± 0.2 35 - 1.2 ± 0.2 0.925 ns a. Means were compared one after the other using the Student t-test when normality and equal variance conditions passed or the Mann-Whitney rank sum test when conditions failed. Ns: no significant difference; * significant difference; #: Mann-Whitney rank sum test Page 3 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 2: Frequency of cervical abnormalities in HIV infected women according to cytological findings Under HAART(35) No HAART (35) Total (70) p-value Groups n% n % n % Normal 18 51.4 13 37.1 31 44.3 LSIL 9 25.7 8 22.9 17 24.3 HSIL 8 22.9 14 40.0 22 31.4 Total abnormalities 17 48.6 22 62.9 39 55.7 0.034* a. Low squamous intra epithelial lesions b. High squamous intra epithelial lesions * Significant difference more than 10 month respectively. Within the same itive patients neither for pregnancy nor for abortion. In period, HSIL decreased from 14.3% to 2.8% and was patients with the highest percentage for pregnancies, i.e. ≤ probably due to the number of patients within the more 10 pregnancies we noticed 76.4% and 45.5% occurrence than 10 months' period of therapy. The difference in the for LSIL and HSIL respectively while for abortion, the incidence of cervical abnormalities was statistically non cytology results findings showed 70.6% and 36.4% for significant (P = 0.069). Table 5 represents CD4+ T cell LSIL and HSIL respectively in patients with 1 or more than count distribution within the study groups according to 2 abortions. Table 7 represents distribution of STI risk fac- cervical abnormalities. The mean of CD4+ T cell count tors that might contribute to HPV infection. The history of decreases with degree of cervical abnormalities in both STIs risk factors shows that: Bacillus vaginalis, Chlamydia sp groups: 289 ± 47.0, 253 ± 69.1 and 173.4 ± 42.4 T cells in and Treponema Pallidum are main microbial infectious patients under HAART while those with no HAART initia- agents. B. vaginalis is the leading infection with 70.6% and tion have 244.5 ± 42.8, 218.4 ± 64.1 and 59.9 ± 14.5 for 54.5% for LSIL and HSIL respectively while Chlamydia is normal, LSIL and HSIL respectively. Table 6 examines the second with 17.6% and 22.7% and T. Pallidum which some of the risk factors that might contribute to HPV count for 5.9% and 13.6% respectively for LSIL and HSIL infection. The risk factors investigated were grouped positives patients. No significant statistical difference was according to the following parameters of personal history: found in correlation with cervical abnormalities. age of first vaginal sex, pregnancy and abortion. The results showed that patients with cervical abnormalities Discussion were mainly ≥ 19 years old at first vaginal sex intercourse This study provides data on the risk of cervical cancer with high percentage: 23.5% and 20.2% for LSIL and HSIL among HIV positive women less than 60 years old in the respectively. There was no statistical difference for this fac- day care centre at Bonassama hospital Douala -Central tor when compared with Mann-Whitney test. Reproduc- Africa. The extent to which HIV increases the risk for cer- tive history of the studied groups showed a statistically vical cancer is especially important in Cameroon referring non significant difference between the LSIL and HSIL pos- to the epidemiology of the HIV especially among women. In our study, HIV positive women are at high risk of inva- sive cervical cancer. This could be due to the competing Table 3: Frequency of cervical abnormalities in HIV infected risk of mortality from other conditions associated with women according to duration of medication (HAART) Duration Cervical abnormality Table 4: Cervical abnormalities incidence in HIV infected women under HAART therapy according to and duration of medication (month) LSIL HSIL Duration Normal LSIL HSIL n % n % Exact p-value (month) n %n%n% 0 08 47.1 14 63.6 0.1308 ns 0 - ----- 1–5 03 17.7 05 22.7 0.6193 ns 1–5 2 5.7 3 8.6 5 14.3 6–10 02 11.8 02 09.1 1.000 ns 6–10 4 11.4 2 5.7 2 5.7 > 10 04 23.5 01 04.5 0.2063 ns > 10 12 34.3 4 11.4 1 2.8 Total 17 - 22 - 0.3652 ns Total 18 51.4 9 25.7 8 22.8 a. Combined data for treated and untreated patients b. Global comparison of raw data: Pearson's chi-square exact a. exact probability using Pearson's Chi-square test for independence probability: P = 0.3725) procedure: P = 0.069 Page 4 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 5: CD4+ T cell count distribution in HIV infected women and specificity are similar among HIV negative and HIV according to cervical abnormalities positive women [27]. We found an association between HAART and the stage of cervical pre-cancer. Our results are Under HAART No HAART in agreement with others that have shown an association between HIV, HAART and cervical abnormalities [[15,16], Groups n% Mean ± SE n% Mean ± SE and [28]]. An additional limitation of our study is that Normal 18 51.4 289.4 ± 47.0 13 37.1 244.5 ± 42.8 complete information regarding the immunological sta- LSIL 9 25.7 253.6 ± 69.1 8 22.9 218.4 ± 64.1 tus of patients has not been documented for all the HSIL 8 22.9 173.4 ± 42.4 14 40.0 59.9 ± 14.5 groups. Similar of different studies by the same author [[9,15,16,20,25], and [29]] have reported that the severity Total 35 - 253.7 ± 31.7 35 - 164.7 ± 26.1 of HIV-related immunodepression is associated with increased incidence of HPV infection and SILs. Data HIV/AIDS, particularly in a setting where antiretroviral obtained from the current study further confirm these therapy was not available at the time and for all patients. findings reported by other investigators of our geographic Our findings that HIV infected women were at a signifi- area [17,22-26]. Several studies suggested that markers of cantly higher risk of LSIL and HSIL confirm the results of advanced HIV disease such as CD4+ T cell counts or HIV- studies carried out in both developed and other develop- RNA plasmatic levels are associated with increased risk of ing countries [7,17,22-24]. The relative prevalence of SILs HPV infection and SIL [8,17,28,29]. However some docu- or cytological abnormalities among HIV positive women mentations and data have revealed that the relationship is higher than that ever been reported by any other study between HIV and HPV is more complex. Human immun- in Africa. Hawes et al. reported a cytological abnormality odeficiency virus infection is associated with an increased prevalence of 37% among women with HIV-1 infection transcriptional activity of early HPV genes. Studies on attending an outpatients infectious disease clinic in Sen- adult women have shown that HPV infection with both egal [17], Yamada 27.1% in urban patients in Kenya [25], high-risk and low-risk HPV types is more likely to persist Moukassa 15.36% among urban dwellers in Congo [26]. among HIV-infected women [8,12]. Because they have more years of sexual activity, adult women may reflect a A potential limitation of this current study is that cytolog- group of women further along in their history of HIV and ical abnormalities were not histologically confirmed. HPV infection. Our data further support the important However, it has been shown that the Pap smear sensitivity role played by CD4+ T cells [28,29] in the control of HPV Table 6: Incidence of risk factors on cervical disease in HIV infected women under treatment (HAART) and those without treatment or HAART initiation LSIL HSIL Mann-Withney test Groups n% Mean ± SE n% Mean ± SE Age at first vaginal sex (years) <15 03 17.6 13.7 ± 0.3 06 27.3 13.2 ± 0.3 0.381 ns 15 – 18 10 58.8 16.5 ± 0.5 11 50.0 16.4 ± 0.3 0.860 ns ≥ 19 04 23.5 19.8 ± 0.5 05 22.7 20.2 ± 0.7 0.905 ns Total 17 - 16.8 ± 0.5 22 - 16.4 ± 0.6 0.571 ns Pregnancy ≤ 4 13 76.4 2.4 ± 0.3 10 45.5 2.8 ± 0.3 0.420 ns 5–9 02 11.8 5.5 ± 0.5 10 45.5 1.4 ± 0.4 0.590 ns ≥ 10 02 11.8 11.5 ± 0.5 02 09.0 0.7 ± 0.5 0.333 ns Total 17 - 3.8 ± 0.8 22 - 5.1 ± 0.6 0.068 ns Abortion 0 03 17.6 0.0 ± 0.0 06 27.3 0.0 ± 0.0 - 1–2 12 70.6 1.3 ± 0.3 08 36.4 1.4 ± 0.2 0.669 ns > 2 02 11.7 3.0 ± 0.0 08 36.4 3.6 ± 0.3 0.400 ns Total 17 - 1.24 ± 0.2 22 - 1.8 ± 0.3 0.372 ns Page 5 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 7: Incidence of History of STD on cervical disease in HIV were strongly associated with high-risk HPV infection and infected untreated and treated women (exact probability using low CD4+ T cell counts. Immunodeficiency as a result of Pearson's Chi-square test for independence procedure: P = HIV infection appears to be important for malignant pro- 0.8224) gression within the cervix. Nationwide prevention of HIV LSIL HSIL infection and cervical cancer screening are necessary for the health of women in Cameroon. The increased public Groups n% n % health burden enhanced by HPV is an important and gen- der-specific aspect of HIV infection. Guidelines on proper B. vaginalis 12 70.6 12 54.5 screening for cervical abnormalities in HIV positive Chlamydia 03 17.6 05 22.7 women are urgently needed in Cameroon. T. Pallidum 01 05.9 03 13.6 Other 01 05.9 02 09.1 Competing interests The authors declare that they have no competing interests. Total 17 - 22 - Authors' contributions infection: the lower the CD4+ T cell count, the more likely KMML conceived the study, participated in its design and that HPV infection will persist. Persistent infection in turn statistical analysis, coordinated and drafted the manu- may increase the risk for the development and persistence script. GMLC participated in CD4 analysis using the flow of squamous intraepithelial lesions. In fact, women cytometry, data collection and helped to draft the manu- whose immunosuppression is related to infection with script. DC participated in flow cytometry analysis, data human immunodeficiency virus are at increased risk of collection and helped to draft the manuscript. WM partic- infection with multiple types of HPV [28]. In developed ipated in study design, clinical examination and recruit- countries it's recommended for HIV positive women to ment of women at the study site and coordination. MA have two cervical cytological assessments within the first carried out cytology analysis. NNA participated in the year after HIV diagnosis and annually thereafter, referred study design, statistical analysis and helped to draft and for colposcopy for any smear showing an ASCUS (atypical review the manuscript. squamous cells of undetermined significance) or more severe lesions [30]. These guidelines are not feasible in set- Acknowledgements These results were obtained thanks to the support of AIRES-Sud, a pro- tings with limited or poor resources. The high prevalence gramme from the French Ministry of Foreign and European Affairs imple- and risk of cervical abnormalities documented in our mented by the Institut de Recherche pour le Développement (IRD-DSF). research projet underscores the importance of developing The authors thank the women for their voluntary participation in the study. screening and management guidelines for HIV positive We would equally like to give thanks to Dr Lehman Leopold for his techni- women. As antiretroviral therapy becomes increasingly cal assistance via the flow cytometry, Dr Kenne Martin for statistics analysis available in Cameroon, the life expectancy of HIV positive assistance and Mr Ewane Leonard for manuscript review. women will increase as well. It's therefore important to conserve this invaluable benefit and avoid its upset by an References increased risk in the development of cervical cancer. A cer- 1. Bosch FX, Munoz N: The viral etiology of cervical cancer. Virus Res 2002, 89:183-189. vical screening program is of critical importance as it 2. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah informs local researchers on the natural history of cervical KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J abnormalities, which might be recommended for HIV Pathol 1999, 189:12-19. positive women. The STIs history of studied subjects 3. 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Yamada R, Sasagawa T, Kirumbi LW, Kingoro A, Karanja DK, Kiptoo M, Nakitare GW, Ichimura H, Inoue M: Human papillomavirus yours — you keep the copyright infection and cervical abnormalities in Nairobi, Kenya, an BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

Incidence of cervical disease associated to HPV in human immunodeficiency infected women under highly active antiretroviral therapy

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Springer Journals
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Copyright © 2009 by Mogtomo et al; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-4-9
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19493339
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Abstract

Background: Women infected with human immunodeficiency virus (HIV) may be at higher risk of developing cervical cancer than non infected women. In a pilot study, we assessed the relationships among cervical cytology abnormalities associated to Human Papillomavirus (HPV), HIV infection and Highly Active Antiretroviral Therapy (HAART) on the development of Squamous Intraepithelial lesions (SILs). Out of the 70 HIV infected women from Douala -Cameroon (Central Africa) that we included in the study, half (35) were under HAART. After obtaining information related to their lifestyle and sexual behaviour, cervicovaginal samples for Pap smears and venous blood for CD4 count were collected and further divided into two groups based upon the presence or absence of cervical cytology abnormalities i.e. those with normal cervical cytology and those with low and high Squamous Intraepithelial lesions (LSIL, HSIL). Results: Assessment was done according to current antiretroviral regimens available nationwide and CD4 count. It was revealed that 44.3% of HIV-infected women had normal cytology. The overall prevalence of LSIL and HSIL associated to HPV in the studied groups was 24.3% (17/70) and 31.4% (22/70) respectively. Among the 22 HSIL-positive women, 63.6% (14/22) were not on antiretroviral therapy, while 36.4% (8/22) were under HAART. HIV infected women under HAART with positive HSIL, showed a median CD4+ T cell count of 253.7 +/- 31.7 higher than those without therapy (164.7 +/- 26.1). The incidence of HSIL related to HPV infection within the study group independently of HAART initiation was high. Conclusion: These results suggest the need for extension and expansion of the current study in order to evaluate the incidence of HPV infection and cervical cancer among HIV-infected and non HIV- infected women in Cameroon. Page 1 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Within eight (08) month, patients aged between 21–56 Background Genital infection by human papillomavirus (HPV) is one years, were recruited in a day care centre at Bonassama of the most common sexually transmitted infections, hospital in Douala for HIV therapy. All were included in a known to be the cause of cervical cancer [1-3]. Although pilot study on clinical and behavioural characteristics HPV is known to be strongly associated with the develop- associated with HIV infection. The study was carried out ment of cervical cancer, most HPV infections in young according to the guidelines for human experimental mod- women are transient [4]. Women with persistent infection els in clinical research as stated by the ministry of public appear to have a higher risk of developing significant cer- Health of Cameroon. vical cancer [2,5]. The burden of this infection on public health is compounded by the recognized causal relations Inclusion criteria between genital HPV infection and cervical dysplasia or Enrolled women were single or married; non-pregnant; cervical cancer [6,7]. Although factors that influence per- aged 21 years old and above and HIV infected, initiated or sistence of HPV are not yet well understood, several stud- not with HAART. Patients were divided in two groups: ies suggest that alterations in cell mediated immune group one consisted of women who were diagnosed HIV responses play a major role in persistence of HPV. The positive and were not yet eligible for antiretroviral ther- higher rates of HPV infection, high-grade squamous apy. Patients in this group were considered untreated only intraepithelial lesion (HSIL), and cervical cancer among at the beginning of the study. The second group com- immunosuppressed individuals, specifically HIV-infected prised HIV-infected women receiving HAART, who were women, underscore the importance of control of immune enrolled on the basis of a three months' minimum length response in HPV infection. Studies on adult women have of treatment. Patients in this group had different thera- consistently shown that the prevalence of HPV infection peutic protocols spread over different periods of treat- and HSIL are higher among HIV infected women and that ment. From the list of patients eligible for the study, these differences are exaggerated among women with subjects were randomly chosen in a systematic manner. lower CD4+ cell counts [8-10]. Several recent prospective The objective of the study was explained to patients and studies have documented that the rate of persistence of verbal consent was sought from each of them. HPV among HIV-infected women is higher than that Collection of Specimens among non HIV-infected women [11,12]. Specific types of HPV are associated with cervical cancer, but whether At the screening visit, venous blood was collected for CD4 these high-risk types have natural histories that are differ- analysis, and pap smears performed for early detection of ent from those of other types not associated with cervical cervical carcinoma as previously described [17]. Subjects cancer is unknown [13,14]. The modification of the viral underwent a general physical examination and completed markers may be the crucial factor of disequilibrium in the a short standardized interview, including questions per- interaction between virus and host: an increased replicat- taining to medical history, sexual behaviour, history of ing capacity of the virus versus a reduced control mecha- STIs, age of first sexual intercourse, pregnancy, parity and nism of the immune system. In this context it's evident abortion. that in HIV-infected women, both viral and host factors conspire, as these patients have an impaired immune sys- Histological analysis tem usually more exposed to HPV infection. Some studies Pap smears were interpreted and classified according to the Bethesda System as negative, atypical squamous cells have also considered the impact on cervical pathology on HIV disease care, mainly represented by the introduction of unknown significance, LSIL, HSIL, or invasive cervical of highly active antiretroviral therapy (HAART), which cancer [18,19]. Conventional Pap smears were used and through the substantial recovery of immune function has slides were read by a pathologist. Blood samples were significantly changed the scenario regarding HIV-related obtained for flow cytometry CD4+ T cell counts using pathologies such as opportunistic infections and cancers AIDS Clinical Trials Group standardized flow-cytometry [15,16]. The objectives of this study were to compare rates protocols as described elsewhere [20]. of cervical abnormalities related to HPV infection among Statistical analysis HIV-infected women with and without HAART initiation and to examine immunological and behavioural risk fac- Data obtained were verified for consistency, coded, and tors associated with persistence of HPV. computerized. Throughout the text, values are given as mean ± s.d. Percentages were calculated from the overall Subjects and methods number of cases. Raw data were compared using Fisher's Study population exact-test (StatXact 2.05 software). Appropriate probabili- A total of 70 HIV-infected women were enrolled in the ties were calculated [21] and size variation with Mann- study after informed consent and divided into two groups: Whitney rank sum test as the normality test failed (Sigma 35 under HAART and 35 not initiated with HAART. Stat 2.03 software). Page 2 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 probably due to the number patients assigned to each Results Subjects characteristics parameter. Seventy HIV infected women were randomly recruited using systemic random sampling from the outpatients at HAART and incidence of cervical abnormalities the day care centre of Bonassama hospital in Douala. Table 2 presents histological analyses of studied samples. Table 1 summarizes the socio-demographic information The Pap smear test results revealed the following within as well as information on reproductive and sexual charac- the study groups: those with normal cervical cytology teristics of the study groups. Sampling was done according (44.3%) and those with abnormal Pap smear; LSIL to: age with a mean age of 35.5 ± 1.9 years and 35.1 ± 1.3 (24.3%), and HSIL (31.4%) respectively. The cervical years; age of first vaginal sex with a mean age of 16.9 ± 5 abnormalities differences were statistically significant for years and 17.2 ± 0.5 years; number of pregnancies with a the two study groups when comparing the total frequency mean number of 3.7 ± 0.5 and 3.9 ± 0.4; parity with a abnormalities (48.6% vs. 62.9%, P = 0.034) for treated mean number of 2.6 ± 0.5 and 2.6 ± 0.4; abortion with a and untreated groups respectively. Table 3 represents the mean number of 1.2 ± 0.2 respectively for women under frequency of distribution of cervical cytology results in the HAART and women not initiated with HAART. Significant treated and untreated groups according to the duration of differences were observed between these groups at base- therapy. Cervical abnormalities are high in the absence of line in terms of ages of patients: when comparing the therapy: 47.1% and 63.6% for LSIL and HSIL respectively. mean age of patients above 40 years (52.3 ± 2.3% (9) vs. The difference in the distribution of the cytological picture 44.9 ± 1.2% (10), P = 0.007) and when comparing the among LSIL and HSIL cases was statistically none signifi- mean parity of more than 4 (9.8 ± 0.7% (4) vs. 5.9 ± 0.5% cant (P > 0.05). Table 4 represents the Incidence of cervi- (8), P = 0.006) for treated and untreated group respec- cal cytology results in the HAART treatment group tively. The significant difference observed between treated according to the duration of therapy. Normal cervical and untreated groups in terms of mean age and parity is cytology increase with the duration of therapy: 5.7% to 34.3% within the period of treatment 1–5 month and Table 1: Selected baseline characteristics of HIV infected women as study subjects. Under HAART No HAART Groups n% Mean ± SE n % Mean ± SE p value A. Age (years) <30 12 34.3 26.4 ± 0.7 10 28.6 26.4 ± 0.9 0.988 ns 30 – 40 14 40.0 32.4 ± 0.8 15 42.8 34.3 ± 0.9 0.115 ns >40 9 25.7 52.3 ± 2.3 10 28.6 44.9 ± 1.2 0.007 * Total 35 - 35.5 ± 1.9 35 - 35.1 ± 1.3 0.872 ns B. Age at first vaginal sex (years) ≤ 16 18 51.4 14.6 ± 0.3 15 42.9 14.5 ± 0.3 0.874 ns >16 17 48.6 19.3 ± 0.7 20 57.1 19.3 ± 0.4 0.956 ns Total 35 - 16.9 ± 0.5 35 - 17.2 ± 0.5 0.643 ns C. Pregnancy 0 2 5.7 0.0 ± 0.0 0 0.0 0.0 ± 0.0 - 1 – 4 23 65.7 2.3 ± 0.3 22 62.9 2.3 ± 0.2 0.971 ns 5 – 9 7 20.0 6.1 ± 0.6 11 31.4 5.9 ± 0.4 0.750 ns >10 3 8.6 11.0 ± 0.6 2 5.71 10.5 ± 0.5 0.800 ns# Total 35 - 3.7 ± 0.5 35 - 3.9 ± 0.4 0.737 ns D. Parity 0 7 20.0 0.0 ± 0.0 5 14.3 0.0 ± 0.0 - 1 – 4 24 68.6 2.1 ± 0.3 22 62.8 2.0 ± 0.2 0.711 ns >4 4 11.4 9.8 ± 0.7 8 22.8 5.9 ± 0.5 0.006 * Total 35 - 2.6 ± 0.5 35 - 2.6 ± 0.4 0.964 ns E. Abortion 0 13 37.1 0.0 ± 0.0 12 34.3 0.0 ± 0.0 - 1 – 2 15 42.9 1.2 ± 0.1 17 48.6 1.4 ± 0.1 0.353 ns >2 7 20.0 3.4 ± 0.2 6 17.1 3.3 ± 0.3 0.628 ns Total 35 - 1.2 ± 0.2 35 - 1.2 ± 0.2 0.925 ns a. Means were compared one after the other using the Student t-test when normality and equal variance conditions passed or the Mann-Whitney rank sum test when conditions failed. Ns: no significant difference; * significant difference; #: Mann-Whitney rank sum test Page 3 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 2: Frequency of cervical abnormalities in HIV infected women according to cytological findings Under HAART(35) No HAART (35) Total (70) p-value Groups n% n % n % Normal 18 51.4 13 37.1 31 44.3 LSIL 9 25.7 8 22.9 17 24.3 HSIL 8 22.9 14 40.0 22 31.4 Total abnormalities 17 48.6 22 62.9 39 55.7 0.034* a. Low squamous intra epithelial lesions b. High squamous intra epithelial lesions * Significant difference more than 10 month respectively. Within the same itive patients neither for pregnancy nor for abortion. In period, HSIL decreased from 14.3% to 2.8% and was patients with the highest percentage for pregnancies, i.e. ≤ probably due to the number of patients within the more 10 pregnancies we noticed 76.4% and 45.5% occurrence than 10 months' period of therapy. The difference in the for LSIL and HSIL respectively while for abortion, the incidence of cervical abnormalities was statistically non cytology results findings showed 70.6% and 36.4% for significant (P = 0.069). Table 5 represents CD4+ T cell LSIL and HSIL respectively in patients with 1 or more than count distribution within the study groups according to 2 abortions. Table 7 represents distribution of STI risk fac- cervical abnormalities. The mean of CD4+ T cell count tors that might contribute to HPV infection. The history of decreases with degree of cervical abnormalities in both STIs risk factors shows that: Bacillus vaginalis, Chlamydia sp groups: 289 ± 47.0, 253 ± 69.1 and 173.4 ± 42.4 T cells in and Treponema Pallidum are main microbial infectious patients under HAART while those with no HAART initia- agents. B. vaginalis is the leading infection with 70.6% and tion have 244.5 ± 42.8, 218.4 ± 64.1 and 59.9 ± 14.5 for 54.5% for LSIL and HSIL respectively while Chlamydia is normal, LSIL and HSIL respectively. Table 6 examines the second with 17.6% and 22.7% and T. Pallidum which some of the risk factors that might contribute to HPV count for 5.9% and 13.6% respectively for LSIL and HSIL infection. The risk factors investigated were grouped positives patients. No significant statistical difference was according to the following parameters of personal history: found in correlation with cervical abnormalities. age of first vaginal sex, pregnancy and abortion. The results showed that patients with cervical abnormalities Discussion were mainly ≥ 19 years old at first vaginal sex intercourse This study provides data on the risk of cervical cancer with high percentage: 23.5% and 20.2% for LSIL and HSIL among HIV positive women less than 60 years old in the respectively. There was no statistical difference for this fac- day care centre at Bonassama hospital Douala -Central tor when compared with Mann-Whitney test. Reproduc- Africa. The extent to which HIV increases the risk for cer- tive history of the studied groups showed a statistically vical cancer is especially important in Cameroon referring non significant difference between the LSIL and HSIL pos- to the epidemiology of the HIV especially among women. In our study, HIV positive women are at high risk of inva- sive cervical cancer. This could be due to the competing Table 3: Frequency of cervical abnormalities in HIV infected risk of mortality from other conditions associated with women according to duration of medication (HAART) Duration Cervical abnormality Table 4: Cervical abnormalities incidence in HIV infected women under HAART therapy according to and duration of medication (month) LSIL HSIL Duration Normal LSIL HSIL n % n % Exact p-value (month) n %n%n% 0 08 47.1 14 63.6 0.1308 ns 0 - ----- 1–5 03 17.7 05 22.7 0.6193 ns 1–5 2 5.7 3 8.6 5 14.3 6–10 02 11.8 02 09.1 1.000 ns 6–10 4 11.4 2 5.7 2 5.7 > 10 04 23.5 01 04.5 0.2063 ns > 10 12 34.3 4 11.4 1 2.8 Total 17 - 22 - 0.3652 ns Total 18 51.4 9 25.7 8 22.8 a. Combined data for treated and untreated patients b. Global comparison of raw data: Pearson's chi-square exact a. exact probability using Pearson's Chi-square test for independence probability: P = 0.3725) procedure: P = 0.069 Page 4 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 5: CD4+ T cell count distribution in HIV infected women and specificity are similar among HIV negative and HIV according to cervical abnormalities positive women [27]. We found an association between HAART and the stage of cervical pre-cancer. Our results are Under HAART No HAART in agreement with others that have shown an association between HIV, HAART and cervical abnormalities [[15,16], Groups n% Mean ± SE n% Mean ± SE and [28]]. An additional limitation of our study is that Normal 18 51.4 289.4 ± 47.0 13 37.1 244.5 ± 42.8 complete information regarding the immunological sta- LSIL 9 25.7 253.6 ± 69.1 8 22.9 218.4 ± 64.1 tus of patients has not been documented for all the HSIL 8 22.9 173.4 ± 42.4 14 40.0 59.9 ± 14.5 groups. Similar of different studies by the same author [[9,15,16,20,25], and [29]] have reported that the severity Total 35 - 253.7 ± 31.7 35 - 164.7 ± 26.1 of HIV-related immunodepression is associated with increased incidence of HPV infection and SILs. Data HIV/AIDS, particularly in a setting where antiretroviral obtained from the current study further confirm these therapy was not available at the time and for all patients. findings reported by other investigators of our geographic Our findings that HIV infected women were at a signifi- area [17,22-26]. Several studies suggested that markers of cantly higher risk of LSIL and HSIL confirm the results of advanced HIV disease such as CD4+ T cell counts or HIV- studies carried out in both developed and other develop- RNA plasmatic levels are associated with increased risk of ing countries [7,17,22-24]. The relative prevalence of SILs HPV infection and SIL [8,17,28,29]. However some docu- or cytological abnormalities among HIV positive women mentations and data have revealed that the relationship is higher than that ever been reported by any other study between HIV and HPV is more complex. Human immun- in Africa. Hawes et al. reported a cytological abnormality odeficiency virus infection is associated with an increased prevalence of 37% among women with HIV-1 infection transcriptional activity of early HPV genes. Studies on attending an outpatients infectious disease clinic in Sen- adult women have shown that HPV infection with both egal [17], Yamada 27.1% in urban patients in Kenya [25], high-risk and low-risk HPV types is more likely to persist Moukassa 15.36% among urban dwellers in Congo [26]. among HIV-infected women [8,12]. Because they have more years of sexual activity, adult women may reflect a A potential limitation of this current study is that cytolog- group of women further along in their history of HIV and ical abnormalities were not histologically confirmed. HPV infection. Our data further support the important However, it has been shown that the Pap smear sensitivity role played by CD4+ T cells [28,29] in the control of HPV Table 6: Incidence of risk factors on cervical disease in HIV infected women under treatment (HAART) and those without treatment or HAART initiation LSIL HSIL Mann-Withney test Groups n% Mean ± SE n% Mean ± SE Age at first vaginal sex (years) <15 03 17.6 13.7 ± 0.3 06 27.3 13.2 ± 0.3 0.381 ns 15 – 18 10 58.8 16.5 ± 0.5 11 50.0 16.4 ± 0.3 0.860 ns ≥ 19 04 23.5 19.8 ± 0.5 05 22.7 20.2 ± 0.7 0.905 ns Total 17 - 16.8 ± 0.5 22 - 16.4 ± 0.6 0.571 ns Pregnancy ≤ 4 13 76.4 2.4 ± 0.3 10 45.5 2.8 ± 0.3 0.420 ns 5–9 02 11.8 5.5 ± 0.5 10 45.5 1.4 ± 0.4 0.590 ns ≥ 10 02 11.8 11.5 ± 0.5 02 09.0 0.7 ± 0.5 0.333 ns Total 17 - 3.8 ± 0.8 22 - 5.1 ± 0.6 0.068 ns Abortion 0 03 17.6 0.0 ± 0.0 06 27.3 0.0 ± 0.0 - 1–2 12 70.6 1.3 ± 0.3 08 36.4 1.4 ± 0.2 0.669 ns > 2 02 11.7 3.0 ± 0.0 08 36.4 3.6 ± 0.3 0.400 ns Total 17 - 1.24 ± 0.2 22 - 1.8 ± 0.3 0.372 ns Page 5 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:9 http://www.infectagentscancer.com/content/4/1/9 Table 7: Incidence of History of STD on cervical disease in HIV were strongly associated with high-risk HPV infection and infected untreated and treated women (exact probability using low CD4+ T cell counts. Immunodeficiency as a result of Pearson's Chi-square test for independence procedure: P = HIV infection appears to be important for malignant pro- 0.8224) gression within the cervix. Nationwide prevention of HIV LSIL HSIL infection and cervical cancer screening are necessary for the health of women in Cameroon. The increased public Groups n% n % health burden enhanced by HPV is an important and gen- der-specific aspect of HIV infection. Guidelines on proper B. vaginalis 12 70.6 12 54.5 screening for cervical abnormalities in HIV positive Chlamydia 03 17.6 05 22.7 women are urgently needed in Cameroon. T. Pallidum 01 05.9 03 13.6 Other 01 05.9 02 09.1 Competing interests The authors declare that they have no competing interests. Total 17 - 22 - Authors' contributions infection: the lower the CD4+ T cell count, the more likely KMML conceived the study, participated in its design and that HPV infection will persist. Persistent infection in turn statistical analysis, coordinated and drafted the manu- may increase the risk for the development and persistence script. GMLC participated in CD4 analysis using the flow of squamous intraepithelial lesions. In fact, women cytometry, data collection and helped to draft the manu- whose immunosuppression is related to infection with script. DC participated in flow cytometry analysis, data human immunodeficiency virus are at increased risk of collection and helped to draft the manuscript. WM partic- infection with multiple types of HPV [28]. In developed ipated in study design, clinical examination and recruit- countries it's recommended for HIV positive women to ment of women at the study site and coordination. MA have two cervical cytological assessments within the first carried out cytology analysis. NNA participated in the year after HIV diagnosis and annually thereafter, referred study design, statistical analysis and helped to draft and for colposcopy for any smear showing an ASCUS (atypical review the manuscript. squamous cells of undetermined significance) or more severe lesions [30]. These guidelines are not feasible in set- Acknowledgements These results were obtained thanks to the support of AIRES-Sud, a pro- tings with limited or poor resources. The high prevalence gramme from the French Ministry of Foreign and European Affairs imple- and risk of cervical abnormalities documented in our mented by the Institut de Recherche pour le Développement (IRD-DSF). research projet underscores the importance of developing The authors thank the women for their voluntary participation in the study. screening and management guidelines for HIV positive We would equally like to give thanks to Dr Lehman Leopold for his techni- women. As antiretroviral therapy becomes increasingly cal assistance via the flow cytometry, Dr Kenne Martin for statistics analysis available in Cameroon, the life expectancy of HIV positive assistance and Mr Ewane Leonard for manuscript review. women will increase as well. It's therefore important to conserve this invaluable benefit and avoid its upset by an References increased risk in the development of cervical cancer. A cer- 1. Bosch FX, Munoz N: The viral etiology of cervical cancer. Virus Res 2002, 89:183-189. vical screening program is of critical importance as it 2. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah informs local researchers on the natural history of cervical KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J abnormalities, which might be recommended for HIV Pathol 1999, 189:12-19. positive women. The STIs history of studied subjects 3. 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Salata RA: Human papillomavirus genotypes associated with Sir Paul Nurse, Cancer Research UK cervical cytologic abnormalities and HIV infection in Ugan- dan women. J Med Virol 2007, 79(6):758-765. Your research papers will be: 24. López-Revilla R, Martínez-Contreras LA, Sánchez-Garza M: Preva- available free of charge to the entire biomedical community lence of high-risk human papillomavirus types in Mexican women with cervical intraepithelial neoplasia and invasive peer reviewed and published immediately upon acceptance carcinoma. Infectious Agents and Cancer 2008, 3:3-10. cited in PubMed and archived on PubMed Central 25. Yamada R, Sasagawa T, Kirumbi LW, Kingoro A, Karanja DK, Kiptoo M, Nakitare GW, Ichimura H, Inoue M: Human papillomavirus yours — you keep the copyright infection and cervical abnormalities in Nairobi, Kenya, an BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)

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Infectious Agents and Cancer – Springer Journals

Published: Jun 3, 2009

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