¶ Membership of the IeDEA West Africa Collaboration is provided in the Acknowledgments.
The authors have declared that no competing interests exist.
Conceived and designed the experiments: AJ AH DKE AJS FD. Wrote the paper: AJ DKE AM FD. Conducted the clinical work and cervical screening training: AH BT. Performed statistical analysis: AJ. Interpreted data: AJ AH DKE FD. Supervised the pathological examinations: BE. First drafted the manuscript: AJ. Critically revised the manuscript for important intellectual content: AJ DKE AM FD AH AJS BT BE PAC SL EM. Agreed on the final version of the manuscript: AJ DKE AM FD AH AJS BT BE PAC SL EM.
Facing the dual burden of invasive cervical cancer and HIV in sub-Saharan Africa, the identification of preventable determinants of Cervical Intraepithelial Neoplasia (CIN) in HIV-infected women is of paramount importance.
A cervical cancer screening based on visual inspection methods was proposed to HIV-infected women in care in Abidjan, Côte d'Ivoire. Positively screened women were referred for a colposcopy to a gynaecologist who performed directed biopsies.
Of the 2,998 HIV-infected women enrolled, 132 (4.4%) CIN of any grade (CIN+) were identified. Women had been followed-up for a median duration of three years [IQR: 1–5] and 76% were on antiretroviral treatment (ART). Their median most recent CD4 count was 452 [IQR: 301–621] cells/mm3. In multivariate analysis, CIN+ was associated with a most recent CD4 count >350 cells/mm3 (OR: 0.3; 95% CI: 0.2–0.6) or ≥200–350 cells/mm3 (OR 0.6; 95% CI 0.4–1.0) (Ref: <200 cells/mm3 CD4) (p<10−4).
The presence of CIN+ is less common among HIV-infected women with limited or no immune deficiency. Despite the potential impact of immunological recovery on the reduction of premalignant cervical lesions through the use of ART, cervical cancer prevention, including screening and vaccination remains a priority in West Africa while ART is rolled-out.
Since 2002, the number of HIV-infected patients accessing to antiretroviral treatment (ART) has dramatically increased with approximately half of those eligible to ART already covered in sub-Saharan Africa in 2010
A cervical screening program based on visual inspection of the cervix was organized in HIV clinics participating to the International epidemiological Database to Evaluate AIDS (IeDEA) West Africa collaboration (
Women characteristics were compared first according to the presence or absence of CIN of any grade or ICC (CIN+) using Pearson's χ2 test or Fisher's exact test when appropriate for qualitative variables and t-test or Kruskall-Wallis test for quantitative variables. A logistic regression model was used for univariate and multivariate analyses of the factors associated with CIN+. For the multivariate analysis, a stepwise descending procedure was applied to derive the model that best predicted the presence of any CIN+. The goodness of fit of the model was assessed using the Akaike Information Criterion (AIC), a lower value of the AIC suggesting a better prediction of the model. All relevant potential confounders were included in the initial multivariate model. Confounders that were not significantly associated with the presence of CIN+ and did not add any significant prediction to the model based on the AIC were sequentially removed. Although, no significant interaction was reported between ART use, the most recent CD4 count and the presence of CIN+, the model was secondarily stratified according to ART use to better explore the respective role of immunological status and ART on the presence of CIN+. Proportions and
Of the 3,090 HIV-positive women who attended the cervical screening consultations, 92 (3.0%) were not eligible. The median age of the 2,998 remaining women was 36 years [interquartile range (IQR): 32–42] and 2,267 (75.6%) were on ART. The median duration of follow-up in HIV care was three years [IQR: 1–5]. Among ART users, the median duration on ART was 2 years [IQR: 1–4]. The overall median most recent CD4 count was 452 [IQR: 301–621] cells/mm3, 439 [IQR: 282–616] cells/mm3 among ART users and 491 [IQR: 361–640] cells/mm3 among the untreated women (p<10−4). A total of 268 (9.0%) women were positively screened with suspected cervical lesions at visual inspection and referred for medical examination. Of these, 132 CIN+ (4.4%; 95% CI: 3.7–5.1) were identified. Biopsy results were as follows; 115 CIN of grade 1, five CIN of grade 2, nine CIN of grade 3 and three ICC.
No CIN+ | Presence of CIN+ | P | Total | |
(n = 2,866) | (n = 132) | (n = 2,998) | ||
0.58 | ||||
MTCT + | 591 (20.6) | 32 (24.3) | 623 (20.8) | |
Cepref | 1,303 (45.5) | 56 (42.4) | 1,359 (45.3) | |
CNTS | 972 (33.9) | 44 (33.3) | 1,016 (33.9) | |
36 [32–42] | 37 [31–41] | 0.40 | 36 [32–42] | |
0.67 | ||||
No | 725 (25.3) | 32 (24.3) | 757 (25.3) | |
Primary school | 926 (32.3) | 39 (29.5) | 965 (32.2) | |
Secondary and over | 1,213 (42.4) | 61 (46.2) | 1,274 (42.5) | |
43 (1.5) | 1 (0.8) | 0.49 | 44 (1.5) | |
45 (1.6) | 0 (0.0) | 0.26 | 45 (1.5) | |
Married, cohabitant | 1,298 (45.3) | 46 (34.9) | 1,344 (44.8) | |
Single, divorced, widowed | 1,568 (54.7) | 86 (65.1) | 1,654 (55.2) | |
0.66 | ||||
≥16 years | 1,949 (69.3) | 93 (71.0) | 1,946 (69.2) | |
<16 years | 863 (30.7) | 38 (29.0) | 866 (30.8) | |
0.21 | ||||
<5 | 1,247 (43.8) | 65 (49.2) | 1,312 (44.0) | |
≥5 | 1,602 (56.2) | 67 (50.8) | 1,669 (56.0) | |
Nulliparous | 448 (15.6) | 10 (7.6) | 458 (15.3) | |
Primiparous | 687 (24.0) | 35 (26.5) | 722 (24.1) | |
Multiparous | 1731 (60.4) | 87 (65.9) | 1818 (60.6) | |
Never on ART | 705 (24.9) | 26 (19.7) | 731 (24.6) | |
≥1 | 906 (32.0) | 54 (40.9) | 960 (32.4) | |
≥2–3 | 617 (21.8) | 33 (25.0) | 650 (21.9) | |
≥4 | 606 (21.3) | 19 (14.4) | 625 (21.1) | |
2,161 (100.0) | 106 (100.0) | 0.44 | 2,267 (100.0) | |
D4T/3TC/NVP | 573 (26.5) | 23 (21.7) | 596 (26.3) | |
D4T/3TC/EFV | 125 (5.8) | 7 (6.6) | 132 (5.8) | |
AZT/3TC/NVP | 397 (18.3) | 23 (21.7) | 420 (18.5) | |
AZT/3TC/EFV | 315 (14.6) | 13 (12.3) | 328 (14.5) | |
Protease inhibitor based regimen | 207 (9.6) | 13 (12.3) | 220 (9.7) | |
Other regimens | 544 (25.2) | 27 (25.4) | 571 (25.2) | |
0.68 | ||||
HIV-1 | 1,694 (59.1) | 78 (59.1) | 1,772 (59.1) | |
HIV-2 or dually reactive | 79 (2.8) | 2 (1.5) | 81 (2.7) | |
Unknown | 1,093 (38.1) | 52 (39.4) | 1,145 (38.2) | |
0.94 | ||||
CDC A & B and/or 1,2 WHO | 1,513 (52.8) | 69 (52.3) | 1,582 (52.8) | |
CDC C and/or 3,4 WHO | 962 (33.6) | 46 (34.8) | 1,008 (33.6) | |
Unknown | 391 (13.6) | 17 (12.9) | 408 (13.6) | |
295 [160–464] | 249 [107–378] | 291 [156–461] | ||
458 [307–629] | 340 [216–500] | 452 [301–621] |
*Current or former use of smoked and/or chewed tobacco.
CD4 count (cells/mm3) measured during first clinical follow-up for HIV infection.
Last known CD4 count (cells/mm3) measured prior or during the cervical cancer screening visit.
Abbreviations: CIN/ICC Cervical Intraepithelial Neoplasia/Invasive Cervical Cancer ART Antiretroviral Treatment.
Univariate analysis | Final multivariate analysis | ||||||
Variables | n/N | OR | 95% CI | P | OR | 95% CI | P |
0.10 | 0.08 | ||||||
≥25–34 | 46/1,211 | 1 | 1 | ||||
≥35–44 | 68/1,265 | 1.4 | 1.0–2.1 | 1.3 | 0.9–2.0 | ||
≥45–54 | 13/434 | 0.8 | 0.4–1.5 | 0.6 | 0.3–1.2 | ||
≥55–65 | 5/88 | 1.5 | 0.6–3.9 | 1.2 | 0.5–3.3 | ||
0.02 | <10−2 | ||||||
Couple (married, cohabitant) | 46/1,344 | 1 | 1 | ||||
Single (alone, divorced, widowed) | 86/1,654 | 1.5 | 1.1–2.2 | 1.6 | 1.1–2.4 | ||
Parity | 0.01 | <10−2 | |||||
No | 10/458 | 1 | 1 | ||||
Yes (≥1) | 122/2,540 | 2.3 | 1.2–4.3 | 2.5 | 1.3–4.9 | ||
0.05 | 0.26 | ||||||
Never | 26/731 | 1 | 1 | ||||
≥1 | 54/992 | 1.6 | 1.0–2.6 | 1.0 | 0.6–1.7 | ||
≥2–3 | 33/650 | 1.4 | 0.9–2.4 | 1.1 | 0.6–2.0 | ||
≥4 | 19/625 | 0.8 | 0.5–1.5 | 0.6 | 0.3–1.2 | ||
0.02 | 0.50 | ||||||
≤200 | 56/965 | 1 | 1 | ||||
>200–350 | 37/768 | 0.8 | 0.5–1.2 | 1.0 | 0.6–1.6 | ||
>350 | 36/1,181 | 0.5 | 0.3–0.8 | 0.7 | 0.5–1.2 | ||
Unknown | 3/84 | 0.6 | 0.2–1.9 | 0.5 | 0.1–4.0 | ||
<10−4 | <10−3 | ||||||
≤200 | 31/346 | 1 | 1 | ||||
>200–350 | 36/621 | 0.6 | 0.4–0.9 | 0.6 | 0.4–1.0 | ||
>350 | 62/1,957 | 0.3 | 0.2–0.5 | 0.3 | 0.2–0.6 | ||
Unknown | 3/74 | 0.4 | 0.1–1.4 | 0.8 | 0.1–5.8 |
Comparison of CD4 count (cells/mm3) according to ART duration (median [interquartile range]): ≥1 years: 358 [212–532], ≥2–3 years: 477 [313–650], ≥ 4 years 512 [366–691] (p<10−4).
*CD4 count (cells/mm3) measured during first clinical follow-up for HIV infection.
Last known CD4 count (cells/mm3) measured prior or during the cervical cancer screening visit.
In univariate analysis, a high CD4 count at first HIV care visit was protective against the presence of CIN+: >350 cells/mm3 (OR: 0.5; 95% CI: 0.3–0.8) (Ref: CD4 <200 cells/mm3) (
In the final multivariate analysis, the presence of CIN+ was associated with a most recent CD4 count >350 cells/mm3 (OR: 0.3; 95% CI: 0.2–0.6) or ≥200–350 cells/mm3 (OR 0.6; 95% CI 0.4–1.0) (Ref: <200 cells/mm3 CD4), parity ≥1 (OR: 2.5; 95% CI: 1.3–4.9) and being single (OR: 1.6; 95% CI: 1.1–2.4) whereas ART use was no longer associated (
In a multivariate analysis restricted to ART users (N = 2267, 75.6% of the sample), CIN+ (n = 106) was significantly associated with a most recent CD4 count >350 cells/mm3 (OR: 0.4; 95% CI: 0.2–0.7) or ≥200–350 cells/mm3 (OR: 0.5; 95% CI 0.3–1.0) (Ref: CD4 <200 cells/mm3) (p<10−2). Among HIV-infected women that never experienced ART, CIN+ was also significantly associated with a most recent CD4 count >350 cells/mm3 (OR: 0.1; 95% CI: 0.0–0.5) (Ref: CD4<200 cells/mm3) (p = 10−2).
Women infected with the HIV-2 type or dually reactive to HIV-1 and HIV-2 did not experience more CIN+ lesions than women infected with HIV-1 only in univariate analysis (p = 0.69) and this variable was thus not kept in the multivariate analysis.
In our study, immunodeficiency (most recent CD4 count <350 cells/mm3) was identified as the main determinant of the presence of CIN+ in HIV-infected women and this association remained although with a lower strength among those on ART. Previous studies have reported an association between the presence of cytological abnormalities and a severe immunodeficiency (most recent CD4 count measure <200 cells/mm3) among HIV-positive women in sub-Saharan Africa
Baseline CD4 count at the time of first clinical follow-up which could be interpreted as a proxy for nadir CD4 count, was not found to be significantly associated with CIN+ in our multivariate model. This result contrasts with other reports from resource-constraint settings
Reports assessing the impact of ART on the occurrence of CIN+ in resources-limited settings have been conflicting. So far, reports from Nigeria and South Africa found no association between squamous intraepithelial lesions (SILs) of the cervix and ART exposure
However, the cross-sectional nature of the study and the relatively long natural history of cervical malignancies are currently limiting our ability to accurately assess the impact of ART on the development of cervical malignancies. A report from Minkoff
Contrary to previous reports which showing a higher risk of CIN+ among women who smoke, the proportion of smokers according to the presence of CIN+ was not statistically different here
We found that single or divorced women were more likely to harbour CIN+ compared to married women. As neither the reported number of lifetime sexual partners nor the age at first sexual intercourse was found to be associated with the presence of CIN+, we believe that the marital status could be interpreted as a proxy for the current number of sexual partners and less subject to prevarication and recall biases. Parity was also associated with the presence of CIN+ in multivariate analysis. This association was expected as parity has been reported as a risk factor for ICC in populations of unknown HIV status
Before the advent of ART in sub-Saharan Africa, HIV-2 infection had been identified as a potential risk factor for the occurrence of premalignant and malignant cervical lesions
The main outcome variable of this analysis was CIN of any grade, including low-grade lesions because of the limited number of high grade cervical lesions (CIN 2/3 or ICC). As low grade lesions (CIN 1) have the ability to spontaneously regress, this outcome might not reflect the true population at risk of developing ICC. Considering the HIV subtypes, there were limited numbers of HIV-2 infections limiting therefore our ability to detect any association with the presence of CIN+. Using visual inspection methods to assess the presence of precancerous lesions exposes to misclassification due to its limited sensitivity and specificity compared to colposcopy with directed biopsy. As there are currently no affordable alternative screening method and as conventional cytology in field conditions has not demonstrated its superiority compared to visual inspection, we support this public health approach as the most appropriate one for targeting HIV-infected women in care and believe this has not interfered with our research findings.
In a context of expanding roll-out of ART in West Africa, immunodeficiency remains a major determinant of the occurrence of CIN+ among HIV-infected women although the frequency of CIN+ lesions decreased with the duration on ART. In resource-limited settings where cervical cancer screening programs are challenging to organize, immunological preservation and reconstitution might partly prevent the occurrence of premalignant cervical lesions. However, cervical cancer prevention, including screening of premalignant lesions as well as HPV vaccination, remains of utmost priority especially in HIV-infected women in a context of expanding roll out of ART in West Africa.
We are indebted to all of the women who agreed to participate in this present study as well as to the midwives who performed the cervical screening procedures and the data collection. We are also indebted to Mrs Rosamonde Yao, Mr Severin Lenaud and Mr Jean-Claude Azani for their implication in data entry and data management process. Special thanks for Rosemary McKaig for encouraging and supporting the study together with Caroline Williams, Geraldina Domingez and Kishor Batia.
Corresponding author for the IeDEA West Africa collaboration: Pr François DABIS (