Discussion

Women living with HIV are at increased risk for HPV infection including CIN2/3 and ICC.[24] [25] Substantial progress has been achieved with the availability of highly active antiretroviral therapy, with decrease in morbidity and mortality associated with HIV infection in both higher- and lower-middle-income countries. Despite improved survival and longevity, women living with HIV/AIDS (WLWHA) continue to be affected by gynecologic and non-gynecologic malignancies at disproportionate rates in lower-middle-income country settings, especially with high HIV burden. This is due to the lack of effective cervical cancer prevention programs.[26] In our retrospective study, we examined the prevalence of HPV infection, screening positivity rates of screening methods of VIA, HPV HC II, and cytology among HIV-infected women. Our study findings have provided useful comparable measures of evaluation of the three cervical cancer screening tools for the most feasible and effective screening strategies among HIV-positive women that can be chosen for implementation in public health program settings.

The three screening tests administered to HIV-infected women showed very high screening test positivity rates of 35.7%, 34.4%-for VIA and HPV HC2, and 9.6%-for cytology (LSIL). Comparative screening test positivity rates among HIV-positive women from other studies in India have reported 15.0%-for VIA, 8.1%-for any abnormal cytology, and 26.4% for HPV.[27] In a study from eastern India, among the 216 HIV-positive women screened, 26.85%-were HPV-positive, 17.11%-had LSIL, 5.35%-had HSIL, and three (1.60%) had carcinoma cervix.[28] In a study from Ethiopia in Africa, 22.1% were found to be positive on VIA.[29] A study from South Africa reported that HIV-positive women were more likely to have an abnormal cytology result as compared to HIV-negative women (35.1%, [n = 20/57] vs. 13.9%, [n = 31/223]; p = 0.0002) and specifically a higher proportion of HSIL (10.5%, [n = 6/57] vs. 3.1%, [n = 7/223]; p = 0.028).[30] Wide variations in the screening test positivity rates among HIV-positive women are largely explained by the provider. They explained the dependent, subjective nature of the VIA test, whereas cytology could be impacted right from adequate collection of the sample to the level of training and nature of quality assurance measures adopted in the respective laboratories for conventional cytology. Out of the three tests, molecular high-risk HPV detection is much less dependent on the quality of the sample and on human judgment than are cytology and visual inspection. The molecular laboratory requirements and overall cost of the test are still very prohibitive for scale-up in low-resource countries.

The prevalence of all categories CIN (CIN 1,2,3) detected in our study was 14.7%. The prevalence of CIN2 and above lesions was 8.6%-which was slightly higher than some of the cross-sectional studies among HIV-infected women. Cross-sectional studies from Kenya,[31] Brazil,[32] and southwestern China[33] reported the prevalence of CIN 2/3 as 5.4, 6.0, and 8.4%, respectively. Two studies from the same region in Maharashtra, India, however, have shown wide variation in the prevalence of CIN2/3 lesions at 4.9%-with more than 1,000 HIV-positive women[27] and 16%-with much smaller sample size of 303 women.[34] Some other studies[35] [36] [37] including those from India[28] [38] have demonstrated a higher prevalence of CIN and cervical cancer among HIV-infected women. HIV-infected women invariably are one of the high-risk groups for the acquisition, persistence, progression, and recurrence of HPV infection and thereby HPV-induced cervical precursor lesions and cervical cancer. Thus, there is a need for updated revised guidelines for more frequent screening and greater follow-up among HIV-infected women than HIV-uninfected women.

With respect to the comparative screening test performance characteristics for screening of cervical cancers, multiple studies in resource-limited settings have extensively evaluated the performance of VIA, HPV, and cytology in the general population.[39] [40] Our study is one of the very few which has concurrently evaluated the screening test performance of three screening tests including diagnostic colposcopy among HIV-infected women in detecting CIN 2 and 3 lesions with minimal verification bias. The study has demonstrated the use of diagnostic colposcopy and, if indicated, histopathology to investigate the true prevalence of CIN in this high-risk cohort of women. With the gold standard of diagnostic colposcopy, with or without biopsy, our results indicate that VIA, HPV testing, and Pap cytology (LSIL + ) have a higher sensitivity in detecting high-grade CIN 2 and above lesions. Pap cytology (HSIL + ) and diagnostic colposcopy (CINII + ) showed low sensitivity but high specificities with very high PPVs.

Screening test performances among general women in developing country settings, the sensitivity of VIA to detect high-grade precursor lesions and ICC has varied from 49 to 96%-and the specificity from 49 to 98%. This is largely due to the subjective nature of the tests and requirements for maintaining adequate training levels of the providers with good-quality assured test procedures.[39] [40] HPV-DNA sensitivity was high (66–100%) with moderate specificity (61–96%). Although it has the special advantage of being high throughput, objective, reproducible, and robust, it, however, requires molecular laboratory platforms and is currently expensive. Conventional cytology demonstrated moderate sensitivity (44–78%) but high specificity (91–96%) and requires adequate health care infrastructure, laboratory-based, stringent training, and quality control measures. Colposcopy sensitivity was low (44–77%), with moderate specificities (85–90%), and is generally expensive to source and maintain with good clinical training skill requirements to perform it.[39] [40]

Performances of the three screening tests among the HIV-positive women population showed comparable measures of accuracy of performing these tests. In a study of cervical cancer screening among HIV-positive women in India, sensitivity for VIA, cytology at ASCUS threshold, and HPV testing was 83.6, 63.3, and 94.6%, and specificity in detecting CIN2/3 lesions was 88.8, 94.5, and 77.4%, respectively.[27] Another study from western India which evaluated VIA and cervical cytology among HIV-positive women with composite disease ascertainment by colposcopy and/or histopathology, the sensitivity, specificity, and PPV, and NPV estimates at the CIN2 and above disease threshold for VIA were 80, 82.6, 47.6, and 95.4 respectively, compared to 60.5, 64.6, 24.8, and 89.4%-for LSIL and above cutoff on cytology, and 20.9, 96.0, 50.0, 86.3%-for HSIL and above cutoff on cytology, respectively.[34] A study from Nigeria reported sensitivity, specificity, and PPV of VIA as 76.0, 83.0, and 34.0%-and those of cervical cytology as 57.0, 95.0, and 55.0% (95% CI 33.0–75.0), respectively.[41] Our study findings add to the existing available literature by providing evidence on comparable test characteristics of three screening modalities and independent diagnostic assessment by colposcopy on limiting verification bias in resource-constrained settings. Here, histopathology services are not always available.

The incidence of cervical cancer is high among HIV-infected women, particularly in countries where there are no organized cervical cancer prevention programs. HPV-related cancers are likely to remain an important problem in HIV-infected women for the foreseeable future, even among those on effective ART.[42] In the call to action to eliminate cervical cancer as a public health problem, WHO has initiated Guideline Development Group for “Initiation and frequency of screening of cervical pre-cancer lesions in women with HIV” in March 2020. Reaching vulnerable women with HIV infection at the high risk of developing cervical cancer will need prioritization of preventive screening and treatment services to be integrated with STD/HIV testing centers. In countries which are low on resources, the screening intervals will depend on financial, infrastructural, and other resources. The guideline indicates that the screening interval for repeat screening should be within 3 years for women who are of HIV-positive status or unknown HIV status in areas with high endemic HIV infection. Our study results provide good evidence of the feasibility of VIA as a primary screening modality for ease and cost of administration.

In a first “real-world” demonstration in a public sector, implementation program in Zambia, in sub-Saharan Africa, successfully showed the integration of delivering cervical cancer screening services, in vertical health initiatives like HIV/AIDS care programs as a routine health care service.[43] Similar efforts of the exploration of adoption and implementation of cervical cancer screening in STD clinics were successfully demonstrated by strategical adaptation of addressing staff concerns, training, specific protocol adaptation, and resource allocation to facilitate greater staff adoption of cervical cancer screening.[44] Centers for Disease Control and Prevention, United States, has provided algorithms for screening and management of women for STD clinics offering cervical screening services to have protocols in place for follow-up of test results and referral.[45]

Limitations

A retrospective study has its own limitations of generalizability of the study findings to similar high-risk populations and parameters applied in the context of the present analysis. The study was performed at a single tertiary cancer care center; hence, our results might not truly represent other health care models in general public health care settings. Owing to our retrospective design, we were unable to capture other important determinants related to HIV health care parameters including treatment that might impact some of the findings for cervical screening among HIV-positive women. Also, in this retrospective study design, true-positive disease of CIN 2 and above lesions were determined by diagnostic investigation of colposcopy that was offered to all participants and directed biopsies in cases of colposcopic abnormalities. Thus, the possibility of misclassification of disease outcomes due to subjective interpretations in colposcopy cannot be entirely ruled out. However, the retrospective study findings may form the basis for conducting larger longitudinal studies to evaluate low-cost cervical cancer screening technologies and implementation research studies to evaluate the feasibility of implementing cervical cancer screening in STD/HIV/AIDS ICTC in government public health care settings in India.

Conclusions

Our study's findings strongly highlight the need for cervical cancer screening among the high-risk group of women living with HIV. Adoption and uptake of the cervical cancer screening services by this high-risk group could be improved by integrating the same with STD/HIV testing and counseling clinics established under the National AIDS Control Program. Irrespective of the HIV status of women attending STD/HIV clinics, implementing cervical cancer screening in STD/HIV clinic settings has immense public health implications for increasing the reach for cervical cancer screening. This is due to these clinics providing a single-window opportunity to symptomatic women who are presenting to the clinic, to screen for cervical cancer in the same/single visit since women are unlikely to revisit for preventive screening activities. Also, women receiving ART visit these clinics on a regular basis, which can help the continuity of care needed for cervical cancer screening and referrals for treatment if needed. Our results need replication in STD/HIV/AIDS testing and counseling services settings and if proven generalizable can be included in policy and programmatic implications for integration into these services where they are currently nonexistent.

Conflict of Interest

None declared.

Acknowledgments

We thank medical social workers, Ms. Parishi Majmudar, Mr. Ashok Patil, and Ms. Bhakti Kabre, for providing pre- and post-counseling services to HIV-positive women. We are grateful to Mr. Suresh Raibhatanavar and Ms. Nicole Aguirre for helping in data retrieval and analysis. We are thankful to Ms. Rupa Sarwaiya and Ms. Darshana Rane for entering the data.

Acknowledgments

This manuscript has been read and approved by all the authors and represents honest work.

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Publication History

Article published online:
27 February 2022

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