AIDS

Primary HPV screening compared with other cervical cancer screening strategies in women with HIV: a cost-effectiveness study

Objective: To compare the model-predicted benefits, harms, and cost-effectiveness of cytology, cotesting, and primary HPV screening in US women with HIV (WWH). Design: We adapted a previously published Markov decision model to simulate a cohort of US WWH. Setting: United States. Subjects, participants: A hypothetical inception cohort of WWH. Intervention: We simulated five screening strategies all assumed the same strategy of cytology with HPV triage for ASCUS for women aged 21–29 years. The different strategies noted are for women aged 30 and older as the following: continue cytology with HPV triage, cotesting with repeat cotesting triage, cotesting with HPV16/18 genotyping triage, primary hrHPV testing with cytology triage, and primary hrHPV testing with HPV16/18 genotyping triage. Main outcome measure(s): The outcomes include colposcopies, false-positive results, treatments, cancers, cancer deaths, life-years and costs, and lifetime quality-adjusted life-years. Results: Compared with no screening, screening was cost-saving, and >96% of cervical cancers and deaths could be prevented. Cytology with HPV triage dominated primary HPV screening and cotesting. At willingness-to-pay thresholds under $250 000, probabilistic sensitivity analyses indicated that primary HPV testing was more cost-effective than cotesting in over 98% of the iterations. Conclusions: Our study suggests the current cytology-based screening recommendation is cost-effective, but that primary HPV screening could be a cost-effective alternative to cotesting. To improve the cost-effectiveness of HPV-based screening, increased acceptance of the HPV test among targeted women is needed, as are alternative follow-up recommendations to limit the harms of high false-positive testing.

Cervical cancer screening integrated in routine clinical care of women with HIV

Objective: To evaluate if integrated cervical cancer screening (CCS) for women with HIV (WWH) in routine HIV care resulted in increased adherence to screening, and to describe the prevalence of human papillomavirus (HPV)-specific genotypes and the incidence of cellular abnormalities. Design: Cohort study. Methods: WWH who accepted the offer of combined CCS and HIV care (group 1), WWH who declined the offer (group 2), and WWH not offered CCS within HIV care (group 3) between 2013 and 2019 were included. Data was collected from The Danish HIV Cohort Study and The Danish Pathology Data Bank. Adherence to the CCS program was defined as fulfilled if WWH were screened annually. Results: A total of 804 WWH were included. WWH who accepted CCS within HIV care (group 1; n = 218) had significantly higher adherence to screening in all study years 22–99% compared with the WWH who declined CCS (group 2; n = 232) 10–16% and WWH who were not invited for CCS (group 3; n = 354) 11–25%. There was no significant difference in the prevalence of HPV-specific genotypes and incidence of cellular abnormalities among the three groups. Conclusion: Integrating CCS for WWH in routine HIV care resulted in higher adherence to the CCS guidelines. Combined services thereby represent an opportunity to engage WWH in HIV care into preventive services.

Cervical cancer screening in women with HIV: an audit of clinical care

Objectives: Women with HIV (WHV) have an increased prevalence of cervical cancer and are recommended three yearly cervical cancer screening. This is compared with five yearly screening their counterparts. We aimed to describe cervical cancer screening practices for WHV receiving HIV care at a large tertiary hospital. Methods: We performed a retrospective audit on all women who were in HIV care up until January 2023 at the Alfred Hospital, a tertiary hospital in Melbourne, Australia, specializing in HIV care. Cervical cancer screening results for Medicare eligible people are recorded in The National Cervical Cancer Screening Register (NCCSR) and these were extracted for women in care. Screening was categorized as up-to-date and consistent with national screening guidelines or overdue. Results: We identified 156 WHV in care of which 115 were included in the analysis. Of these, 57 (49.6%) had cervical screening on time and consistent with national guidelines, including 49 (86%) who had a normal last result and 8 (14%) with an abnormal last result. Half the women, 58 (50.4%) were overdue screening. Of those overdue, 52 (89.7%) were more than 6 months and 45 (76.3%) were more than 12 months overdue. Among the women overdue, 47 (81%) had a normal last result and 7 (12.1%) an abnormal last result. Conclusion: We found that over half of the women included were overdue for their cervical screening test, with the vast majority being overdue by more than twelve months. Improved access to cervical cancer screening is needed in this population to achieve national guidelines targets.

Achieving maternal viral load suppression for elimination of mother-to-child transmission of HIV in South Africa

Objective: To describe changes in maternal viral control over time in South African women living with HIV (WLHIV) using surveillance data from the National Health Laboratory Service's Corporate Data Warehouse (NHLS CDW). Design: A retrospective cohort analysis of maternal viral load during pregnancy and up to 15 months postpartum was performed amongst WLHIV (15–49 years) within the public-health sector between 2016 and 2017. Methods: HIV and pregnancy-related test data were used to create a synthetic cohort of pregnant WLHIV from the NHLS CDW. Syphilis-screening, in association with ward type and/or postpregnancy cervical screening and/or birth HIV test and/or positive β-hCG, was used as a proxy for pregnancy. The syphilis-screening date marked the first antenatal care visit (fANC). Fractional polynomial models described viral load evolution from fANC up to 15 months postdelivery. Piecewise linear regression models determined factors associated with viral load decline. Findings: Among 178 319 pregnant WLHIV, 345 174 viral load tests were performed [median = 2 (IQR: 2–3) per woman]. At fANC, 85 545 (48%) women were antiretroviral therapy (ART) experienced; 88 877 (49.8%) were not and 3897 (2.2%) unknown. Proportions of viraemia (viral load ≥50 copies/ml) were 39 756 (53.6%) at first viral load performed during pregnancy, 14 780 (36.9%) at delivery and 24 328 (33.5%) postpartum. Maternal age at least 25 years, CD4+ cell count at least 500 cells/μl and viral load less than 50 copies/ml at baseline predicted sustained viral load suppression during follow-up. Conclusion: Despite high-ART coverage among pregnant women in South Africa, only 63% of WLHIV achieved viral load less than 50 copies/ml at delivery. Maternal viral load monitoring requires prioritization for maternal health and eMTCT.

High-risk human papillomavirus genotype distribution among women living with and at risk for HIV in Africa

Objective: Cervical cancer is a common preventable cancer among African women living with HIV (WLWH). Molecular diagnostics for high-risk human papillomavirus (HR-HPV) genotypes are standard components of cervical cancer screening in resource-rich countries but not in resource-limited settings. We evaluated HR-HPV genotypes among women with and without HIV in four African countries to inform cervical cancer preventive strategies. Methods: The African Cohort Study (AFRICOS) enrolled participants with and without HIV at 12 clinics in Tanzania, Kenya, Uganda, and Nigeria. Cervical cytobrush specimens from women were genotyped for 14 HR-HPV types using the multiplex Seegene Anyplex real-time PCR assay. Robust Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with HR-HPV in WLWH. Results: From January 2015 to March 2020, 868 WLWH and 134 women living without HIV (WLWoH) were tested for HR-HPV with prevalence of 50.9 and 38.1%, respectively (P = 0.007). Among WLWH, 844 (97.4%) were antiretroviral therapy (ART)-experienced and 772 (89.7%) virally suppressed 1000 copies/ml or less. The most frequent HR-HPV types among WLWH were HPV-16 (13.5%), HPV-52 (9.5%), and HPV-35 (9.3%). HR-HPV infection was more common among Tanzanian WLWH (adjusted RR: 1.23, 95% CI 1.05–1.44, P = 0.012). Also, WLWH with CD4+ T cells of less than 200 cell/μl had 1.51-fold increased risk of having HR-HPV (95% CI 1.23–1.86, P < 0.001). Conclusion: HR-HPV was common in WLWH in four African countries, particularly among women with low CD4+ cell count. Scale up of HPV vaccines and development of vaccines with broader activity against less common HR-HPV types may improve cervical cancer prevention in Africa.

Cervical cancer incidence stratified by age in women with HIV compared with the general population in the United States, 2002–2016

Objective: Recommendations for the age of initiating screening for cervical cancer in women with HIV (WWH) in the United States have not changed since 1995 when all women (regardless of immune status) were screened for cervical cancer from the age of onset of sexual activity, which often occurs in adolescence. By 2009, recognizing the lack of benefit as well as harms in screening young women, guidelines were revised to initiate cervical cancer screening for the general population at age 21 years. By comparing cervical cancer incidence in young WWH to that of the general population, we assessed the potential for increasing the recommended age of initiating cervical cancer screening in WWH. Design: We compared age-specific invasive cervical cancer (ICC) rates among WWH to the general population in the United States HIV/AIDS Cancer Match Study. Methods: We estimated standardized incidence ratios as the observed number of cervical cancer cases among WWH divided by the expected number, standardized to the general population by age, race/ethnicity, registry, and calendar year. Results: ICC rates among WWH were elevated across all age groups between ages 25 and 54 years (SIR = 3.80; 95% CI 3.48--4.15) but there were zero cases among ages less than 25 years. Conclusion: The absence of ICC among WWH less than 25 years supports initiating cervical cancer screening at age 21 years, rather than adolescence, to prevent cancers in WWH at ages with higher risk of ICC.

Posttreatment monitoring by ASCL1/LHX8 methylation analysis in women with HIV treated for cervical intraepithelial neoplasia grade 2/3

Objective: Women with HIV (WWH) have an increased risk to develop recurrent cervical intraepithelial neoplasia grade 2/3 (rCIN2/3) after treatment compared with HIV-negative women. Therefore, appropriate posttreatment monitoring of WWH is important. This study evaluates the performance of ASCL1 and LHX8 methylation analysis as posttreatment monitoring test in WWH treated for CIN2/3, as alternative to cytology or human papillomavirus (HPV) as follow-up test. Design: Prospective observational cohort study. Methods: WWH treated for CIN2/3 by large loop excision of the transformation zone (LLETZ) (n  = 61) were invited for follow-up study visits at 1, 2.5 and 4 years after baseline. Baseline and follow-up cervical scrapes were tested for cytology, HPV and DNA methylation of ASCL1 and LHX8 genes. The performance of these strategies for the detection of rCIN2/3 was evaluated in the first follow-up cervical scrape. Results: Thirteen (21.3%) rCIN2/3 lesions were detected within 4 years of follow-up. In women without rCIN2/3 in follow-up, methylation levels of ASCL1 and LHX8 decreased significantly after LLETZ treatment (P  = 0.02 and 0.007, respectively). In women with rCIN2/3, methylation levels remained high after LLETZ treatment. The 4-year rCIN2/3 risk was 4.9% (95% CI: 0.6–16.5) for ASCL1/LHX8-negative women, 8.1% (95% CI: 1.7–21.9) for HPV-negative women and 7.7% (95% CI: 2.1–18.5) for cytology-negative women. Conclusion: A negative ASCL1/LHX8 methylation test in follow-up is associated with a low rCIN2/3 risk and could serve as an objective test of cure and well tolerated alternative for HPV and/or cytology screening in the posttreatment monitoring of WWH.

Longitudinal assessment of abnormal Papanicolaou test rates among women with HIV

To describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV. Prospective cohort study with sequential enrollment subcohorts. Four waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994-1995, 2001-2002, 2011-2012, 2013-2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests. The unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001-2002 cohort, 46/231 (20%) in the 2011-2012 cohort, and 71/449 (16%) in the 2013-2015 cohort. In multivariable analysis, compared with risk in the 1994-1995 cohort, the adjusted risk in the 2001-2002 cohort was 0.79 (95% CI 0.59-1.05), in the 2011-2012 cohort was 0.67 (95% CI 0.43-1.04), and in the 2013-2015 cohort was 0.41 (95% CI 0.27-0.62) with P for trend less than 0.0001. Rates of abnormal cytology among women with HIV have fallen during the past two decades.

Human papillomavirus infection and cervical dysplasia in HIV-positive women

To assess the associations between microbiological markers of vaginal dysbiosis and incident/cleared/type-swap/persistent high-risk human papillomavirus (hrHPV) infection; and incident/cured/cleared/persistent high-grade cervical intraepithelial neoplasia (CIN2+) while controlling for persistent hrHPV infection. Two nested case-control studies (N = 304 and 236) within a prospective cohort of HIV-positive women in Johannesburg, South Africa. Participants were examined for hrHPV type (INNO-LiPA), cervical dysplasia (histology), and vaginal microbiota (VMB) composition (V3-V4 Illumina HiSeq 2x300 bp) at baseline and endline, a median of 16 months later. Women with incident hrHPV compared to those who remained hrHPV-negative were less likely to have an optimal Lactobacillus crispatus or jensenii-dominated VMB type at end-line [relative risk ratio (RRR) 0.125, P = 0.019], but not at baseline. Having different hrHPV types at both visits was associated with multiple anaerobic dysbiosis markers at baseline (e.g. increased bacterial vaginosis-associated anaerobes relative abundance: RRR 3.246, P = 0.026). Compared to women without CIN2+, but with hrHPV at both visits, women with incident CIN2+ had increased Simpson diversity (RRR 7.352, P = 0.028) and nonsignificant trends in other anaerobic dysbiosis markers at end-line but not baseline. These associations persisted after controlling for age, hormonal contraception, and CD4 cell count. Current hormonal contraceptive use (predominantly progestin-only injectables) was associated with increased CIN2+ risk over-and-above persistent hrHPV infection and independent of VMB composition. hrHPV infection (and/or increased sexual risk-taking) may cause anaerobic vaginal dysbiosis, but a bidirectional relationship is also possible. In this population, dysbiosis did not increase CIN2+ risk, but CIN2+ increased dysbiosis risk. The CIN2+ risk associated with progestin-only injectable use requires further evaluation.

Nonvaccine human papillomavirus genotype common in women with HIV failing cervical precancer treatment

Objective: The aim of this study was to assess failure after treatment of high-grade cervical intraepithelial neoplasia (CIN2+) by HIV status and human papillomavirus (HPV) type. Design: A population-based register study. Methods: The Swedish National HIV Registry, the Swedish Population Registry and the Swedish National Cervical Screening Registry were linked to identify all women in Stockholm and Gothenburg counties (Sweden) living with HIV and diagnosed with CIN2+ sometime between 1983 and 2014 (n = 179). HIV-negative controls with CIN2+, were matched (2 : 1) for country of birth. CIN2+ biopsies were retrieved from biobanks and genotyped. Absolute risk and adjusted odds ratios (adjOR) of treatment failure by HIV status given HPV type (HPV16/18 vs. non-HPV16/18) were calculated. Results: HPV16 (32%) and HPV35 (24%) dominated in women living with HIV (WLWH) with failure, HPV35 mainly in women born in sub-Saharan Africa (67%). The absolute risk of failure in women with HPV16/18 was 26% [95% confidence interval (95% CI) 14–44] in WLWH and 12% in HIV-negative (95% CI 7–19). The absolute risk of failure in women with non-HPV16/18 was 20% (95% CI 12–31) in WLWH and 5% in HIV-negative (95% CI 2–11). WLWH with non-HPV16/18 were six times more likely to fail than HIV-negative (adjOR 6.1, 95% CI 2.0–18.6). Conclusion: HPV35, not included in current HPV vaccines, was the second most common type in WLWH with failure. WLWH with non-HPV16/18 were six times more likely to fail than HIV-negative. This could have implications for surveillance and vaccination post CIN2+ treatment, particularly in WLWH from sub-Saharan Africa.