Abstract
Objectives
We sought to determine the clinical performance of visual inspection with acetic acid (VIA), digital cervicography (DC), Xpert HPV, and OncoE6 for cervical cancer screening in an HIV-infected population.
Methods
HIV-infected women 18 years and older were included in this cross-sectional validation study conducted in Lusaka, Zambia. The screening tests were compared to a histological gold standard. We calculated sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and odds ratios using cervical intra-epithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) thresholds.
Results
Between January and June 2015, 200 women were enrolled. 15% were screen positive by VIA, 20% by DC, 47% by Xpert HPV, and 6% by OncoE6. Using a CIN2+ threshold, the sensitivity and specificity of VIA was 48% (95% confidence interval [CI]: 30-67%) and 92% (95% CI: 86-95%), respectively. Similarly, the sensitivity and specificity of DC was 59% (95% CI: 41-76%) and 88% (95% CI: 82-93%). The sensitivity and specificity of Xpert HPV was 88% (95% CI: 71-97%), and 60% (95% CI: 52-68%). Finally, the sensitivity and specificity of OncoE6 was 31% (95% CI: 16-50%) and 99% (95% CI: 97-100%).
Conclusions
VIA and DC displayed moderate sensitivity and high specificity. Xpert HPV performed equivalently to currently approved HPV DNA tests, with high sensitivity and moderate specificity. OncoE6 displayed excellent specificity but low sensitivity. These results confirm an important role for VIA, DC, and Xpert HPV in screen-and-treat cervical cancer prevention in low- and middle-income countries, such as Zambia.
Keywords: Cervical cancer screening, HIV, clinical performance validation, visual screening, molecular screening, low- and middle-income countries
Introduction
Invasive cervical cancer (ICC) is responsible for much of the cancer-related morbidity and mortality among women worldwide, with approximately 85% of the disease burden occurring in low- and middle-income countries (LMICs).1,2 HIV-infected women are at increased risk of persistent high-risk HPV (hrHPV) infection and cervical cancer precursors, as well as a more rapid progression from cancer precursors to ICC.3,4
The vast majority of cervical cancers can be prevented by vaccination against HPV, the principal cause of cervical cancer, and by organized, population-based cervical cancer screening.5 Comprehensive national programs to promote and provide HPV vaccination and cervical cancer screening are urgently needed in sub-Sarahan Africa, Southeast Asia, and Latin America. Evaluation of cost-effective and scalable cervical cancer screening and treatment modalities is also of central importance in settings of high disease burden, including in Zambia where the age-standardized incidence of cervical cancer is above 30 per 100,0006 and the prevalence of HIV among adults aged 15-49 years is 13%.7
The cost-effectiveness and scalability of visual inspection with acetic acid (VIA) have previously been established in various LMIC settings.5,8-10 However, the test's sensitivity is moderate.11 Molecular cervical cancer screening – based on the detection of HPV DNA, RNA, or oncoproteins – has the potential to overcome some of the shortcomings of VIA. While molecular testing was once thought to be cost and resource prohibitive for LMICs, newer tests are cheaper, available for use at the point of care, and vastly simplified. These advancements enable molecular tests to be more easily integrated into screening algorithms in a wide range of settings.
We included 2 such molecular tests in our validation study: Xpert HPV and OncoE6. Xpert HPV is a rapid HPV DNA test run on the Cepheid GeneXpert platform, and has a turn-around-time (TAT) of ∼ 60 minutes. The Arbor Vita OncoE6 test, which detects the presence of the HPV E6 oncoprotein, a protein upregulated in ICC and cancer precursors, has a TAT of ∼ 90 minutes. The objective of our study was to determine the clinical performance (i.e., sensitivity, specificity, positive predictive value, and negative predictive value) of VIA, digital cervicography (DC), Xpert HPV, and OncoE6 for cervical cancer screening in HIV-infected women. The screening tests were compared to a histological gold standard using both cervical intra-epithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) thresholds.
Methods
Study design and setting
We conducted a cross-sectional clinical performance validation of 4 cervical cancer screening tests: 2 visual and 2 molecular. Our study clinic was co-located with a Cervical Cancer Prevention Program in Zambia (CCPPZ) clinic on the campus of the University Teaching Hospital in Lusaka, Zambia. Since its inception in 2006, CCPPZ has implemented cervical cancer screening based on a “see-and-treat” approach, where women undergo visual screening, followed by immediate ablation with cryotherapy or cold coagulation (thermocoagulation), or referral for biopsy. CCPPZ has screened over 300,000 women through see-and-treat services provided within the public clinics and is integrated within the PEPFAR-supported HIV care and treatment infrastructure.12,13 Trained nurses apply acetic acid to the cervix (VIA), looking with the naked eye for acetowhite changes and vascular abnormalities. In our setting, VIA is routinely augmented with DC, which uses digital photographs captured with a commercial brand camera for magnification, patient education, telemedicine support, and quality assurance.14-16
Study population and procedures
Women attending the CCPPZ screening clinic were invited to participate in our study. HIV-infected women 18 years and older were eligible for inclusion. Pregnant women were excluded. After written informed consent, demographic and clinical information was collected on standardized case report forms. All participants then underwent pelvic examination with cervical samples for Xpert HPV (GeneXpert, Cepheid, 2014, Sunnyvale, CA, USA) and OncoE6 (Arbor Vita, 2013, Fremont, CA, USA) collected using a cytobroom and placed in ThinPrep solution (Hologic, 2005, Marlborough, MA, USA). Thinprep collection was followed by VIA and then DC, after which all participants underwent two-quadrant cervical biopsies to obtain tissue specimens for histology.17 For those with acetowhite changes, cervical biopsies were obtained from areas of the transformation zone that appeared abnormal (i.e., the worst-appearing lesions). For women with no acetowhite changes, biopsies were obtained from 6 and 12 o'clock. Biopsy specimens were placed in 10% buffered formalin. Finally, blood samples were collected for HIV plasma viral load and CD4+ count testing.
VIA and DC results were communicated to participants during the initial study visit. Women returned 2-4 weeks after the initial visit to receive their histology results, HIV viral load, and CD4+ count, as well as additional treatment recommendations. (The results of the Xpert HPV and OncoE6 tests were not communicated to participants, nor were they incorporated into recommendations for clinical management, as neither test has been approved for clinical use in Zambia.) In accordance with CCPPZ clinical guidelines, those diagnosed with CIN1+ were referred to the CCPPZ clinic for further management of CIN, with either ablative or excisional treatment, or to the University Teaching Hospital or Cancer Diseases Hospital for further management of ICC. Women with no intra-epithelial lesion or malignancy (NILM) seen on histology were counseled to return for routine screening in 3 years. With the woman's permission, HIV viral load and CD4+ cell count results were also communicated to her HIV treatment clinic.
Laboratory testing
Cervical Thinprep (Hologic, 2005, Marlborough, MA, USA) samples were transported from the study clinic to the Centre for Infectious Disease Research in Zambia (CIDRZ) Central Laboratory and stored at room temperature for ∼ 90 days before testing by Xpert HPV and OncoE6 in accordance with the manufacturers' instructions. The Xpert HPV test (GeneXpert, Cepheid, 2014, Sunnyvale, CA, USA) carries out multiplexed amplification of target DNA by real-time PCR of 13 hrHPV types and 1 possible hrHPV type (HPV66) in a single cartridge-based analysis. Xpert HPV identifies HPV16 and HPV18/45 in two distinct detection channels and reports 11 other HPV types (HPV31/33/35/39/51/52/56/58/59/66/68) as a pooled result. A human reference gene (hydroxymethylbilane synthase [HMBS]), which confirms sample adequacy, and internal probe checks are integrated within the test cartridge. The OncoE6 test (Arbor Vita, 2013, Fremont, CA, USA) is based on the capture and detection of E6 proteins from HPV16 and HPV18 using high-affinity monoclonal antibodies in a lateral-flow assay. The E6 proteins are detected by an alkaline phosphatase-conjugated monoclonal antibody, and a positive result is visualized by the addition of an enzyme substrate.
Cervical biopsies stored in formalin were transported to the Cancer Disease Hospital Pathology Department, embedded in paraffin, sectioned, stained with hemotoxylin and eosin, and read by a certified pathologist to determine the histologic diagnosis. Blood samples collected in EDTA tubes were transported to the CIDRZ Central Laboratory on the day of collection. Plasma was isolated from the blood samples and analyzed for HIV-1 viral load and CD4+ cell counts. Viral load was measured using the Cobas Ampliprep/Taqman platform (Roche Molecular Diagnostics, 2007, Pleasanton, CA, USA) and CD4+ cell count using an FC500 flow cytometer (Beckman Coulter, 2004, Pasadena, CA, USA) according to the manufacturers' recommendations.
Statistical analysis
Demographic, clinical, and laboratory data were entered into a custom-built database. Data were cleaned in MS Excel (Microsoft, 2015, Redmond, WA, USA) and exported to Stata version 12.1 (StataCorp, 2012, College Station, TX, USA) for analysis. Our primary outcome was clinical performance (sensitivity, specificity, PPV, NPV) of VIA, DC, Xpert HPV, and OncoE6 for identification of CIN2+. Our secondary outcomes included clinical performance of the tests for CIN3+, as well as likelihood ratios (LRs), odd ratios (ORs), and number needed to screen.
Descriptive analysis included generating frequencies, measures of central tendency, and measures of variability for demographic and clinical variables. Missingness was also assessed for each variable. We then calculated the sensitivity, specificity, PPV, and NPV of all 4 screening tests for identification of both CIN2+ and CIN3+. The point estimates of these parameters are reported with corresponding 95% confidence intervals (CIs). For each of the screening tests, we also determined the positive and negative LRs and the odds of CIN2+ or CIN3+ among women who were screen positive compared to those who were screen negative. Once again, point estimates of the LRs and ORs are reported with corresponding 95% CIs.
Ethics statement
Regulatory approval was provided by the University of Zambia's Biomedical Research Ethics Committee and the University of North Carolina at Chapel Hill's Institutional Review Board. All participants provided written informed consent.
Role of the funding source
Financial support was provided through the National Cancer Institute Award 1D43CA153784, the Fogarty International Center Award R25TW009340 to the UNC Hopkins Morehouse Tulane Fogarty Global Health Fellows Program, and a Fulbright-Fogarty Fellowship Award. The funding agencies had no role in the study design, data collection, analysis, interpretation of findings, and manuscript writing, or in the decision to submit the manuscript for publication.
Results
Characteristics of the study participants
Between January and June 2015, 200 eligible HIV-infected women were enrolled. The median age of women in the study was 42 years (interquartile range [IQR]: 34-47). Roughly half of the participants had completed at least some secondary school education (47%) and were married to or cohabiting with their primary partner (47%) (Table 1).
Table 1. Descriptive characteristics of the study participants.
| Total (N, %) | |
|---|---|
| Age (n=200), median years (IQR) | 42 (34-47) |
| Education (n=200) | |
| No education | 1 (1%) |
| Primary education | 48 (24%) |
| Secondary education | 93 (47%) |
| Tertiary education | 58 (29%) |
| Marital status (n=200) | |
| Never married | 21 (11%) |
| Married/cohabiting | 93 (47%) |
| Divorced/separated | 30 (15%) |
| Widowed | 56 (28%) |
| Tobacco use (n=199) | |
| Yes | 10 (5%) |
| Age at sexual debut (n=186), median (IQR) | 18 (16-20) |
| Lifetime sexual partners (n=188), median (IQR) | 3 (2-5) |
| Number of pregnancies (n=197), median (IQR) | 3 (2-5) |
| Vaginal cleansing (n=196) | |
| Yes | 27 (14%) |
| Prior cervical screening (n=194) | |
| Yes | 90 (46%) |
| On antiretroviral therapy (n=199) | |
| Yes | 179 (90%) |
| CD4+ cell count (n=), median cells/uL (IQR) | 456 (328-590) |
| HIV plasma viral load (n=200) | |
| <20 copies/mL | 153 (77%) |
IQR: interquartile range
Participants were asked to provide a brief gynecologic and sexual history. The median age of sexual debut was 18 years (IQR: 16-20) and the median number of lifetime sexual partners was 3 (IQR: 2-5). Although vaginal “cleansing” with herbs, detergents, cloth, and similar items is thought to be common in settings like Zambia, only 27 (14%) women reported this practice. Encouragingly, 90 (46%) participants reported prior cervical cancer screening by VIA, 179 (90%) were receiving antiretroviral therapy (ART), and 153 (77%) had an HIV viral load < 20 copies/mL. The median CD4+ cell count was 456 cells/uL (IQR: 328-590). Despite the overwhelming majority of women receiving ART and being virologically suppressed, however, the burden of cervical disease in this population was high. Six (3%) women were diagnosed with ICC. Additionally, 14 (7%) women had CIN3, 12 (6%) had CIN2, and 35 (18%) had CIN1.
Screening test positivity
Twenty-nine (15%) women were screen positive by VIA, 30 (20%) by DC, 94 (47%) by Xpert HPV, and 11 (6%) by OncoE6. The Xpert HPV test also provided results for HPV16 and HPV18/45, for which 29 (15%) and 22 (11%) women were positive, respectively. Using OncoE6, 9 (5%) women were HPV16 positive and 3 (2%) HPV18 positive. There were no statistically significant differences in the proportion of screen positive women by ART status (Table 2).
Table 2. Screening test positivity for VIA, DC, Xpert HPV, and OncoE6 by antiretroviral status.
| Total | On antiretroviral therapy | Not on antiretroviral therapy | |
|---|---|---|---|
| VIA (n=199) | |||
| Positive | 29 (15%) | 24 (14%) | 5 (25%) |
| DC (n=200) | |||
| Positive | 39 (20%) | 33 (18%) | 6 (30%) |
| Xpert HPV (n=199) | |||
| Any hrHPV positive | 94 (47%) | 82 (46%) | 12 (60%) |
| HPV16 positive | 29 (15%) | 26 (15%) | 3 (15%) |
| HPV18/45 positive | 22 (11%) | 20 (11%) | 2 (10%) |
| HPV31/33/35/52/58 positive | 64 (32%) | 54 (30%) | 10 (50%) |
| HPV51/59 positive | 14 (7%) | 13 (7%) | 1 (5%) |
| HPV39/68/56/66 positive | 18 (9%) | 15 (8%) | 3 (15%) |
| OncoE6 (n=200) | |||
| Any hrHPV positive | 11 (6%) | 11 (6%) | 0 |
| HPV16 positive | 9 (5%) | 9 (5%) | 0 |
| HPV18 positive | 3 (2%) | 3 (2%) | 0 |
VIA: visual inspection with acetic acid; DC: digital cervicography;
p<0.05;
p<0.01;
p<0.001
Clinical performance using a CIN2+ threshold
Using a CIN2+ threshold, the sensitivity and specificity of VIA was 48% (95% CI: 30-67%) and 92% (95% CI: 86-95%), respectively. Similarly, the sensitivity and specificity of DC was 59% (95% CI: 41-76%) and 88% (95% CI: 82-93%). The sensitivity and specificity of Xpert HPV was 88% (95% CI: 71-97%) and 60% (95% CI: 52-68%). The sensitivity and specificity of OncoE6 was 31% (95% CI: 16-50%) and 99% (95% CI: 97-100%) (Table 3).
Table 3. Clinical performance of the cervical cancer screening tests using a CIN2+ threshold.
| VIA | DC | Xpert HPV | OncoE6 | |
|---|---|---|---|---|
| True positive | 15 | 19 | 28 | 10 |
| False positive | 14 | 20 | 66 | 1 |
| True negative | 153 | 147 | 100 | 166 |
| False negative | 16 | 13 | 4 | 22 |
| Sensitivity (95% CI) | 48% (30-67%) | 59% (41-76%) | 88% (71-97%) | 31% (16-50%) |
| Specificity (95% CI) | 92% (86-95%) | 88% (82-93%) | 60% (52-68%) | 99% (97-100%) |
| PPV (95% CI) | 52% (33-71%) | 49% (32-65%) | 30% (21-40%) | 91% (59-100%) |
| NPV (95% CI) | 91% (85-95%) | 92% (87-96%) | 96% (90-99%) | 88% (83-93%) |
| PLR (95% CI) | 10 (4-25) | 5 (3-8) | 2 (2-3) | 52 (7-394) |
| NLR (95% CI) | 0.6 (0.4-0.8) | 0.5 (0.3-0.7) | 0.2 (0.1-0.5) | 0.7 (0.5-0.9) |
| OR (95% CI) | 10 (4-25) | 11 (4-25) | 11 (4-30) | 76 (12-.) |
VIA: visual inspection with acetic acid; DC: digital cervicography; 95% CI: 95% confidence interval; PPV: positive predictive value; NPV: negative predictive value; PLR: positive likelihood ratio; NLR: negative likelihood ratio; OR: odds ratio
Compared to women who were screen negative, the odds of CIN2+ was 10 times higher among women who were VIA positive (95% CI: 4-25), and 11 times higher among those DC positive (95% CI: 4-25) and Xpert HPV positive (95% CI: 4-30). Additionally, we determined that to detect 1 case of CIN2+, 13 women would need to be screened by VIA, 11 women by DC, 7 by Xpert HPV, and 20 by OncoE6.
Clinical performance using a CIN3+ threshold
Using a CIN3+ threshold, the sensitivity and specificity of VIA was 63% (95% CI: 38-84%) and 91% (95% CI: 85-94%), respectively. Similarly, the sensitivity and specificity of DC was 75% (95% CI: 51-91%) and 87% (95% CI: 81-91%). The sensitivity and specificity of Xpert HPV was 90% (95% CI: 68-99%) and 57% (95% CI: 48-65%). Finally, the sensitivity and specificity of OncoE6 was 40% (95% CI: 19-64%) and 98% (95% CI: 95-100%).
The results of the likelihood ratio analysis for CIN3+ were similar to those obtained using a CIN2+ threshold. However, the confidence intervals were wider because we had relatively few cases of CIN3+ (Table 4). The calculation of the number needed to screen also showed a similar trend, such that to detect 1 case of CIN3+ 17 women would need to be screened by VIA, 13 women by DC, 11 by Xpert HPV, and 25 by OncoE6.
Table 4. Clinical performance of the cervical cancer screening tests using a CIN3+ threshold.
| VIA | DC | Xpert HPV | OncoE6 | |
|---|---|---|---|---|
| True positive | 12 | 15 | 18 | 8 |
| False positive | 17 | 24 | 76 | 3 |
| True negative | 162 | 155 | 102 | 176 |
| False negative | 7 | 5 | 2 | 12 |
| Sensitivity (95% CI) | 63% (38-84%) | 75% (51-91%) | 90% (68-99%) | 40% (19-64%) |
| Specificity (95% CI) | 91% (85-94%) | 87% (81-91%) | 57% (48-65%) | 98% (95-100%) |
| PPV (95% CI) | 41% (24-61%) | 39% (23-55%) | 19% (12-29%) | 73% (39-94%) |
| NPV (95% CI) | 96% (92-98%) | 97% (93-99%) | 98% (93-100%) | 94% (89-97%) |
| PLR (95% CI) | 7 (4-12) | 6 (4-9) | 2 (2-3) | 24 (7-83) |
| NLR (95% CI) | 0.4 (0.2-0.7) | 0.3 (0.1-0.6) | 0.2 (0.1-0.6) | 0.6 (0.4-0.9) |
| OR (95% CI) | 16 (6-46) | 19 (7-56) | 12 (3-.) | 39 (10-154) |
VIA: visual inspection with acetic acid; DC: digital cervicography; 95% CI: 95% confidence interval; PPV: positive predictive value; NPV: negative predictive value; PLR: positive likelihood ratio; NLR: negative likelihood ratio; OR: odds ratio
Discussion
Our study confirms a substantial risk of CIN2+ among HIV-infected Zambian women receiving combination ART (cART), nearly half of whom had previously been screened for cervical cancer. Specifically, 3% of women were diagnosed with ICC and 13% with high-grade CIN. It should be noted that the burden of cervical disease in our study was somewhat lower than in previously published Zambian studies, which have reported that ∼30-50% of HIV-infected women are VIA/DC positive,18,19 20% have CIN2+,19 and 53% are hrHPV positive.20 These studies were conducted before cART was widely available in Zambia and before the introduction of the so-called Option B+ strategy (through which the overwhelming majority of HIV-infected women of reproductive age have obtained access to cART regardless of their CD4+ cell count), possibly accounting for the observed differences.
The visual screening tests evaluated (VIA and DC) both displayed moderate sensitivity and high specificity for CIN2+ (sensitivity: 48% and 59%, respectively; specificity: 92% and 88%), which is broadly consistent with previously published validation data.11,15,21 Not surprisingly, Xpert HPV, an HPV DNA PCR assay, demonstrated high sensitivity and moderate specificity for CIN2+ (88% and 60%, respectively). Previous validation studies of the Xpert HPV in the U.S. have yielded similar results, with the initial evaluation (n=141) demonstrating that Xpert HPV was equally sensitive for high-grade squamous intra-epithelial lesions (HSIL) as Cobas HPV (90.8% vs. 90.8%) and more sensitive than Digene HC2 (90.8% vs. 81.6%, p=0.004). Xpert HPV was also more specific than Cobas HPV (42.6% vs. 39.6%, p=0.02) but less specific than Digene HC2 (42.6% vs. 47.7%, p<0.001). Our study adds evidence that Xpert HPV performs well in HIV-infected women and, as expected, appears to have higher PPV for CIN2+ than in HIV-uninfected women.22 Again, not surprisingly, OncoE6, a lateral flow oncoprotein assay, demonstrated high specificity but low sensitivity (99% and 31%, respectively) for CIN2+. This finding was similar to previously published OncoE6 validation data.23
All of the tests we selected for our validation study can be performed at (or near) the point-of-care, a characteristic of great importance when considering which testing modalities to scale in screen-and-treat cervical cancer prevention programs. Same-day screening and treatment services are highly efficient,24 and offer women and providers several advantages. First, they reduce attrition from care, a near-ubiquitous problem in both non-communicable disease care and HIV treatment programs across sub-Saharan Africa.25,26 Second, same-day services have the potential to decrease health care costs, as well as the financial burden that women and their families face when multiple return visits are required to obtain test results, referral, and treatment.
Although well established, it bears repeating that limited access to cervical cancer screening, prevention, and treatment services is among the most important reasons for the disparities in cervical cancer incidence and mortality observed globally between high and low- and middle-income countries, between urban and rural women, and between rich and poor women.27 Screen-and-treat programs can help to address these disparities. We have previously shown that in the CCPPZ VIA/DC see-and-treat program, 1 cancer death is prevented for every 46 HIV-infected women screened (range: 28–68).28 A landmark randomized trial conducted by Denny and colleagues in South Africa also showed that for every 100 women screened, a VIA see-and-treat strategy can prevent 7 cases of CIN2+ among HIV-infected women and 1 case among HIV-uninfected women. Among 100 women screened using an HPV test-and-treat strategy, 12 cases of CIN2+ would be prevented among HIV-infected women and 3 among HIV-uninfected women.29 Encouragingly, the cost-effectiveness of both screen-and-treat approaches has also been confirmed.5,8,24 With the efficacy and cost-effectiveness of screen-and-treat cervical cancer prevention proven, what remains to be seen is how rapidly and how fully global guidance30 can be implemented and scaled to reduce the burden of this preventable cancer, including among HIV-infected individuals who are at the highest risk of cervical disease.
We acknowledge several limitations of our work. As noted above, the burden of cervical disease in our study population was somewhat lower than anticipated, affecting measures of variability, such as 95% confidence intervals. We were also unable to evaluate the other available near-patient HPV DNA test, careHPV, or other FDA-approved HPV tests (e.g., Digene HC2 and Roche Cobas HPV) due to limited commercial availability of these tests in Zambia. Despite these limitations, we anticipate that our work will help to expand the nascent literature on point-of-care molecular diagnostics for cervical cancer screening and to create a foundation for future clinical and implementation science research exploring optimal strategies for HPV-based screening in LMICs.
Conclusions
Among HIV-infected women, VIA and DC displayed moderate sensitivity and high specificity, Xpert HPV high sensitivity and moderate specificity, and OncoE6 excellent specificity but low sensitivity. Based on these results, we recommend that future evaluations of screen-and-treat cervical cancer prevention modalities include HPV DNA testing with the GeneXpert platform, as well as with VIA/DC to determine the comparative effectiveness of these strategies for reducing CIN2+. Due to its poor sensitivity, OncoE6 is not recommended for primary screening, but may be investigated as a triage test. Importantly, we also show that the burden of hrHPV and CIN2+ among HIV-infected Zambian women remains substantial despite rapidly increasing access to cART and measurable improvements in immune function.
Acknowledgments
Disclosure of sources of financial support: Financial support was provided through the National Cancer Institute Award 1D43CA153784, the Fogarty International Center Award R25TW009340 to the UNC Hopkins Morehouse Tulane Fogarty Global Health Fellows Program, and a Fulbright-Fogarty Fellowship Award. The funding agencies had no role in the study design, data collection, analysis, interpretation of findings, and manuscript writing, or in the decision to submit the manuscript for publication.
List of all abbreviations and acronyms
- ART
Antiretroviral therapy
- cART
Combination antiretroviral therapy
- CCPPZ
Cervical cancer prevention program in Zambia
- CI
Confidence interval
- CIDRZ
Centre for Infectious Disease Research in Zambia
- CIN
Cervical intra-epithelial neoplasia
- DC
Digital cervicography
- DNA
Deoxyribonucleic acid
- FDA
Food and Drug Administration
- HC2
Hybrid Capture 2
- HIV
Human immunodeficiency virus
- HMBS
Hydroxymethylbilane synthase
- HPV
Human papillomavirus
- hrHPV
High-risk human papillomavirus
- ICC
Invasive cervical cancer
- IQR
Interquartile range
- LMICs
Low- and middle-income counties
- LR
Likelihood ratio
- mL
Milliliter
- NILM
No intra-epithelial lesion or malignancy
- NPV
Negative predictive value
- OR
Odds ratio
- PEPFAR
President's Emergency Plan for AIDS Relief
- PPV
Positive predictive value
- RNA
Ribonucleic acid
- SIL
Squamous intra-epithelial lesion
- uL
Microliter
- VIA
Visual inspection with acetic acid
Footnotes
Conflict of interest statement: The authors declare that there are no conflicts of interest regarding the publication of this paper.
IRB status: This study was approved by the Biomedical Research Ethics Committee of the University of Zambia (Lusaka, Zambia) and Institutional Review Board of University of North Carolina at Chapel Hill (Chapel Hill, NC, USA). All participants provided written informed consent.
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