HIV-infected women are disproportionately affected by cervical cancer. Most studies report a higher prevalence of multiple human papillomavirus (HPV) infections among HIV-infected women with a wide diversity of HPV genotypes, which persist and recur. As a result, compared with women in the general population, HIV-infected women have a higher prevalence of high-grade dysplastic precursor lesions. These lesions, if left untreated, can lead to invasive cervical cancer. Widespread availability of combination antiretroviral therapy (cART) extends the lifespan of HIV-infected women, but they remain at risk for the development of HPV-related cervical disease.
The incidence and mortality rates for cervical cancer have decreased substantially because of organized and timely screening for and treatment of precursor lesions. This benefit has been demonstrated with cytology-based screening programs,1,2 but these programs require substantial infrastructure in laboratory services and clinical care, and multiple visits for women with abnormal results. “Screen and treat” approaches using noncytological methods, such as visual inspection with acetic acid (VIA) or high-risk HPV DNA screening, coupled with outpatient treatment of precancerous lesions with cryotherapy or loop electrosurgical excision procedure (LEEP), are attractive alternatives to cytology-based algorithms, and emerging data suggest that these noncytologic approaches may reduce mortality from cervical cancer in the general population.3,4 Fewer data are available on the utility of these methods in HIV-infected women, and the diagnostic accuracy of visual screening methods and the complication rates of standard outpatient treatment procedures may be different in this population.
Since 2008, the US President's Emergency Paln for AIDS Relief (PEPFAR) has provided support for limited efforts for cervical screening and treatment of precancerous lesions among HIV-infected women. Specific PEPFAR-supported interventions include VIA screening and outpatient treatment of precancerous cervical lesions with cryotherapy or LEEP. The impact of these procedures on important outcomes, such as morbidity and mortality, in HIV- infected women has not been described.
To inform most the efficient use of resources, we conducted a systematic review of the literature to evaluate the impact of VIA screening and outpatient treatment of cervical precursor lesions with cryotherapy or LEEP among HIV-infected women in low- and middle-income countries (LMICs) on 5 outcomes (morbidity, mortality, HIV transmission, retention in HIV care, and quality of life).
We searched MEDLINE, Global Health, Embase, CINAHL, Sociological Abstracts (SOCA), and African Index Medicus (AIM) databases for all citations published between January 1995 and July 2013, which addressed cervical screening with VIA method, or cervical precancer treatment with cryotherapy or with LEEP, among HIV-infected women in LMIC.
Our search used HIV and cervical dysplasia or cancer-related key words and followed the strategy described in the literature review search method in the introductory article to this supplement.5 Search terms for the cervical screening and outpatient precancer treatment interventions fell into 7 categories (key words). These included the following: (1) anatomy (cervix), (2) abnormality (acetowhite lesion, cervical lesion, cervical precancer, cervical dysplasia), (3) malignancy (cancer, cervical cancer), (4) precancer/cancer etiology (human papillomavirus, HPV), (5) screening (screening method, visual inspection with acetic acid, VIA, acetic acid, vinegar, prevention, secondary prevention), (6) precancer treatment method (treatment, cryotherapy, loop electrosurgical excision procedure, LEEP), and (7) cancer prevention approach (“screen and treat,” “see and treat,” “single visit approach”). No language exclusions were applied.
After an initial screen of citation titles and abstracts, full-text copies of the articles eligible for inclusion were reviewed independently by the team, with at least 2 reviewers per article. A title search of references was also performed on these articles to determine other articles that were eligible for inclusion but not identified on the original database search.
Articles met inclusion criteria if they (1) evaluated HIV-infected women, exclusively or within the broader population of women screened (2) were conducted in LMICs, (3) used at least one of the following PEPFAR-supported cervical cancer screening or cervical precancer treatment interventions: VIA, cryotherapy, or LEEP, and (4) reported on at least one of the 5 outcomes of interest (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). No restrictions on study design were imposed. Articles that met inclusion criteria were also scanned for cost-effectiveness and costing information.
Data Extraction/Quality Assessment
From each article that met inclusion criteria, we extracted information about study characteristics, methodological quality—on the basis of study design, internal consistency and generalizability, key findings, and magnitude of effect in a tool developed for this review. Information was extracted by 1 reviewer and independently verified by a second reviewer. Any discrepancies were discussed by the group and resolved by consensus. These methods are described in the introductory article by Kaplan et al5 in this supplement.
Summary of the Body of Evidence
To summarize the body of evidence, we grouped studies by the outcome they addressed. Using criteria agreed on a priori that are described in the introductory article in this supplement, we rated the quality of the body of evidence pertaining to each outcome as good, fair, or poor, evaluated the cost-effectiveness information, and rated the expected impact on of the interventions by outcome as high, moderate, low, or uncertain.5
Our initial database search identified 2159 citations after removal of duplicate citations. Citation titles and abstracts were scanned for possible eligibility. Full-text articles of 135 potentially eligible studies were assessed for inclusion; most did not examine any of the PEPFAR-supported interventions (VIA, cryotherapy, or LEEP) or lacked one of the defined outcomes. Fourteen studies met the review inclusion criteria (Fig. 1).
The 14 studies described data on 11,712 HIV-infected women (see Table S1, Supplemental Digital Content, https://links.lww.com/QAI/A658); however, some of these women may have been included in more than 1 study (patients in the study by Phaendler et al6 were a subset of those evaluated by Parham et al7 and therefore were counted only once). Studies were conducted in 9 countries, including Brazil (1 study), India (1), Kenya (3), Nigeria (1), South Africa (2), Tanzania (1), Thailand (2), Zambia (2), and Zimbabwe (1).
Observational research methods were used in all 14 studies; however, specific study designs were mixed, including 5 cross-sectional, 1 prospective cohort, 3 secondary analyses, 1 case–control, 1 case series, and 3 retrospective descriptive studies.
Of the 5 outcomes of interest (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life), the studies that met inclusion criteria evaluated only topics related to morbidity. Four morbidity-related topics were addressed in the selected studies; some studies evaluated more than one. The specific morbidity-related topics included frequency of cervical dysplasia detection by VIA (6 studies), posttreatment recurrence of dysplasia (3 studies), posttreatment complications (7 studies), and programmatic studies with data describing mass screening (2 studies). Table S1 lists studies by the morbidity-related outcome topic(s) that each addressed (see Supplemental Digital Content, https://links.lww.com/QAI/A658).
Six studies addressed cervical abnormality detection in HIV-infected women using VIA, with abnormal VIA results reported in 28%–55% of women. Five studies used cross-sectional design and compared VIA with other screening methods.8–12 In the studies that compared VIA to colposcopic or histologic findings, VIA sensitivity ranged from 65% to 80% and specificity ranged from 51% to 83%.8–10,12 Sensitivity of VIA was similar or better than that of cytology but VIA specificity was somewhat lower. One study, a secondary analysis of data from the HIV-infected participants in a large randomized controlled trial (RCT), compared outcomes after a “screen and treat” intervention using several screening methods [HPV DNA or VIA or delayed (control) screening] coupled with cryotherapy treatment.13 This analysis described follow-up for up to 36 months. The study showed that HIV-infected women who underwent VIA and cryotherapy had a significant reduction in detection of cervical intraepithelial neoplasia (CIN) 2+ compared with the control group (relative risk = 0.51, 95% confidence interval: 0.29 to 0.89), providing estimation of potential risk reduction for cervical precancer or cancer.
Recurrent cervical dysplasia after either cryotherapy or LEEP treatment was evaluated in 4 studies.13–16 The researchers used different study designs, but identified higher rates of recurrent dysplasia of any grade among HIV-infected women relative to HIV-uninfected women. However, Kuhn et al13 who examined data specifically on recurrent high-grade dysplasia after VIA and cryotherapy, noted no significant difference between HIV-infected and HIV-uninfected women. Lima et al,14 assessing the effect of immunosuppression, found the risk for recurrent dysplasia after LEEP was 2.9-fold higher (95% confidence interval: 1.3 to 6.4) in HIV-infected women with CD4+ lymphocyte counts less than 200 cells per microliter compared with those with higher CD4+ cell counts. Chirenje et al15 published the only comparative study of cryotherapy and LEEP among HIV-infected women in an LMIC. The authors examined recurrent dysplasia up to 12 months after treatment for CIN2+ in a subset of 109 HIV-infected women enrolled in a larger RCT. In these HIV-infected women, the researchers found a higher failure rate (persistent or recurrent disease) with cryotherapy treatment than with LEEP.
Five studies examined posttreatment complications among HIV-infected women.6,13,16–18 Early complications included discharge, bleeding, abdominal pain, and infection; delayed complications included cervical stenosis. Kuhn et al,13 comparing 252 HIV-infected and 696 HIV-uninfected women treated with cryotherapy, found no significant differences with respect to rates of postcryotherapy complications by HIV status. In this study, 1 HIV-infected woman required transfusion for severe bleeding, and 3 HIV-uninfected women who received cryotherapy required hospitalization within 1 month of treatment. Two studies that compared post-LEEP complications between HIV-infected and HIV-uninfected women found no significant differences.16,17 However, Kietpeerakool et al noted 2 cervical stenosis cases among the HIV-infected women at 6 months posttreatment. Phaendler et al, in a retrospective study of cryotherapy-ineligible women identified in a population-based cervical cancer prevention program in Zambia, reported only mild infrequent complications, including anesthetic reaction, intra- and post-operative bleeding, among the subset of 465 HIV-infected women who underwent LEEP.6 Woo et al,18 in a secondary analysis of data from a prospective cohort study in Kenya, reported complications among 2.8% of HIV-infected women after LEEP; none of the complications reported in this study were severe.
Programmatic data were reported in 2 studies.7,19 Both studies, 1 population-based from Zambia and 1 clinic-based from Kenya, confirmed high rates of cervical abnormalities among HIV-infected women screened with VIA. They also highlighted the attrition that occurs at various time points after screening, including before treatment (on- or off-site), after referral for further evaluation, or during the course of ongoing follow-up. Parham et al described experience with nearly 6600 HIV-infected women screened in a program in Zambia from 2006 through 2008. Among women with VIA-identified cryotherapy-eligible lesions, the researchers found a 22% loss to follow-up before cryotherapy. Among women referred for further evaluation of cryotherapy-ineligible lesions, loss to follow-up before evaluation was 25%. More than 80% of HIV-infected women who were screened failed to return for their recommended follow-up visit, either at 6 months after treatment or 1 year after VIA-negative screening.
The quality of evidence from individual studies varied from medium, as in the case of the secondary analysis of a large RCT, to weak, as among some retrospective analyses and studies with limited sample sizes or those that did not use an accepted gold standard for diagnostic comparisons. Taken together, the overall quality of the articles was considered fair (Table 1). Quality-rating definitions are described by Kaplan et al5 in this supplement.
No studies that met inclusion criteria compared the long-term rates of cervical cancer development between screened and unscreened women; none evaluated the effect of VIA and outpatient treatment of cervical dysplasia on subsequent death from cervical cancer (mortality), on HIV transmission to sexual partners, on retention in HIV care, or on quality of life outcomes. Furthermore, none examined the cost of the screening and treatment interventions or cost-effectiveness data. Because no information was available on these important outcomes, the impact of these interventions (VIA screening, cryotherapy, and LEEP treatment) was judged uncertain (Table 1).
Cervical cancer is the fourth most common cancer among women worldwide20; high rates are found in many LMICs, particularly in sub-Saharan Africa, the region with the world's highest HIV prevalence. Persistent HPV infection, the precursor to cervical cancer, is more common among HIV-infected women relative to HIV-uninfected women. As cART does not eliminate the risk of HPV-related cervical disease, the burden of cervical cancer among HIV-infected women in LMIC is expected to increase as access to cART improves and these women live longer.
In our extensive search of the literature, we found major gaps regarding evaluation of screening with VIA and treatment of cervical dysplasia with cryotherapy or LEEP among HIV-infected women in LMIC. Importantly, there was a paucity of data examining the effect of screening and treatment on our key outcomes (mortality, morbidity, HIV transmission, retention in HIV care, and quality of life). We found no studies which reported on mortality or on the impact of simple cervical screening and treatment on cervical cancer occurrence in HIV-infected women.
Most studies included in this review reported alarmingly high rates of cervical lesions among HIV-infected women. Studies that confirmed VIA findings with histopathology reported that 23%–55% of HIV-infected women screened had high-grade precancerous lesions. Many of these women were being screened for the first time, although this information was not provided in several studies. Performance of VIA in HIV-infected women was similar to that seen in general populations21 sensitivity was comparable or better than that of cytology; but VIA specificity was somewhat lower than that of cytology.
Recurrence of cervical dysplasia after treatment was common in HIV-infected women. The studies that addressed this issue presented various methodological limitations. These included treatment of both low- and high-grade cervical lesions, absence of information about the size and location of lesions (ie, cryotherapy eligibility), and limited description of specific methods used during LEEP treatment. High rates of recurrence among HIV-infected women after treatment have also been described in resource-rich settings.22 The high recurrence rates described in these articles underscore the need to evaluate repeat testing schedules to detect and treat recurrences before cervical disease progression. However, no studies provided data that would inform the appropriate screening intervals for HIV-infected women in LMICs.
One aim of this review was to establish complication rates after treatment with cryotherapy or LEEP in HIV-infected women. In the single study reporting on complications after cryotherapy, Kuhn et al found no significant differences in rates of postcryotherapy complications in HIV-infected vs. HIV-uninfected women; overall, complications were infrequent and not severe. Likewise, researchers reported relatively mild infrequent complications after LEEP.6,16–18 The 2 studies that examined the risk of complications after LEEP among HIV-infected women compared with HIV-uninfected women16,17 showed similar complications rates among the 2 groups. No study discussed the effect of treatment on quality of life or compared the rates of offensive discharge between the treatment modalities, which may represent a barrier to care. Nonetheless, these data are reassuring as wider implementation of outpatient treatment with cryotherapy and LEEP is planned in numerous high HIV prevalence areas.
Loss to follow-up was an important consideration from the Zambia program where population-based screening was conducted. Among HIV-infected women, 22% of women did not receive treatment for cryotherapy-eligible lesions. In addition, loss to follow-up among women requiring referral for LEEP treatment or further evaluation was high. This underscores the need for same day treatment for all women with eligible lesions and the need for referral tracking systems. More than 80% of women did not return for follow-up after screening or treatment, which is concerning given high rates of incident and recurrent cervical disease in HIV-infected women.
External validation of both clinical and laboratory findings is critical to the provision of high quality care. Although some studies reported external quality assurance (QA) of procedures performed by midlevel providers, none reported on QA for procedures performed by medical staff. From a laboratory standpoint, QA procedures among the studies varied significantly. In 1 study, cytology and histology were subject to rigorous QA procedures,8 and in another,13 histology was subjected to a blinded second review. However, other studies did not report on quality control and verification of histopathology. A recent report on QA for cervical dysplasia at the international sites of the AIDS Clinical Trials Group identified multiple issues that compromised diagnostic accuracy in the site laboratories, confirming the importance of laboratory quality assurance.23
In summary, there were striking differences in the methodologies used in these studies, in the quality of the research and the duration of follow-up. Because of this, it is difficult to draw conclusions about the overall impact of VIA, cryotherapy, and LEEP on cervical cancer rates and subsequent mortality in HIV-infected populations in LMIC.
Screening for visible HPV-related lesions using VIA has been shown to reduce invasive cervical cancer incidence among populations of predominantly HIV-uninfected women.3 Although VIA screening and prompt treatment would be expected to reduce rates of high-grade dysplasia and subsequent cervical cancer in HIV-infected women, more data are needed to confirm benefit.
Although VIA and cryotherapy are less complex than cytologic screening and colposcopy for screening and treatment of cervical cancer precursors, the simpler techniques still require significant infrastructure, training of providers, and quality assurance. Screening for high-risk (HR) HPV may provide a promising avenue of screening. In a population that was not screened for HIV, screening with HPV testing was associated with a reduction in mortality from cervical cancer.4 Newer screening tests for HR HPV have been developed; these tests hold promise for the future as they may be performed on self-collected vaginal specimens, thereby saving provider time and examination equipment costs. Examination of HPV-positive women and treatment of precursor lesions will still be necessary to prevent cervical cancer. Further study in HIV-infected women is needed to evaluate the feasibility, utility, and cost of primary HPV-based cervical screening followed by VIA with cryotherapy treatment among the subset of women with HPV. Ultimately, the impact of any screening algorithm on rates of cervical cancer among HIV-infected women must be assessed.
Given the limited availability of LEEP in many LMIC, understanding the effectiveness and limitations of cryotherapy is clearly an important issue. Data on the proportion of HIV-infected women with extensive cervical lesions inappropriate for cryotherapy among 700 HIV-infected women presenting for cervical screening will be available later this year (ClinicalTrials.gov; NCT01315353). Additionally, an RCT currently ongoing in Kenya is evaluating the effectiveness of cryotherapy relative to LEEP in treating biopsy-proven CIN2/3 among HIV-infected women, following women for 24 months after treatment [PEPFAR Public Health Evaluation (PHE) KE09.0238].
Optimal screening methodologies and screening intervals, the appropriate algorithm for triage, and the effect of screening and treatment on disease recurrence, cervical cancer rates, and mortality all represent research gaps for HIV-infected women in LMIC. Kuhn et al13 reported a reduction in high-grade lesions among HIV-infected women who underwent VIA and cryotherapy compared with unscreened women, estimating that 7.4 cases of CIN2+ were prevented for every 100 women screened. There are no data on mortality outcomes as a result of treatment of cervical lesions in LMIC. Importantly, there are few data that inform screening frequency and follow-up intervals posttreatment of precancerous lesions among HIV-infected women as longitudinal studies are rare.
The role of immune reconstitution in ameliorating recurrence risk remains a gap in our understanding of the pathogenesis of HPV-related dysplasia in HIV-infected women. It is postulated that antiretroviral therapy enhances the clearance of HPV and reduces the risk of dysplasia recurrence, and there are some epidemiological data that support these assertions.24–26 If treatment with antiretroviral therapy and the resultant restored immune status had significant effect on cervical disease, one might expect to see a change in cervical cancer rates in areas most affected by the HIV epidemic, but this has not yet been demonstrated.27
Our review underscores the need for more studies of the optimal methods of screening for and treating precancerous lesions among HIV-infected women in LMIC to prevent cervical cancer. Based on data in HIV-uninfected women, the “See and Treat” VIA/cryotherapy strategy is a reasonable screening and treatment approach among HIV-infected women. However, these methods require further validation among HIV-infected women. Innovative screening methods, potentially using patient self-collected specimens, for HPV testing and triage would add value, might reduce cost, and should be evaluated.
The major limitation of this review was the paucity of data available on this important clinical topic. The best data came from cross-sectional assessments or substudies of larger cohorts. No study specifically addressed the effect of treatment on cervical cancer rates and mortality in HIV-infected women. Plans for programmatic scale-up of this modality will need to include appropriate referral guidelines and to perform adequate quality assurance of programs. Similarly, the frequency of screening for HPV-infected and HPV-uninfected women is unknown as is the requirement for follow-up posttherapy. We found no data to inform recommendations.
These studies show that dysplasia is more common and recurs more frequently in HIV-infected women than in HIV-uninfected women. VIA is a reasonably sensitive screening method and common methods of treating dysplasia are safe in HIV-infected women; however, high recurrence rates after 1- to 3-year posttreatment suggest that cervical neoplasia may have a different disease course among women who are HIV infected than those in the general population. We found the current evidence insufficient to report certainty of long-term impact of VIA, cryotherapy, or LEEP interventions on morbidity.
The authors thank Gail Bang and Emily Weyant for their work on the literature search, and Dr. Gina Brown for her early review of the article.
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