Woo, Victoria G. BA; Cohen, Craig R. MD, MPH; Bukusi, Elizabeth A. MB, PhD; Huchko, Megan J. MD, MPH
Developing effective cervical cancer screening programs in resource-limited settings is of tantamount importance for providing comprehensive health care to the millions of women infected with human immunodeficiency virus (HIV). Cervical cancer is a major health burden in the developing world, where more than 85% of cases occur.1 In Kenya, cervical cancer is the second most common cancer among women, with a crude incidence rate of 12.7 cases per 100,000 women per year.2 The adult HIV prevalence rate in Kenya is estimated to be 7.1%, with the prevalence rate among women found to be higher at 8.4%.3 HIV has been shown to increase the risk for the development, progression, and recurrence of cervical intraepithelial neoplasia (CIN), the cervical cancer precursor.4
A major factor in cervical cancer prevention is coupling accurate screening techniques with safe and effective treatment for CIN 2 or 3. Loop electrosurgical excision procedure (LEEP) has been shown to have several advantages over the alternative outpatient treatment for CIN 2 or 3, cryotherapy. LEEP can treat women with larger or multiple cervical lesions, which are more common among HIV-infected women.5 LEEP has been shown to have a significantly higher overall cure rate than cryotherapy, especially among HIV-infected women.6 Although LEEP has been well-studied and is the standard of care among HIV-infected women in resource-rich settings, studies in resource-limited settings and specifically among HIV-infected women in these settings are few.7,8 Further, safety of LEEP performed in resource-limited settings overall and among HIV-infected women has not been well-documented.7
In almost all reported studies of LEEP, physicians have performed the procedure. Kenya has a very high patient-to-doctor ratio, reported to be 308,878 to 1 in rural areas.9 Given the severe shortage of physicians, training midlevel HIV primary care providers to perform LEEP could help improve cervical cancer prevention among HIV-positive women. Whereas mid-level HIV primary care providers have been utilized to perform cryotherapy,7 few programs have considered training this cadre of providers to perform LEEP.
We have recently reported on the low numbers of serious adverse events after LEEP performed in Kenyan primary care HIV treatment clinics by clinical officers and nonphysician health care providers as assessed by clinicians based on clinical data and patient files.10 Further factors influencing feasibility of the procedure include side effects and tolerability, as well as compliance with instructions after procedure. Women are counseled to avoid intercourse for 4 weeks after LEEP. This is to avoid an increased risk of complications from disruption of the healing wound and a theoretical risk of increased transmission to their partners from increased HIV-1 genital shedding.
In this study, we sought to more closely estimate the safety, tolerability, and acceptability of LEEP performed by clinical officers for CIN 2 or 3 in HIV-infected women. To do this, we used patient response data to assess the rate of reported side effects and early return to intercourse after LEEP using a questionnaire administered to women 4 weeks after LEEP.
MATERIALS AND METHODS
This secondary analysis is part of a prospective cohort study of HIV-infected women undergoing surgical excision of biopsy-confirmed CIN 2 or 3 to assess rates and predictors of CIN 2 or 3 recurrence. The goal of this current article is to present data on the safety, tolerability, and acceptability of LEEP as measured at the 4-week postprocedure follow-up visit. Institutional Review Board approval was received from both collaborating institutions (University of California, San Francisco Committee on Human Research and the Kenya Medical Research Institute Ethical Review Committee). Eligibility criteria included HIV-infected women enrolled at the Family Acquired Immune Deficiency Syndrome Care and Education Services clinics in Kisumu, Kenya, who were between the ages of 25 and 65, either not using antiretrovirals or using antiretrovirals for at least 6 months and able to provide informed consent. Those who declined to participate in the study were still offered LEEP per the clinic's protocol. The number of participants who declined LEEP was recorded along with reason for declining the procedure.
Baseline clinical demographics were collected from the electronic medical records at Family Acquired Immune Deficiency Syndrome Care and Education Services for each woman at time of procedure, including age, CD4+ count, World Health Organization stage, antiretroviral therapy use and duration, hormonal contraception use, and partner's HIV status. LEEP was performed by one of five clinical officers who had undergone didactic and practical training and received certification in the procedure.10 Training took place over a period of 2 to 3 months and consisted of theoretical training and then on-site training with supervision of a U.S.-trained gynecologist or medical officer. All clinical officers had to successfully perform 10 supervised LEEPs to achieve certification.
Colposcopy was performed immediately before each procedure. Information on lesion size and location, loop size, and medications used during the procedure were recorded. The procedures were performed in “blend” mode, a current that maximizes cut and cauterization to reduce intraprocedure bleeding. When necessary, excision was performed with two passes to ensure that the entire lesion was removed. Monsel solution was applied as needed after the procedure to control any immediate postprocedure bleeding. Specimens were evaluated by a pathologist for confirmation of CIN 2 or 3 and to rule out more invasive lesions. Margin involvement and endocervical curettage specimens were also unable to be assessed because of the multipass technique and laboratory limitations.
Women were instructed to remain abstinent until their 4-week follow-up visit at the clinic to avoid the risk of increased complications or the theoretical increased risk of transmission to partners. They were told to seek care from a clinician if they experienced heavy bleeding, fever, foul discharge, or severe abdominal pain. Information for women who called or returned to clinic for adverse events was recorded.
At the 4-week follow-up visit, a paper questionnaire was administered to participants by the study coordinator. They were asked if they had experienced any symptoms after the procedure, including bleeding, pain, foul discharge, and fever. A visual Likert scale was administered to assess severity of pain and bleeding symptoms. Participants were asked if their symptoms interfered with daily activities. They were also asked if they needed to seek medical attention after the procedure and, if so, if they received any additional treatment. The questionnaire also assessed abstinence rates. For those women who reported early resumption of intercourse, condom usage and discomfort or problems during intercourse after the procedure were assessed. Questionnaires consisted of mainly close-ended questions; however, participants were encouraged to expand on any of the items for which they had positive responses.
Statistical analysis was performed using STATA 11. Univariable analysis was performed using χ2 for categorical variables and t tests for continuous variables; multivariable analysis was performed using linear regression estimated association between clinical and demographic factors and presence of symptoms and assessed association between abstinent rates and symptoms.
Between April 2008 and December 2010, 265 HIV-positive women underwent LEEP for biopsy-diagnosed CIN 2 or 3 at the Family Acquired Immune Deficiency Syndrome Care and Education Services Clinic in Kisumu, Kenya. Of the 270 women with CIN 2 or 3 offered LEEP, 265 (98%, confidence interval [CI] 97–99%) agreed to undergo the treatment. Among those declining LEEP, two cited fear of the procedure and one cited futility of the procedure as reasons for not accepting. Two others moved out of the area before follow-up. Twenty-seven (10%, CI 7–15%) of women who underwent LEEP returned outside of their 1-month follow-up visit window, at which time study enrollment took place. Of the remaining 238 women, 197 (83%, CI 77–87%) were eligible and agreed to enroll in the 2-year prospective cohort study. Questionnaire results are available for 180 women.
At the 4-week follow-up visit, 52% (CI 45–60%) of participants (n=94) reported experiencing any symptom after the procedure, 23% (CI 17–30%) of participants (n=42) reported foul discharge, 16% (CI 31–46%) of participants (n=29) reported bleeding, and 14% (CI 10–20%) of participants (n=26) reported pain. No participant reported fever. Among the women reporting symptoms, 99% (CI 97–100%, n=179) characterized them as very mild to mild, with only one participant reporting moderate symptoms of bleeding and pain. Only 1.7% (CI 0.3–5%, n=3) reported that these symptoms interfered with their daily activities; 2.8% (CI 0.8–6.3%, n=5) had consulted a clinician for any of these symptoms. Most of these women (80%, CI 28–99%, n=4) received treatment; three received treatment for sexually transmitted infection and one received pain relief.
Baseline clinical and demographic characteristics were examined for correlation with postprocedure symptoms (Table 1). Women who reported symptoms had a significantly higher mean CD4+ count compared with women who reported no symptoms after LEEP (419 cells/mm3 compared with 349 cells/mm,3 P<.05). This association remained significant after adjusting for antiretroviral therapy using linear regression (P<.001).
Only 16% (CI 11–22%, n=29) of women reported early resumption of intercourse before their 4-week follow-up visit. Of these women, the majority (76%, CI 56–90%, n=22) reported having intercourse within the second or third week. Seventy-nine percent (CI 60–92%, n=23) of these women reported using a condom during intercourse. Seventeen percent (CI 5.8–36%, n=5) reported having bleeding or discomfort after intercourse. No difference in reported symptoms was found between women who had remained abstinent and women who did not remain abstinent (Table 2). Intercourse without a condom was not significantly associated with experiencing bleeding, discomfort, or foul-smelling discharge after LEEP (Table 3). Women who reported symptoms also had a significantly higher CD4+ count compared with women who did not report symptoms (567 cells/mm3 compared with 270 cells/mm,3 P<.05). However, this association did not remain significant when adjusting for antiretroviral use in linear regression (P=.30). Although not significant, those who reported symptoms were less likely to be using antiretrovirals than those who reported no symptoms (73.7% compared with 100%, P=.08). Of the women with early resumption of intercourse and reported symptoms, 32% (CI 13–57%) reported that their partners were HIV-negative and 42% (CI 20–67%) reported partners with unknown status.
Since undergoing LEEP, two women have reported becoming pregnant. Both pregnancies had no complications and the neonates were born at full term.
LEEP performed by clinical officers had a high acceptance rate and appears to be safe and tolerable for HIV-positive women. When assessing safety, there were no reports of major side effects from any of the women up to 4 weeks after the procedure. Approximately half of the women reported some minor symptoms, but only five participants sought further medical care, and only three reported that these interfered with their daily activities. These results concur with other studies that also reported low adverse effects rates after LEEP in HIV-negative women in low-resource settings11 and add insight into the growing body of literature regarding safety of the procedure in HIV-positive women in similar settings.
Particularly important is that our report shows no difference in side effect rates for LEEP performed by trained clinical officers compared with the side effect rates reported in studies of LEEP performed by physicians working in teaching facilities.12 As providers look to scale-up cervical cancer screening and treatment programs in resource-limited settings, utilization of mid-level health care providers presents an important opportunity and viable solution for providing cervical cancer screening and prevention services in areas where traditional surgical providers are scarce.
Our reported abstinence rate was 84%, and it was reassuring that such a large number of patients were able to comply with instructions given after the procedure. Also reassuring was that those who were not abstinent did not have more symptoms compared with those who remained abstinent. Because women are not always able to negotiate intercourse with their partners,13 it is reassuring that this vulnerable population does not appear to be at higher risk for worse outcomes. Our abstinence rate is higher than a previously reported 4-week postprocedure abstinence rate of 50% for women undergoing cryotherapy in South Africa.14 It should be noted that the majority of participants reported partners who were either HIV-negative or of unknown status. It is possible that the high reported abstinence rate was related to fear of the theoretical increased transmission of HIV after the procedure. However, this has not been explored in the literature.
Given that many participants reported a partner who was HIV-negative or has unknown status, further examination needs to be completed assessing the risk of HIV transmission by women with early resumption of intercourse. Limited studies have reported increased HIV-1 genital shedding in women with CIN15 and after treatment for cervical dysplasia.16 Further research examining HIV shedding after LEEP needs to be completed to fully assess the risk posed by LEEP on HIV shedding and HIV female-to-male transmission.
Interestingly, our study found that a higher CD4+ count was associated with an increase in reported positive symptoms. One possibility for this finding could be that women with a higher CD4+ count could have a better immune response and were more likely to have an inflammatory response to the procedure compared with women with a lower CD4+ count. Another possibility could be that a higher CD4+ count is associated with better overall health status, and thus these women might have been more likely to engage in activities that resulted in more symptoms. This association deserves further investigation, especially as more women become enrolled in HIV care in sub-Saharan Africa who have higher CD4+ counts and who have improvement of CD4+ counts with access to antiretroviral therapy.
Our study is limited in that the results are self-reported and only reflect 4 weeks after the procedure. Although this reflects the immediate sequelae after the procedure, it does not allow us to comment on any longer-term adverse events, such as preterm birth rates.17 Whereas we are able to comment on the number of women who have since become pregnant and their outcomes, a more formal analysis of long-term reproductive outcomes remains to be performed.
Our study findings demonstrate that LEEP can be performed with minimal adverse effects, even with noncompliance to abstinence stipulations, in HIV-positive women by mid-level health care providers. With the growing evidence that LEEP can be performed safely, with minimal sequelae in HIV-positive patients, the next step is to examine the efficacy of treatment by LEEP for prevention of recurrent CIN 2 or 3 and invasive cervical cancer along with scale-up of cervical cancer prevention services.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.