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ORIGINAL RESEARCH |
From the Colposcopy Clinic of the Department of Obstetrics and Gynecology and the Department of Pathology, Luis Castelazo Ayala Hospital, The Mexican Institute of Social Security, Mexico, Mexico.
Address reprint requests to: Jose Luis Gonzalez-Sanchez, MD Rancho La Aguja 3 Residencial Los Sauces 04940 Coyoacan, Mexico, D.F. Mexico E-mail: jlgs1943{at}aol.com
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Abstract |
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Methods: Women with recurrent HPV of the cervix were assigned randomly to received either 3 million IU of interferon beta daily for 5 days, followed by 2 days of rest for 3 weeks, or placebo on the same schedule (N = 61 in each group). They were evaluated at 6 and 12 months after cytology, colposcopy, and directed punch biopsy. Comparison between groups was carried out by 
2, Fisher exact test, and Student t test, depending on the variable. Multivariable logistic regression was used to evaluate influence of variables to treatment and categorical and continuous variables were compared by Mantel–Haenszel and Wilcoxon tests.
Results: When treatment success rates for all patients at 6 and 12 months were compared, a highly significant statistical difference was found in the treated group compared with the placebo group [48 of 61 (79%) versus 33 of 61 (54%), P = .001, and 43 of 61 (70%) versus 26 of 61 (43%), P = .002, respectively]. Multivariable analysis showed treatment success rates with interferon beta were higher between the group with initial histopathology of cervical intraepithelial neoplasia (CIN) (odds ratio 4.86; 95% confidence interval 1.75, 13.49), and the group receiving placebo (P = .002). Side effects treatments were minimal in 70% of women; the most severe events were headaches and flulike symptoms that did not interfere with the treatment. No clinically significant changes were found in laboratory measurements of glucose or transaminases during treatment or follow-up.
Conclusions: Intramuscular injections of interferon beta were effective for treating recurrent HPV lesions, particularly when associated with CIN. The only side effects were mild and controllable.
The natural history of human papillomavirus (HPV) is uncertain. It spontaneously disappears in 33–50% of cases 8 months after diagnosis or it has progressed to cervical intraepithelial neoplasia (CIN), thus choosing the correct treatment has been difficult.1,2 Interferon alone or combined might be effective.3–6 For the last decade, intramuscular administration of interferon beta has been used to treat HPV7,8 either alone9,10 or with other treatments.11,12 However, results were varied. In a meta-analysis, Torrejon et al13 reported 532 cases of HPV infection treated with interferon beta with regimen cures in 6.6–82% of women. The controlled trial with placebo showed a significantly higher remission rate than groups that were given interferon beta treatment, which has been used systematically with intramuscular injections, generally 2 million or 3 million IU daily for 10 days.14,15 The objective of this study was to evaluate the effectiveness and safety of intramuscular injections of interferon beta in women with recurrent HPV of the cervix, after other treatments.
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Material and Methods |
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All subjects’ partners were examined on the first day and at the end of treatment only in cases in which women had acuminata clinical lesions. Using condoms was suggested to partners during subjects’ treatment. After enrollment, women were randomly assigned to interferon beta (n = 61) or placebo (n = 61). Women were assigned to interferon beta or placebo in a sequence determined by a computerized random-number generator, with assignments sealed in numbered opaque envelopes. The sample size of 61 per group was chosen arbitrarily. The groups were similar in age, sex, social and economic status, lesion recurrence, and previous treatment, with no statistically significant differences. Treatments were scheduled within 1–3 weeks of diagnoses. The interferon beta group (n = 61) received intramuscular injections of 3 million IU, interferon beta (Frone, Ares-Serono Group, Laboratorios Serono, Mexico City, Mexico) daily for 5 days, followed by 2 days of rest for 3 weeks. In the placebo group (n = 61), subjects received 2 mL of 0.9% normal saline solution intramuscularly on the same schedule as the interferon beta group.
Women were observed for 1 year. During the first month, subject visits were weekly, then were bimonthly for 6 months, and every 3 months thereafter. At each follow-up visit, evidence of HPV was evaluated by complete physical and pelvic examination, colposcopic examination, and Papanicolaou smear. In cases in which lesions were evident, colposcopically directed biopsies were done. Laboratory tests for hemoglobin, hematocrit, leukocyte and platelet counts, glucose, urea, creatinine, bilirubin, transaminases, and alkaline phosphatase were done during the first, second, fourth, and 12th weeks of treatment. Effectiveness was evaluated at 6 and 12 months after the beginning of the treatment.
After the start of treatment, all lesions were examined, and any new lesions that appeared since the previous visit were observed. Disappearance of cytologic (koilocytosis, dyskaryosis, atypical parabasal cells, and multinucleation), colposcopic, and direct punch biopsy diagnoses of HPV lesions (basal cell hyperplasia, acanthosis, papillomatosis, koilocytosis, parakeratosis, and mild nuclear atypia) were considered complete responses. Absence of therapeutic response was considered when HPV lesions did not change, did not disappear completely, or progressed. For follow-up cytologic and histologic evaluations, data on women were abstracted from charts, and the pathology department was masked to which treatment had been given, under direction of one of the authors (AFAM).
Local and systemic effects were evaluated during treatment, with special attention given to secondary grouped reactions such as flulike symptoms, cardiovascular toxicity (primarily mild to moderate hypotension), central nervous system toxicity (somnolence and confusion or depression), or nausea or vomiting. During treatment, serial counts of blood cells and liver function tests were done, which involved a quantitative analysis of intensity and duration, and analytical hematologic (thrombocytopenia), hepatic, or renal changes.
Statistical analyses were 2 test and Fisher exact test, depending on the case, whereas Student t test was done to compare general characteristics between groups. Multivariable logistic regression method SPSS for Windows (SPSS, Inc., Chicago, IL) was applied to evaluate influence of several variables to treatment results, considering 95% confidence intervals (CI). Categorical and continuous variables were compared using Mantel–Haenszel and Wilcoxon tests, respectively. In all statistical analyses, P < .05 was considered statistically significant.
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Results |
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). No difference was observed in age, beginning of sexual relationships, number of pregnancies, use of contraceptives, and types of previous CIN treatments.
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2; 48 of 61 (79%) versus 33 of 61 (54%), P = .001, and 43 of 61 (70%) versus 26 of 61 (43%), P = .002, respectively].
Table 2 shows the final multivariable logistic regression model corresponding to general variables associated with treatment results. All modalities remained without statistically significant difference in the model, except for initial histopathology CIN results, which contributed significantly to risk of the effectiveness of interferon beta when data from other characteristics were considered. In that model, the highest risk corresponded to women with initial histopathology CIN in the placebo group, who were 4.86 times more likely to have treatment success rates with interferon beta than with other covariates, when associated with CIN [odds ratio (OR), 4.86; 95% CI 1.75, 13.49], P = .002. None of the other covariates analyzed showed statistical difference.
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shows the most common adverse events. Asthenia, headache, and flulike symptoms were all more significant in women who received interferon beta (P = .026, .002, .001, respectively) than placebo. Those symptoms usually disappeared in 7 days and consequently the therapeutic scheme was not interrupted in any cases. No clinically significant changes were found in laboratory parameters during treatment or follow-up. In laboratory testing, glucose (90–135 mg/dL), glutamic-oxaloacetic transaminase (10–48 U/mL), and glutamic-pyruvic transaminase (10–50 U/mL) were lightly elevated in 10, 15, and 8 patients, respectively, at the third week, returning to normal values 12 weeks later.
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Discussion |
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In our experience, the dosage used in the present study was well tolerated and in no case did treatment have to be reduced or interrupted because of side effects. That finding was consistent with other studies that used the same schedule of interferon beta.14,22 Laboratory irregularities that are often associated with large doses of the systematic administration of interferon beta were mild in the present study, and similar to those of others.23,24 In our study, irregularities were visible at the third and seventh weeks, principally referring to increased levels of glucose and transaminases, which occurred at week 3 then returned to normal during the following 12 weeks.
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Footnotes |
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Received March 24, 2000. Received in revised form November 29, 2000. Accepted December 7, 2000.
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References |
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