Experience with combined immunomodulatory and antiviral therapy for chronic endometritis with a viral component in women with reproductive failure: A prospective study

Background. Chronic endometritis (CE) is a multifaceted pathology, with ongoing revisions in the understanding of its etiology, pathogenesis, and treatment modalities. The lack of standardized, universally accepted algorithms for diagnosing and managing CE results in inconsistent diagnoses and patient care. While the role of bacterial infection is well established, it is recognized that antibacterial therapy does not yield favorable outcomes in every case. Increasing evidence suggests that various microorganisms, alongside bacteria, contribute significantly to this condition. Notably, CE associated with viral factors in the endometrium presents with various cytopathic effects, often resulting in persistent morphofunctional disorders of the uterine mucosa. Viral agents such as human papillomavirus (HPV) and herpes simplex viruses types 1 and 2 (HSV-1, HSV-2) can persist in the endometrium. In women with CE and reproductive failure (RF), the prevalence of HPV and HSV endometrial infections may reach up to 93.3%. Combination therapy, integrating antiviral medications with immunomodulatory agents, is emerging as a promising strategy to enhance interferon production and activate cellular immunity. Aim. To conduct a comparative analysis of the clinical efficacy of two therapeutic regimens: monotherapy with valacyclovir vs. a combination therapy with 1 mg of alloferon (Allokin-alpha®) and valacyclovir in patients with RF, associated with viral contamination of the endometrium and CE. Materials and methods. The prospective study involved 30 women diagnosed with CE and RF. A comprehensive morphological study of endometrial biopsy specimen was performed within days 19–23 of the menstrual cycle, along with an immunohistochemical assessment to identify viral antigens and evaluate p16ink4a protein expression. Following clinical and laboratory examinations that confirmed the diagnosis of viral CE, participants were randomized into two groups: Group 1 (n = 15) received valacyclovir monotherapy (500 mg twice daily for 10 days from Day 1 of the menstrual cycle for two months); Group 2 (n = 15) received combination therapy with valacyclovir (according to a similar regimen for two months) and alloferon (Allokin-alpha®) administered subcutaneously at 1 mg in 1 ml of 0.9% NaCl solution every other day from Day 1 of the menstrual cycle, totaling nine injections in the first month of treatment. Follow-up endometrial biopsies were collected for control examinations four months post-treatment, within the luteal phase of the cycle (Days 19–23). Results. At the preliminary stage, all patients were diagnosed with chronic virus-associated endometritis. Mono-infection was detected in 33.3% of cases, whereas combined viral infections, primarily HPV in association with HSV-1 and/or HSV-2, accounted for 66.7% of observations. A comparative analysis showed that the combination regimen was statistically superior to monotherapy in terms of treatment efficacy. Complete eradication of viruses from the endometrium was observed in 60% of patients receiving combination therapy, compared with 20% in the monotherapy group. Furthermore, no mixed viral associations were detected following combination treatment (p = 0.025). Morphological evaluations confirmed a marked regression of chronic inflammation in the combination therapy group, with mild lymphohistiocytic infiltration noted in 86.7% of patients. An important effect of combination therapy was a substantial reduction in p16ink4a expression in the endometrium (p = 0.011), thereby suggesting a restoration of cell cycle regulation. Follow-up assessments over 12 months post-treatment revealed significant differences in reproductive outcomes during this period (p = 0.026). Conclusion. The combination therapy involving alloferon and valacyclovir demonstrated superior efficacy when compared to valacyclovir monotherapy, as evidenced by pronounced improvements in the histological findings in the endometrium and a decrease in p16ink4a protein expression. This combined therapeutic approach presents a promising approach for enhancing reproductive outcomes in patients with viral CE.