A randomized phase II clinical trial has demonstrated that prophylactic use of acyclovir significantly reduces the incidence of chemotherapy-induced oral mucositis (CIOM) in patients undergoing autologous hematopoietic stem cell transplantation (AHSCT). The study, published on November 4, 2023 in BMC Oral Health, provides evidence supporting the use of antiviral prophylaxis in this patient population.
The open-label, randomized controlled trial was conducted at Seoul National University Hospital in South Korea. Funding was provided by grants from the National Research Foundation of Korea. The study aimed to evaluate whether acyclovir prophylaxis could reduce CIOM incidence by inhibiting intraoral herpes simplex virus (HSV) reactivation during the neutropenic period following AHSCT.
A total of 54 adult patients with hematologic malignancies undergoing AHSCT were enrolled and randomized to receive either oral acyclovir 400 mg twice daily or no prophylaxis from the start of conditioning chemotherapy until neutrophil engraftment. Eligible patients were HSV IgG positive and IgM negative within one month prior to AHSCT. Key exclusion criteria included recent HSV reactivation, existing oral ulcers or severe dental disease, and renal impairment.
The study population consisted of patients with lymphoma (59%) or multiple myeloma (41%), with a median age of 56 years (range 19-69). Baseline characteristics were well-balanced between the two groups. All patients received standard antibacterial and antifungal prophylaxis during the transplant period.
In the intention-to-treat analysis of all 54 randomized patients, the incidence of CIOM was significantly lower in the acyclovir group compared to the control group (16.0% vs 58.6%, p=0.001). HSV-1 PCR positivity during AHSCT was also reduced with acyclovir prophylaxis (8.0% vs 41.4%, p=0.005).
The per-protocol analysis of 49 patients who completed the study without protocol violations showed even more pronounced differences. CIOM incidence was 13.0% with acyclovir versus 61.5% without prophylaxis (p=0.001). HSV-1 reactivation was detected in only 4.3% of the acyclovir group compared to 46.2% of controls (p=0.001).
Importantly, the study confirmed a strong association between HSV-1 reactivation and development of CIOM. Among patients with oral HSV-1 reactivation, 92.3% developed CIOM, compared to only 19.4% of those without detectable HSV-1. This reinforces the role of HSV as a major contributor to CIOM in the setting of modern transplantation practices with routine antibacterial and antifungal prophylaxis.
The authors note some limitations of the study, including the open-label design and relatively small sample size. Additionally, the optimal prophylactic dose of acyclovir remains to be determined. However, the substantial reduction in both HSV reactivation and CIOM incidence provides compelling evidence for the efficacy of this approach.
In their conclusions, the researchers state that prophylactic use of oral acyclovir effectively reduced the incidence of CIOM in patients with hematologic malignancies undergoing AHSCT. They emphasize that these results provide solid evidence to support current clinical practices at many transplant centers.
The findings have important potential clinical impacts for the management of AHSCT recipients. CIOM is a common and often severe complication of high-dose chemotherapy regimens used for AHSCT conditioning. It can lead to significant morbidity, increased infection risk, prolonged hospitalization, and reduced quality of life. Effective prevention strategies are therefore highly desirable.
While many centers already utilize acyclovir prophylaxis for AHSCT patients, this study provides robust data to support that approach. For institutions not routinely using antiviral prophylaxis in the autologous transplant setting, these results may prompt reconsideration of those policies. The dramatic reduction in CIOM incidence with a simple, well-tolerated oral medication regimen represents a significant benefit for patients undergoing this intensive treatment.
The study also highlights the evolving understanding of CIOM pathogenesis in the era of routine antimicrobial prophylaxis. Earlier studies had suggested oral HSV reactivation was not a major factor in CIOM development. However, this work demonstrates that with effective antibacterial and antifungal prophylaxis, HSV has emerged as a predominant contributor to mucosal injury. This emphasizes the importance of ongoing research to elucidate the complex microbial and immunological factors involved in chemotherapy-related mucosal toxicity.
For clinicians managing AHSCT patients, these findings underscore the value of HSV serological screening prior to transplantation. Identifying HSV-seropositive patients who may benefit from antiviral prophylaxis could significantly reduce the burden of CIOM. The study also reinforces the need for careful oral examination and HSV testing in patients who develop mucositis despite prophylaxis, as non-HSV etiologies may require different management approaches.
The researchers suggest several areas for future investigation, including defining the optimal prophylactic dose and duration of acyclovir in this setting. Studies examining the cost-effectiveness of universal HSV prophylaxis versus targeted use in seropositive patients would also be valuable. Additionally, evaluation of newer antiviral agents with improved pharmacokinetics or broader spectrum of activity against herpesviruses may be warranted.
It is worth noting that while this study focused on autologous transplant recipients, the findings may have implications for allogeneic HSCT as well. Although acyclovir prophylaxis is more routinely used in allogeneic transplantation due to the higher risk of viral reactivation with immunosuppression, the strong association between HSV reactivation and CIOM observed here supports that practice. Future studies comparing CIOM incidence and severity between autologous and allogeneic recipients receiving standardized antiviral prophylaxis could provide additional insights.
In summary, this randomized phase II trial provides compelling evidence for the efficacy of acyclovir prophylaxis in preventing both HSV reactivation and CIOM in autologous HSCT recipients. The significant reduction in mucositis incidence represents an important advance in supportive care for patients undergoing this intensive therapy. While some questions remain regarding optimal implementation, these findings strongly support the use of antiviral prophylaxis as a standard of care for HSV-seropositive patients undergoing autologous stem cell transplantation.
References
Hong J, Park HK, Chang SH, et al. A randomized phase II study of acyclovir for the prevention of chemotherapy-induced oral mucositis in patients undergoing autologous hematopoietic stem cell transplantation. BMC Oral Health. 2023;23(1):1008. Published 2023 Dec 15. doi:10.1186/s12903-023-03623-6
