Evaluation of AHCC Supplementation to Clear High-Risk Human Papillomavirus Infections: A Bench-to-Bedside Approach

Laura M. Alwan, PharmD BCOP
Clinical Oncology Pharmacist
University of Washington Medical Center/Seattle Cancer Care Alliance
Seattle, WA

Cervical cancer remains a prevalent disease, accounting for almost 10% of all cancer diagnoses worldwide. Cervical cancer is known to be associated with the human papillomavirus (HPV), particularly with high-risk (HR) strains such as HPV 16 and 18. HPV infection is ubiquitous in the population. However, most HR-HPV infections are cleared without intervention in about 6–18 months. Although the use of the HPV 9-valent vaccine can decrease HR-HPV infections, about 10% of women will have persistent HR-HPV infections. Persistent HR-HPV infections put these patients at high risk for cervical cancer because the vaccine is ineffective in patients already infected with the HR strains. The only interventions available for treating persistent HR-HPV infections are local surgical procedures, but lesions that are removed often recur.

Recently, interest in modulating the host immune system to try to eradicate HR-HPV infection has increased. Judith A. Smith and colleagues evaluated the effect of AHCC, proprietary extract of shiitake mushroom (Lentinula edodes mycelia).¹ In animal studies, AHCC has shown immune-modulating effects such as enhancing antigen activation of CD4 and CD8 T cells as well as increasing natural killer cells and production of other antigen-specific T cells. In clinical studies, AHCC has shown the ability to decrease risk of infections and improve symptoms associated with infections. The hypothesis of this study was that AHCC supplementation would modulate the host immune system to effectively clear chronic HR-HPV infection. The current study is unique in that it evaluated this hypothesis from bench to bedside, looking at in vitro studies, in vivo mouse studies, and human studies, demonstrating an effective translational medicine approach.

Smith and colleagues first looked to demonstrate the efficacy of AHCC supplementation in vitro. Four human cervical cancer cell lines, including SiHa (HPV 16/18 positive) and C-33A (HPV negative), were treated with a one-time dose of AHCC at a concentration of 0.42 mg/mL (estimate of the clinically relevant plasma concentration after a 3-gram oral dose, as recommended by the manufacturer). AHCC suppressed HR-HPV expression in the first 24 hours, but the expression was recovered by 48 hours. However, when AHCC supplementation was given at this concentration every 24 hours for 7 consecutive days, HR-HPV expression was cleared.

In the in vivo mouse studies, AHCC was given at a dose of 50 mg/kg once daily for 60 days and was associated with clearance of HR-HPV expression sustained after 30 days off supplementation. Smith and colleagues then completed two pilot studies in patients with confirmed chronic HR-HPV infections, defined as infections persisting for more than 2 years. The primary objective of these studies was to determine the success rate of AHCC supplementation, defined as the proportion of women free of HR-HPV infection at 6 months following initiation of supplementation. In the first pilot study, patients were given supplementation with AHCC 3 grams by mouth once daily on an empty stomach. Based on immune-response data, the dosing time was extended to 3–6 months of continuous AHCC supplementation and required 1 month of AHCC supplementation beyond the first negative HR-HPV result. Six patients completed this dosing strategy, and of those, four patients were able to achieve durable clearance of HR-HPV infection (no HR-HPV DNA for more than 30 days off supplementation). No side effects were reported with this dosing strategy. An additional pilot study was completed with AHCC supplementation of 1 gram by mouth once daily on an empty stomach for 6–8 months to see whether lower doses would also be effective. Nine patients completed this pilot study, and of those, four patients achieved durable clearance of HR-HPV. As in the other pilot study, no side effects were reported with this dosing strategy.

In both human pilot studies, interferon beta suppression was measured, and a level of <25 pg/mL was found to be a marker for successful clearance of HR-HPV infection, which has been seen in clearance of other chronic viral infections. As such, this ability to suppress interferon beta and upregulate interferon gamma is the defined mechanism of AHCC immune modulation that leads to clearance of chronic HR-HPV infections. In the human pilot studies, the AHCC 3-gram dosing regimen achieved response slightly more quickly and more consistently than the lower AHCC dose, with good tolerability. Confirmatory phase 2 randomized double-blinded placebo-controlled studies are ongoing to further determine the efficacy of AHCC in HR-HPV clearance in a larger patient population.

This bench-to-bedside approach allowed Smith and the study team to identify efficacy in the lab that could be translated directly to patient care in the clinic setting. No medications are currently available to eradicate chronic HR-HPV infections, and these patients represent women with a high risk of progression to cervical cancer. In this study, Smith and colleagues were able to show in vitro efficacy of AHCC in clearing HR-HPV DNA, which was then translated into HR-HPV infection clearance in about 40%–60% of patients in the pilot studies. This AHCC supplementation was well tolerated, with no side effects reported. The mechanism of immune modulation by AHCC was determined to be through reduction of interferon beta levels, which has been noted with other chronic viral infections. The results of this study give clinicians a blueprint for formulating a strategy for other bench-to-bedside research and have helped identify a possible therapeutic strategy in this unmet area of need in prevention of cervical cancer.

Reference

1. Smith JA, Mathew L, Gaikwad A, et al. From bench to bedside: evaluation of AHCC supplementation to modulate the host immunity to clear high-risk human papillomavirus infections. Front Oncol. 2019;9:173.