JS was a recipient of various unrestricted research grants supporting preclinical studies on AHCC prior to 2014 from Amino Up, Ltd. The human immune system begins to weaken at about 25 years of age, which perhaps could be the contributing factor to why persistent HPV infections are most often observed in women over the age of 30 or with other immunosuppressive conditions. These statements have not been evaluated by any official health authority. These products are not intended to diagnose, treat, cure, or prevent any disease. If you breach these conditions and we take no action, we will still be entitled to use our rights and remedies in any other situation where you breach these conditions. Governing Law and Jurisdiction

Results: HR -HPV clearance was observed in vitro and confirmed in the animal studies as a durable response. Four of six (66.7%) patients had confirmed HR-HPV clearance after 3–6 months of AHCC 3g. Similarly, 4 of 9 (44%) patients had confirmed HR-HPV clearance after 7 months of AHCC 1g. Suppression of IFNβ<25 pg/mL was observed in those clearing the HR-HPV infection. The proprietary, standardized extract of cultured Lentinula edodes mycelia, AHCC (Amino Up Chemical Co. Ltd, Sapporo, Japan), was developed in Japan in 1992. Several studies have reported a variety of therapeutic effects, including antioxidant and anticancer activity and improvement of immune response ( 9, 10). In animal studies, AHCC has shown the ability to treat and prevent cancer, and modulate the immune system to prevent infectious processes ( 9– 11). Gao et al. demonstrated the immunomodulating effects of AHCC in a study that showed enhanced antigen (Ag) activation of CD4 (+) and CD8 (+) T cells, and the increased frequency of tumor Ag-specific IFN-gamma producing CD8 (+) T cells as well as increases in cell numbers of NK cells and gamma delta T cells ( 10). In clinical studies AHCC has demonstrated benefit to decrease risk of infection and ameliorate symptoms of existing infections ( 9– 11, 13). Since studies have demonstrated AHCC induces apoptosis ( 12– 14), it is possible that AHCC may also prevent/delay tumor growth regardless of the role of HR-HPV.Kentaro Kitadate, president and chief operating officer of AminoUp believes AHCC has the potential to support the health of an ageing population. Patients must agree to return to clinic for follow-up visits (including repeat HPV testing) and complete medication administration calendar. A standardized cultured extract of basidiomycetes (medicinal mushroom) mycelia (roots), AHCC® is one of the world's most researched specialty immune supplements, supported by over 30 human clinical studies. Research on AHCC® has been conducted at some of the finest research institutions worldwide, including highly regarded Ivy League universities. Patients with significant medical comorbidities at the discretion of the primary gynecologist. Including immunosuppressive conditions (i.e., HIV+ and rheumatoid arthritis) or taking immune modulation mediations (i.e., immunosuppressants).

Women who have taken commercial supply of AHCC within the past 6 months on their own. Those who have been participating in the AHCC 1 g day pilot study are eligible to enroll in this study.Patients must provide an approved informed consent indicating that they are aware of the investigational nature of this study. The original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author. Ethics Statement Patients were monitored once every 3 months during the study with a clinic visit to review the pill diary to assess compliance, evaluate any toxicity experienced over the previous 90 days, and collect HPV samples via cervical swab/brush and peripheral blood sample. The study was unblinded at 12 months to determine HPV status and immune marker results and reveal study arm assignments. All patients who received AHCC and were HPV negative at 12 months were monitored for an additional 6 months (for a total of 12 months of monitoring after completion of AHCC supplementation). At 12 months, if on placebo the control arm patients were still HPV positive, then patients were offered to continue on AHCC unblinded to gain more information on its toxicity and efficacy. The purpose of “crossover” after unblinding time point was to also help enhance recruitment and enrollment since AHCC is a readily available nutritional supplement.

Worldwide, cervical cancer is the fourth most common malignancy in women and a major cause of morbidity and mortality ( 1). It accounts for nearly 10% of all cancers, and ~265,700 women die from this disease every year worldwide ( 1). The etiology of cervical cancer has been identified and confirmed associated with high risk-human papillomavirus (HR-HPV) ( 2– 5). The human papillomavirus (HPV) is classified as a non-enveloped, double stranded DNA virus that generally infects the epithelial layer of cells including cutaneous and mucosal surfaces and associated with benign warts, carcinoma in situ and ultimately malignant lesions ( 6, 7). When HR-HPV infections persist overtime, patients have an increased risk of developing cervical cancer ( 8). In the absence of an available vaccine against coronavirus, there is broad interest in alternative approaches to immune system maintenance. AminoUp has funded laboratory studies on mice that have further revealed that AHCC is effective at activating immune cells against West Nile virus, influenza, and avian flu. A clinical study in Nutrition Research suggests that supplemental AHCC may boost the antibody titre when given at the time of vaccination for influenza B.FRIENDLY, PULLULAN CAPSULES. Pullulan is the next generation in encapsulation, derived from tapioca and processed with water. This was the first double-blind, placebo-controlled clinical study to demonstrate that the nutritional supplement, AHCC, is effective in eliminating persistent, high-risk HPV infections with durable response in those patients who achieved an IFN-β level below 20 pg/ml. Overall, AHCC was well tolerated and had comparable adverse effects as compared to placebo. Two pilot studies recently were conducted on women who had documented persistent HPV positive for greater than 2 years, were otherwise healthy, and met the remaining eligibility criteria ( 15). Ten women were enrolled in the first study to evaluate the effectiveness of AHCC supplementation of 3 g by mouth once daily to support the host immune system to eliminate persistent high-risk HPV infections. The regimen was repeated monthly until the patient tests HPV negative or until 6 months of active treatment has elapsed. Patients who test positive after 6 months of treatment were considered a treatment failure. HPV testing and immune marker panel screening were completed once a month to monitor for clearance of high-risk HPV persistent infections. There was an encouraging response in 4 of 8 (50%) patients with confirmed HR-HPV DNA eradication after at least 3 months and up to 6 months of daily 3-g AHCC supplementation ( 15). In the second pilot study with 1-g AHCC supplementation once daily, a similar response was observed in 4 of 9 (44%) patients with confirmed clearance of high-risk HPV persistent infections after 7 months of supplementation ( 15). These results from two pilot studies confirm the previous preclinical findings that AHCC supplementation has the potential to be effective to support the host immune system to clear persistent high-risk HPV infections and supported the rationale to continue forward with a formal phase II evaluation to confirm these preliminary findings ( 16). Materials and Methods Study Design The studies involving human participants were reviewed and approved by the University of Texas Health Sciences Center Institutional Review Board. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Author Contributions The presented bench-to-bedside research provides step-wise data to support the hypothesis that AHCC supplementation modulates host immune system, specifically via suppression of elevated IFNβ levels, to effectively clear chronic, persistent HR-HPV infections. After observing elimination of HR-HPV in vitro in the panel of human cervical cancer cell lines, animal studies were completed that also demonstrated successful, durable elimination of HR-HPV after completing AHCC supplementation. Finally, in two “proof of concept” pilot studies of daily AHCC supplementation successful elimination of HR-HPV was achieved that was durable response. Both the animal and human data suggests the mechanism AHCC supplementation supports the host immune system to clear HPV infections is attributed to the modulation of the expression and signaling of IFNβ that is known to be elevated in chronic viral infections (16, 17).

There are limited effective treatment options for clearing HR-HPV infections; majority being local treatment modalities is to alleviate symptoms and remove symptomatic lesions that often reoccur. Fortunately, most HR-HPV infections are cleared within 6–18 months on their own without interventions; only ~10% of women will suffer from persistent HR-HPV infections ( 15, 24). To date, there is no readily available effective systemic interventions to clear HR-HPV infections. Currently prevention of HR-HPV infections with the HPV vaccine nine-valent product before exposure to HPV has demonstrated the best potential for eliminating HR-HPV infections. However, these vaccines have little benefit in those already infected with HR-HPV infections. VEGAN WITH NO FILLERS, BINDERS OR ADDITIVES. We believe in clean nutrition which is why you won’t find any nasty stuff in our products, unlike some of our competitors. In conclusion, the results from this phase II study demonstrated that AHCC 3 g once daily was effective to support the host immune system to clear persistent HPV infections and was well tolerated with no significant adverse side effects reported. The duration of AHCC supplementation required beyond the first negative result needs more evaluation to optimize durable outcomes based on both HPV infection status and the target IFN-β level. Data Availability Statement This phase II study confirmed findings from the two previous pilot studies that demonstrated that AHCC supplementation will modulate the host immune system to eliminate persistent high-risk HPV infections ( 14). While it may not help all patients, in the absence of other systemic treatments, clinicians can recommend AHCC, which is a readily available nutritional supplement that offers a good chance of clearance of persistent HPV infections. HPV samples were evaluated initially with HPV E6/E7 RNA testing (APTIMA, Hologic, Marlborough, MA, USA) at the UTHealth McGovern Medical School Molecular Pathology laboratory. HPV RNA-negative results were confirmed with COBAS HPV DNA testing (Roche Molecular Systems, Inc., Branchburg, NJ, USA) at Methodist Molecular Pathology laboratory to detect the presence of HPV DNA and rule out latent HPV infections. Immune Marker and Natural Killer Cell Assays

References

REVOLUTIONARY ECO-FRIENDLY, PULLULAN CAPSULES. Many cheaper supplements use capsules made from plant cellulose which goes through heavy processing and produces non-environmentally friendly, harmful bi-products. Pullulan is the next generation in encapsulation, derived from tapioca and processed with water. Each ingredient listed in this ADVANCED product has been specially selected from many different specialist manufacturers from around the world. This is different from our High Strength formula which just comes from one manufacturer that only specializes in the Mixed Active Hexose Correlated Compound. VEGAN WITH NO FILLERS, BINDERS OR ADDITIVES. At Time Health we believe in clean nutrition which is why you won’t find any nasty stuff in our products including any binders, fillers or additives, unlike some of our competitors.