Key studies for treatments, data on HIV/HCV co-infection, and the benefits of costs of curing HCV
By Andrew Reynolds @projectinform

In November, approximately 10,000 researchers, clinicians and advocates from around the world came to San Francisco for the annual American Association for the Study of Liver Diseases (AASLD) Liver Meeting. As in years past, hepatitis C (HCV) was prominently featured, with data presented on a wide range of topics from new investigational treatments to cost-effectiveness and benefits of treating HCV early. This review article will highlight some of the key studies for treatments that will soon to be available, data on HIV/HCV co-infection, and cost-effectiveness and benefits of curing HCV.

Treat Everyone with Hepatitis C: Views from the Experts

As has been reported in POSITIVELY AWARE and elsewhere, current HCV regimens are both remarkably effective, curing people up to 90 to 100% of the time, and have few and relatively easily managed side effects. Despite the effectiveness of these medications and a high willingness of both patients and providers to take them, their high-cost have created significant barriers to access. Many insurance carriers, both public and private, have instituted a number of restrictions such as liver disease severity (that is, only those with more advanced disease as indicated by fibrosis scores are eligible for treatment) or substance use requirements (the arbitrary provision that 3 or more months of abstinence from all substances occur before treatment) that prevent many with this curable disease from accessing a cure.

There has been much work by patients, advocates, and medical providers to overcome these barriers. November saw two significant events that may indicate an important shift towards improved access to HCV treatment, which created a backdrop for the Liver Meeting.

First, on November 5, the Center for Medicare and Medicaid Services (CMS) released a letter to all Medicaid beneficiaries on the coverage and use of HCV direct-acting antivirals (DAAs). While recognizing the stress that these high-cost drugs may place upon Medicaid budgets, the CMS letter serves as a warning that some states may be denying “access to effective, clinically appropriate and medically necessary treatments” and they should ensure that they do not “unreasonably restrict coverage of effective treatment using the new DAA HCV drugs.”

The CMS letter also encourages states to rely upon the clinical judgement and recommendations of professional societies and organizations, and utilizing the guidance of the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) for the management of HCV. This guidance is very clear in when and whom to treat:

“Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert.”

In other words: Nearly everyone with HCV should be treated.

To that end, AASLD issued a statement at the start of the Liver Meeting calling on all patients with HCV to be treated, and that denying treatment is harmful to patients. Their stance is clear: “There is no medical evidence to justify (denying treatment) and much to justify treating all patients.”

It is with this backdrop in mind that we review the following studies from the Liver Meeting. Results from this meeting re-confirmed the belief that all patients with HCV be treated and cured and that the benefits of cure far outweigh the cost.

The Value of Curing HCV

Zobair Younossi and colleagues embarked on a study to look at the value to society that comes with curing all patients with HCV genotype (GT) 1. Using a mathematical model, the study authors determined that the cost of not treating HCV was significantly higher than the cost of treating it.

Looking at long-term health outcomes and other measures, treating HCV led to a savings of between $91–$274 billion at the lower end of the spectrum, and $144–$432 billion at the higher end. Even at current cost of treatment—$80–$93 billion—this is a cost-effective intervention.

Another study, entitled “Treating Hepatitis C in the U.S.: Measuring Impact and Value in the Context of Other Major Health Interventions,” found similar results. Mai Pho and colleagues found that treating and curing HCV is more financially viable and effective than even flu vaccinations or X-ray shielding. The authors acknowledge that there are short-term costs to treating HCV, but even at current cost the net benefit of treating it is very large.

The Next Treatment on the Scene: Grazoprevir/Elbasvir

The next direct acting antiviral (DAA) likely to be approved will be the fixed dose combination (FDC) grazoprevir/elbasvir. Merck, the manufacturer of this treatment embarked on a wide-range of clinical trials and many were presented at this conference. This regimen is effective against GT 1, 4 and 6, and works extremely well in a wide variety of patient populations including people who inject drugs (PWID), HIV/HCV con-infected persons, and those with kidney disease. This medication is up for FDA review by January 28.

People who inject drugs (PWID) are often left out of the treatment discussion because assumptions are made about their ability to properly adhere to medications, cope with side effects, or get re-infected after cure due to their lifestyle. We have ample experience and evidence from real-world data that this is not the case, but traditionally PWID have been left out of clinical trials for HCV medications so we do not have that level of evidence to show the effectiveness of treating this population.

The C-EDGE CO-STAR study, presented by Greg Dore and colleagues, demonstrated that PWID can be effectively treated and cured. The study included 201 participants, all of whom were on opiate substitution therapy (OST) or may have been actively injecting drugs, included HIV/HCV co-infected persons (n=16) and those with cirrhosis (n=40). The overall SVR rate in this study was 95.5%, which were comparable to the SVR rates found among non-PWID.

Rationales for denying HCV treatment to PWID include poor adherence and risk of re-infection, neither of which were a significant problem in this study: Adherence rates ranged from 96.5 to 100%, and only 5 patients were re-infected post-cure. The treatment regimen was very well-tolerated in this group, with only 2 participants discontinuing treatment due to side effects. These results show that treating HCV in people undergoing OST or who are actively using drugs is both possible and effective.

HIV/HCV co-infected patients also did very well on this regimen. Jurgen Rockstroh and colleagues presented results from the C-EDGE Co-infection study. This study included 218 participants, all of whom were on HIV treatment and included people with cirrhosis (n=34). Overall, 93.1% achieved an SVR24 (when the study was modified to account for those lost to follow-up or were re-infected, the SVR24 rate increases to 97.6%). The medications did not have any serious interactions with HIV medications, as participants did not see a significant change in their HIV viral load or CD4 counts. The regimen was very well tolerated and no one discontinued due to side effects. These results show that people living with HIV/HCV co-infection can be effectively treated with this regimen.

Calling All Genotypes: Valprepavir/Sofosbuvir

The next DAA that will be reviewed by the FDA will be the FDC sofosbuvir/velpatasvir at a date to be determined. This regimen is pan-genotypic, that is, it is effective against genotypes 1 to 6. Jordan Feld and colleagues presented the results from the ASTRAL-1 study, and found an overall SVR rate of 99% for patients with HCV GT 1, 2, 4, 5 and 6. Patients with GT 3 were reviewed in the ASTRAL-3 study (reported below).

ASTRAL-1 included 624 patients who received the medication and 116 who received a placebo. Participants were given 12 weeks of medication and followed for 12 weeks afterward. The 99% percent SVR12 rate was consistent across genotypes, with GT 2 (104/104), 4 (116/116) and 6 (41/41) achieving 100%, GT1a (206/210) achieving 98%, GT1b achieving 99% and GT 5 (34/35) achieving 97%. This study included participants with cirrhosis and those who were treatment experienced, and 99% of patients in each of these two groups achieved an SVR12 as well. This treatment was very well tolerated, with only one person discontinuing it due to side effects. The most commonly reported side effects were headaches (29%), fatigue (20%), nasopharyngitis (13%), and nausea (12%).

The ASTRAL-3 study looked the effectiveness of 12 weeks of sofosbuvir/velpatasvir for the treatment of HCV GT3. This study included 277 participants, 95% of whom achieved an SVR12. Within this overall percentage, 97% without cirrhosis and 91% with cirrhosis achieved an SVR12, while 97% of treatment naïve and 90% of treatment experienced did the same. Like those in ASTRAL-1, the participants found this regimen to be quite tolerable: No one discontinued due to side effects, of which the most commonly reported were fatigue (38%), headaches (32%), insomnia (27%), and nausea (21%). Should this regimen get approved, it will provide a safe, easy-to-take, and highly effective alternative for people living with HCV GT3.

The Mystery of Sex and Hepatitis C: A Possible Break in the Case

Sexual transmission of HCV is a poorly understood issue that leads to much confusion among patients and providers. It’s widely accepted that people living with HIV are at greater risk of sexual transmission of HCV, but the way in which this happens is poorly understood. We know that HCV is transmitted from blood-to-blood contact, but what about other bodily fluids?

Daniel Fierer and colleagues reported on a small study looking for the presence of HCV in rectal fluids with the absence of visible blood. In this study, they took rectal fluid samples from 45 HIV/HCV con-infected gay men, 12 of whom were chronically infected with HIV and 33 who were acutely infected (that is, infected within the past 6 months). They detected HCV in 47% (20 of 43 rectal specimens, with 2 that were invalid so they we not included). The rectal HCV viral load related to the blood viral load, and it appears to be higher in the acute stage of infection. There did not appear to be a relationship with rectal HCV and presence of a co-existing rectal STD.

Although the exact mechanism of sexual transmission of HCV could not be identified from this study, the researchers hypothesized that a penis inserted into the rectum of a person shedding HCV would be exposed to high levels of the virus and become directly infected. In group sex settings, a penis with HCV-infected rectal fluids could contribute to transmission as a fomite. A fomite is an object that can transmit an infectious agent (bacteria, fungus, or virus) from one person to another. If we take the “penis as fomite” concept, we can see how a penis inserted into the anus of a person with HCV and then put into the anus of another without it could transmit the virus. Although not studied, wearing a condom to prevent exposure to HCV-infected fluids, and changing it with each new partner could lessen the risk of sexual transmission of HCV. More study on this subject is needed, but this is a welcome addition to the topic.

Conclusions

This brief snapshot of the Liver Meeting offers a glimpse of two medications that should be available in 2016, and data and research to support the treatment of all those living with HCV. With new treatments, new evidence to support the use of these treatments, and renewed political will to fight for better access to these treatments, we can make HCV a rare disease in our lifetime.

Andrew Reynolds is the Hepatitis C Education Manager at Project Inform, and facilitates several HCV support groups in the San Francisco Bay Area. He’s also a counselor on the HELP-4-HEP HCV toll-free phone line, (877) 435-7443.