New York State Drug Utilization Review Board
November 6, 2014
Re: Harvoni Clinical Criteria for the treatment of Hepatitis C
To whom it may concern:
On behalf of people living with hepatitis C, medical providers, advocates, and organizations committed to ending the hepatitis C epidemic in New York, the undersigned groups call upon the Drug Utilization Review Board to reconsider its clinical criteria for hepatitis C treatment in light of the recent FDA approval of Harvoni (ledipasvir/sofosbuvir) for the treatment of hepatitis C genotype 1. Harvoni marks the first FDA-approved treatment for hepatitis C which requires neither interferon nor ribavirin, and additionally the first treatment with labeling to support a shortened duration of only eight weeks of treatment in select patients. Major clinical trials for Harvoni reported consistently high sustained virologic response (SVR) rates exceeding 90%, regardless of prior treatment experience or cirrhosis, with a remarkably low rate of side effects and adverse events and few clinically relevant drug-drug interactions. These factors represent a substantial advance in hepatitis C treatment and warrant reconsideration of current clinical criteria developed for earlier sofosbuvir-based regimens.
Specifically, we call upon the Drug Utilization Review Board to align clinical criteria with the best available clinical evidence, with substantial deference to patient-provider decision-making. We highlight a recent clarification to the AASLD/IDSA Hepatitis C Guidance:
Successful hepatitis C treatment results in sustained virologic response (SVR), which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non–liver-related comorbid conditions. [hcvguidelines.org, emphasis added]
In addition, AASLD released a policy statement clarifying that the Guidance’s prioritization of patients in highest and high need of HCV treatment was intended solely as a guide to patient-provider decision making, and not as a rationale for denial of coverage of treatment by payers:
Our recent addition to the Guidance prepared by a committee of leading liver experts from AASLD and The Infectious Diseases Society of America (IDSA) proposed that the sickest patients be treated first, but all patients who receive advice from their doctor to take newest medications should not be denied. The decision across the board should be in the hands of the clinician and the patient to make the decision. Unfortunately payers across America are denying treatment when a doctor has prescribed it for their patient. We adamantly disagree with this decision.
Our Guidance is not intended to be used by payers to deny access to treatment. In no way does this position contradict the evidence evaluated to produce the Guidance and the recommendation made in the Guidance to treat the sickest first, but recognizes need to treat all.[1]
The following discussion highlights aspects of the current clinical criteria which appear to be in conflict with the AASLD/IDSA Hepatitis C Guidance, not otherwise supported by evidence, and inappropriate for guiding utilization of Harvoni.
- Restricting treatment eligibility by disease severity
The clinical criteria developed for initial sofosbuvir-based regimens requires that patients demonstrate either stage 3 or 4 fibrosis, or extra-hepatic manifestations of HCV, or at least one of a select list of co-infections, comorbidities, or underlying conditions. These roughly correspond to the AASLD/IDSA Hepatitis C Guidance’s classification of patients at highest or high priority of treatment due to risk for complications and greatest likelihood of immediate and impactful benefits. Notably, the DURB criteria omit the AASLD/IDSA classification of patients with moderate fibrosis (METAVIR score F2), as well as those whose risk of HCV transmission is high and for whom treatment may yield transmission reduction benefits (i.e., active injection drug users).
We reiterate that the Guidance Statement affirms the benefit of HCV treatment for virtually all patients, and that the prioritization schema for patient-provider decision making should not be used to deny treatment to those falling outside of disease severity criteria. HCV treatment with Harvoni improves patient-reported outcomes across a range of domains, including health-related quality of life, vitality, fatigue, and work productivity.[2] Indeed, these benefits accrue to equal degree among both patients with early fibrosis (F0-F2) and those with advanced fibrosis (F3-F4).[3]The current clinical criteria for sofosbuvir-based regimens would exclude a substantial number of New York State Medicaid beneficiaries – nearly 40% of those with a hepatitis C diagnosis, according to an analysis presented at the September 18th, 2014 DURB meeting – from these significant benefits of treatment.
Moreover, hepatitis C treatment is the only evidence-based intervention to prevent liver disease progression. A significant proportion of those with earlier stages of fibrosis (F0-F2) will ultimately progress to cirrhosis in the absence of treatment, and there is currently no way to predict which patients will develop advanced liver disease. While various mediators and predictors of liver disease progression have been identified or proposed, some (such as male sex, older age at initial infection, HIV co-infection, and potential genetic factors) are not modifiable. Other factors, such as heavy alcohol use, obesity, and insulin resistance, may be modifiable, but to date there is no evidence that a reduction or improvement in these risk factors effectively reduces the risk or rate of fibrosis progression. Therefore, for hepatitis C patients with earlier stages of fibrosis, effective hepatitis C treatment is the only evidence-based strategy to prevent liver disease progression and complications.In addition, patients who have F2 or milder liver fibrosis have no residual risk of liver complications due to hepatitis C once they achieve a cure. Patients who wait until they have F3 or F4 fibrosis require life-long screening for hepatocellular carcinoma (liver cancer) even if they are cured. Forcing patients to wait until they have a residual but life-long increased risk of liver cancer before they are allowed to undergo antiviral treatment is unethical at best. Indeed, the current DURB criteria may be construed as the state assuming responsibility – and potentially liability – for the risks and complications of further disease progression for those patients denied HCV treatment based on current disease severity criteria.[4]
Furthermore, the clinical management strategy implied by the current DURB clinical criteria for patients falling outside of the specified disease severity categories – “watchful waiting” – can itself be potentially harmful to patients. Hepatitis C patients whose providers recommended deferring treatment in favor of watchful waiting have been found to be at high risk for anxiety, illness uncertainty (the inability to determine the meaning of illness-related events) and depressive symptoms, regardless of fibrosis stage.[5],[6],[7] These findings are particularly disturbing in light of the already high rate of co-occurring depression and cognitive impairment among people with chronic hepatitis C, including those without advanced liver disease, which may be alleviated following successful treatment.[8],[9],[10]
New York State law defines medical necessity as the following:
"Medical assistance" shall mean payment of part or all of the cost of medically necessary medical, dental and remedial care, services and supplies, as authorized in this title or the regulations of the department, which are necessary to prevent, diagnose, correct or cure conditions in the person that cause acute suffering, endanger life, result in illness or infirmity, interfere with such person's capacity for normal activity, or threaten some significant handicap and which are furnished an eligible person in accordance with this title and the regulations of the department. (Section 365-A)
Treatment with Harvoni clearly meets medical necessity guidelines for all persons living with HCV, for the reasons described above: it cures the condition of hepatitis C, preventing or correcting the development or advancement of life-threatening liver disease, and otherwise restoring HCV patients’ capacity for normal activity.
In summary, to quote again the AASLD/IDSA HCV Guidance, “[e]vidence clearly supports treatment in all HCV-infected persons.” Restrictions based on disease severity criteria deny a substantial proportion of beneficiaries the range of benefits of treatment, as well as the only established intervention to prevent the development of advanced liver disease, while posing a risk of inducing or exacerbating depressive symptoms.
- Restrictions on qualified prescribers
We acknowledge and share the goal that all hepatitis C patients receive quality care and appropriate treatment from knowledgeable providers, and appreciate DURB’s attempt to outline pathways to expand the pool of eligible providers of hepatitis C treatment beyond the narrow and insufficient range of specialists. In light of the approval of Harvoni, we recommend revisiting the clinical criteria developed for sofosbuvir-based regimens.
Harvoni further simplifies hepatitis C treatment for genotype 1 patients by offering a regimen consisting of one pill taken once-daily for eight, twelve or twenty-four weeks, depending solely on baseline viral load, prior treatment experience, and cirrhosis status. Harvoni’s label references few drug-drug interactions, no contraindications, minimal side effects, and no dose adjustments. Unlike with previous interferon- and/or ribavirin-containing regimens, on-treatment monitoring of laboratory values (e.g. hemoglobin levels, white blood cell and platelet counts) is not required. For these reasons, a much broader range of prescribers, including non-specialists with little prior hepatitis C treatment experience, couldreadily provide quality care and appropriate treatment to their genotype 1 patients with Harvoni.
Over the past decade, an abundance of anecdotal evidence indicates that the shortage of specialists has limited access to hepatitis C treatment, particularly for those living outside of New York City. Even in urban areas with multiple specialists, a substantial proportion of hepatitis C patients do not complete referrals from primary care to a specialist. The promise of a hepatitis C cure should not be inequitably distributed based on geography. Clinical criteria must strike a balance between ensuring appropriate care while not posing unnecessary barriers to access. As Harvoni and future treatments – includingpan-genotypic therapies and regimens that hold the promise of shortening treatment duration to as little as 6 or even 4 weeks – simplify the management and treatment of hepatitis C, that balance will continue to shift in favor of broadening the prescriber base. Further loosening of restrictions and criteria for eligible HCV treatment prescribers will ultimately advance the goals of reducing racial/ethnic health disparities by ensuring that all beneficiaries have access to HCV treatment in their communities and, ideally, through their primary care providers. Moreover, broadening the prescriber base for HCV treatment will fulfill the spirit of the federal requirements of “statewideness” in Medicaid benefit design by eliminating geographic barriers in access to care. Until then, it is incumbent upon the Department of Health to monitor HCV treatment access and uptake among Medicaid beneficiaries to guard against disparities and ensure an appropriately trained healthcare workforce capable of managing, curing, and ultimately eliminating hepatitis C in New York State.
- Requirements for undetectable HIV viral load
HIV/HCV co-infected patients are at significant risk of liver disease progression, and HCV-related liver disease isa leading cause of mortality among people with HIV. The clinical criteria for sofosbuvir appropriately include HIV co-infection as a qualifying condition for HCV treatment. However, the criteria also require that HIV/HCV co-infected patients have no detectable viral load for the past 6 months.While the AASLD/IDSA HCV Treatment Guidance includes people with HIV/HCV co-infection as a high priority group for treatment, the Guidance imposes no qualifications regarding HIV viral suppression as a condition for initiating HCV treatment.
We share the goal of viral suppression through antiretroviral therapy for all New Yorkers living with HIV. However, the timing of initiating HIV treatment must remain a shared decision between patient and provider. Denial of HCV treatment cannot be the “stick” to incentivize co-infected patients to initiate antiretroviral therapy, and the well-documented phenomenon of sporadic but clinically insignificant HIV viral load “blips” does not justify deferring HCV treatment initiation. Moreover, there is no data supporting the assumption that successful HCV treatment with currently recommended direct-acting antivirals in co-infected patients requires an undetectable HIV viral load. Indeed, a study sponsored by the National Institutes for Health evaluated Harvoni in 13 co-infected patients who were not on antiretroviral therapy. All 13 achieved an SVR, with no changes in CD4 counts norHIV viral load, nor any serious adverse events.[11] Similarly, a study of sofosbuvir plus ribavirin for 12-24 weeks in HIV/HCV co-infected patients with genotypes 1-4 included a small group of patients not on antiretroviral therapy. The overall results demonstrated high SVR rates in co-infected patients, and no significant changes in HIV viral load among those not on a concurrent antiretroviral regimen.[12]Given these results and the absence of evidence of harm in treating HCV in co-infected patients with detectable HIV viral loads, DURB should reconsider and remove its HIV viral load suppression criteria.
- Restrictions related to “high risk behavior”
The criteria for continuation of sofosbuvir therapy require that patients present “[n]o sign(s) of high risk behavior (recurring alcoholism, IV drug use, etc.).” The criteria do not elaborate on precisely what risks alcohol consumption or injection drug use may pose, though from context ‘risk’ presumably refers to risk of non-adherence to treatment. Paradoxically, those with alcohol use disorders and persons who inject drugs represent two of the groups who stand to derive the greatest benefits from new HCV treatments. Heavy chronic alcohol use accelerates liver disease progression among people with HCV, making those with alcohol use disorders a high priority for treatment. People who inject drugs have historically been deterred from interferon-based HCV treatment, and pose a risk of transmission through shared injection equipment if left untreated. Alcohol consumption and injection drug use are poor proxies for measuring risk of non-adherence.A recent systematic review and meta-analysis of research on interferon-based hepatitis C treatment among people who inject drugs found “high adherence, low discontinuation of therapy, and a low rate of reinfection among PWUDs [people who use drugs]”, with SVR rates comparable to those observed in “real-world” treatment cohorts.[13]If non-adherence weretruly the risk which these clinical criteria are meant to manage, an appropriate safeguardwould be documentation of adherence counseling or referral to additional adherence support. The net impact of this requirement is to dissuade health care providers from considering HCV treatment for their “high risk” [sic] patients through conjuring up pre-existing biases and tapping into a deep reservoir of stigma.
Thisrequirement for continuation of therapy alsoexceeds and conflicts with the AASLD/IDSA HCV Guidance Panel recommendations for on-treatment monitoring, which do not recommend discontinuation of treatment for alcohol or substance use, and indeed such discontinuation is neither ethical nor grounded in any evidence base. We urge the DURB to reconsider these criteria and the implicitly stigmatizing message they convey. In addition, we call upon DURB to make an affirmative statement in the next iteration of clinical criteria that states unequivocally that neither alcohol nor substance use are contraindications or exclusions to successful HCV treatment, any more than they would be to antiretroviral therapy for HIV or to the treatment of any other chronic and/or infectious disease. HCV treatment decisions related to active alcohol or substance use should best be made on an individual basis between patient and provider, and not imposed categorically by clinical criteria that are tantamount to stigmatization and discrimination.
Policies like this one that deny access to new, highly effective hepatitis C treatment to certain populations and limit treatment only to the sickest patients also violate federal Medicaid laws that ban discrimination against specific patient populations. Federal Medicaid law mandates that states which offer a prescription drug benefit must cover all drugs that are approved by the Federal Food and Drug Administration (FDA) and whose manufacturer participates in the Medicaid drug rebate program, as is the case with Harvoni. “A covered outpatient drug may be excluded with respect to the treatment of a specific disease or condition for an identified population (if any) only if, based on the drug's labeling… the excluded drug does not have a significant, clinically meaningful therapeutic advantage in terms of safety, effectiveness, or clinical outcome of such treatment for such population over other drugs included in the formulary.”[14] Contrary to New York’s proposed policy, the FDA makes no such distinction with respect to meaningful therapeutic advantage in patient populations with past or current alcohol or substance use disorders.