New York State Drug Utilization Review Board
dur@health.ny.gov
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.
1. 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 coinfections, 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
1
http://www.aasld.org/aboutus/publicpolicy/Pages/aasldhcvposition.aspx, accessed 11/6/14.
Younassi et al. Treatment with Interferon (IFN) and Ribavirin (RBV)-Free Regimens with Ledipasvir (LDV) and
Sofosbuvir (SOF) Improves Patient-Reported Outcomes (PRO) for Patients with Genotype 1 (GT1) Chronic Hepatitis
C (CH-C): Results from the ION-1, 2 and 3 Clinical Trials. 65th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2014). Nov 7-11, 2014; Boston, MA.
3
Younassi et al. Sustained Virologic Response with Ledipasvir (LDV) and Sofosbuvir (SOF) Regimens Leads to
Substantial Improvement in Patient-Reported Outcomes (PROs) Among Chronic Hepatitis C (CHC) Patients with
Early Hepatic Fibrosis as Well as Those with Advanced Hepatic Fibrosis. 65th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2014). Nov 7-11, 2014; Boston, MA.
2
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.
4
Ahmed et al. Evaluation of the Health Outcomes for Ledipasvir/Sofosbuvir in Early vs. Delayed Treatment
According to Fibrosis Stage of Patients with Chronic Hepatitis C Virus (HCV) Genotype 1 Infection: Results from a
Decision-Analytic Markov Model. 65th Annual Meeting of the American Association for the Study of Liver Diseases
(AASLD 2014). Nov 7-11, 2014; Boston, MA.
5
Colagreco et al. Watchful waiting: role of disease progression on uncertainty and depressive symptoms in
patients with chronic Hepatitis C. J Viral Hepat. 2014 Oct;21(10):727-33.
6
Kraus et al. Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C.
Psychosomatics. 2000 Sep-Oct;41(5):377-84.
7
Fontana et al. Emotional distress in chronic hepatitis C patients not receiving antiviral therapy. J Hepatol. 2002
Mar;36(3):401-7.
8
Perry et al. Cognitive dysfunction in chronic hepatitis C: a review. Dig Dis Sci. 2008 Feb;53(2):307-21
9
Senzolo et al. Neuropsychological alterations in hepatitis C infection: the role of inflammation. World J
Gastroenterol. 2011 Aug 7;17(29):3369-74.
10
Alsop et al. Cerebral MR spectroscopy and patient-reported mental health outcomes in hepatitis C genotype 1
naïve patients treated with ledipasvir and sofosbuvir. 65th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2014). Nov 7-11, 2014; Boston, MA.
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.
2. 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,
could readily 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 – including pangenotypic 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.
3. Requirements for undetectable HIV viral load
HIV/HCV co-infected patients are at significant risk of liver disease progression, and HCV-related liver
disease is a 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 nor HIV viral load, nor any
serious adverse events.11 Similarly, a study of sofosbuvir plus ribavirin for 12-24 weeks in HIV/HCV coinfected 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.
4. 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 nonadherence were truly the risk which these clinical criteria are meant to manage, an appropriate
safeguard would 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
11
Townsend et al. High Efficacy of Sofosbuvir/Ledipasvir for the Treatment of HCV Genotype 1 in Patients
Coinfected With HIV on or off Antiretroviral therapy: Results from The NIAID ERADICATE Trial. 65th Annual
Meeting of the American Association for the Study of Liver Diseases (AASLD 2014). Nov 7-11, 2014; Boston, MA.
12
Molina et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotypes 1, 2, 3 and 4
infection in patients co-infected with HIV (PHOTON-2). AIDS 2014. 20th International AIDS Conference. July 20-25,
2014. Melbourne.
13
Aspinall et al. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a
systematic review and meta-analysis. Clin Infect Dis. 2013 Aug;57 Suppl 2:S80-9.
treatment for their “high risk” [sic] patients through conjuring up pre-existing biases and tapping into a
deep reservoir of stigma.
This requirement for continuation of therapy also exceeds 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.
Further, a “Medicaid agency may not arbitrarily deny or reduce the amount, duration, or scope of a
required service . . . to an otherwise eligible beneficiary solely because of the diagnosis, type of illness,
or condition.”15 Similarly, individuals newly eligible for Medicaid who receive coverage through
alternative benefits packages are entitled to essential health benefits (EHB), including prescription drug
coverage, and the state may not implement an EHB “benefit design that discriminates based on an
individual's age, expected length of life, present or predicted disability, degree of medical dependency,
quality of life or other health conditions.”16 This proposed policy would, for example, arbitrarily exclude
individuals with substance use disorders from accessing medically necessary treatment on the basis of
their illness and condition. Pursuant to this policy, as between two individuals who were both suffering
from advanced fibrosis (each with Metavir scores of F3/F4), an individual with a substance use disorder
would be arbitrarily and discriminatorily denied continuation of treatment that the state had already
determined to be medically necessary, while the individual who did not suffer from a substance use
disorder would be treated.
14
42 USC §1396r-8(d)(4)(C)
42 CFR § 440.230(c)
16
42 CFR § 440.347(e)
15
In conclusion, we strongly believe that the review of Harvoni should trigger an expeditious yet rigorous
reconsideration of clinical criteria adopted for sofosbuvir. This reconsideration should result in a better
alignment between clinical criteria, the evidence base, and clinical guidance, while affirming the role of
patient-provider decision making, medical ethics, nondiscrimination, and the goal of ensuring access to
treatment. People living with hepatitis C and their loved ones have waited far too long for safe and
effective treatments and deserve a chance to be cured. Health care providers should not be dissuaded
from offering HCV treatment by cumbersome and unnecessary criteria that exceed those warranted by
FDA labeling, scientific evidence, and the expert opinion of professional societies’ guidance. New York
State’s nationally recognized leadership in responding to the hepatitis C epidemic should not be
tarnished by unjustified restrictions that reproduce stigma and impose arbitrary barriers to treatment.
We appreciate the opportunity to submit these comments, and ask that the DURB be guided by the
voices, experiences and wisdom of people with hepatitis C, their health care providers, and advocates in
updating the clinical criteria for HCV therapy. Please do not hesitate to contact us if you have questions
or require additional information.
Sincerely,
Daniel Raymond (on behalf of the undersigned organizations)
Director of Policy
Harm Reduction Coalition
22 West 27th Street, 5th Floor
New York, NY 10001
raymond@harmreduction.org
(212) 377-9121
Organizations
ACT UP New York
American Run To End AIDS (AREA)
End AIDS Now
Harm Reduction Coalition
Health GAP
Hepatitis C Mentor and Support Group
Housing Works
National AIDS Treatment Advocacy Project (NATAP)
Treatment Action Group
VOCAL New York