Tackling High Drug Costs -Lessons from Australia and Brazil

In two related commentaries referenced below, the authors detail how Australia and Brazil managed to provide a blockbuster hepatitis C virus (HCV) medication without following the going-broke example of Blockbuster video stores.

  • Australia: S Moon et al. NEJM 2019; 380: 607-9
  • Brazil: EM da Fonseca et al. NEJM 2019; 605-6.

Australia provided a lump-sum payment of approximately 770 million dollars (in U.S.) over 5 years in exchange for an unlimited volume of direct-acting antivirals (DAAs). As a result of this approach, Australia managed to treat many more patients at a much lower cost.  “The government would have to spend …U.S. $4.92 billion more to treat the same number or it could treat 93,000 fewer patients with a fixed budget” of approximately U.S. $766 million.

With the Australian approach, the authors note that it is analogous to a patent buyout and works if the ongoing drug manufacturing cost is low and the manufacturer is able to meet growing volume demand.

Brazil’s approaches for DAAs relied on either threatening loss of patent protections and/or enabling local generic production of sofosbuvir.  This resulted in ~90% price discount. Patent protection in Brazil is granted only if a medication is approved by both INPI (Instituto Nacional da Propriedade Industrial) and ANVISA (Brazilian Health Regulatory Agency).

My take: Given the rising costs of medicines, examining how other countries surmount these financial barriers is important.  In my view, the often arbitrary and exorbitant pricing by pharmaceutical companies will erode the support of protective policies in the U.S. which thus far has helped produce many advances.

Skull Rock, Joshua Tree National Park

 

December Liver Briefs

B Wildman-Tobriner et al. Gastoenterol 2018; 155: 1428-35.  This retrospective study which pooled data from 3 phase 2a trials with 370 subjects with nonalcoholic fatty liver disease (NAFLD) found that MRI iwth proton density fat fraction (PDFF) “did not accurately identify patients with NAS ≥4 (AUROC – 0.72) or fibrosis stage ≥3 (AUROC =0.66).”  Thus, this study indicates that currently liver histology remains the gold standard to determine severity of liver damage in paitents with NAFLD.

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P Nahon et al. Gastroenterol 2018; 155: 1436-1450. This study looks closer at whether direct-acting antivirals (DAA) for hepatitis C could increase the risk of hepatocellular carcinoma (HCC) in patients (n=1270) with cirrhosis. The authors found that the crude 3-year cumulative incidence of HCC were 5.9% in the DAA and 3.1% in the SVR-IFN group. However, after Cox analysis, “we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89).”  The authors indicated that patient characteristics (age, diabetes, reduced liver function) and lower screening intensity were the reasons for the increased crude rates of HCC.

Related blog post: Liver Short Takes December 2017

Love this sign –it indicates the truth of the saying:  ‘common sense is not that common’ (attributed to Voltaire)

Genotyping Still Matters with Hepatitis C

A recent study (R Esteban et al. Gastroenterol 20018; 155: 1120-7) evaluated the efficacy of sofosbuvir and velpatasvir in patients with hepatitis C genotype 3.

Overall, the study shows good efficacy of this regimen with and without ribavirin, though with higher SVR12 and lower relapse with the addition of ribavirin.

The difference in response was driven almost entirely based on whether there were pretreatment NS5A resistance-associated substitutions (RASs) present.

  • In those with NS5A RASs the difference in response with added ribavirin compared to without was 96% vs 84%.
  • In those without NS5A RASs the difference in response with ribavirin compared to without was 99% vs. 96%.

My take:

  • If RAS testing is available and baseline Y93H is absent, then ribavirin is not likely needed
  • Genotyping is still important.  The associated editorial (pg 969-71) labeled genotype 3 ‘the problem child in the era of direct-acting antivirals.”   That is, there are still differences in treatment recommendations based on HCV genotype.

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Changing Liver Mortality Trends Since 2007

A recent study (D Kim et al. Gastroenterol 2018; 155: 1154-63) used a CDC database which captures >99% of deaths in the U.S. to analyze mortality trends from 2007 through 2016.  Full text link available online: Changing Trends in Etiology-Based Annual Liver Mortality

When looking at all-cause mortality, there has been a significant decline in deaths associated with hepatitis C (HCV) but not in deaths associated with alcoholic liver disease (ALD).  The image below shows the trend and the impact of direct-acting antivirals.  Deaths associated with nonalcholic fatty liver disease (NAFLD) and due to hepatitis B (HBV) are described in this study as well, though both together account for less than 1/4th deaths associated with ALD.  Interestingly, mortality related to NAFLD was increasing slowly over the study period.

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Liver Shorts August 2018

M Yakoot et al. JPGN 2018; 67: 86-89. This prospective, open-label, unblinded study from Egypt indicated that 29 of 30 (96.7%) pediatric (12-17 yr) patients with HCV (genotype 4) attained an SVR12 with sofusbuvir/daclatasvir.  No serious adverse effects were evident.  The one patient who did not achieve SVR12 was lost to followup but had viral negativity after completing treatment.

Related blog post: New HCV Treatment Effective in Adolescents –Important Study Now Published Online

O El-Sherif, ZG Jiang et al. Gastroenterol 2018; 154: 2111-21. This study showed that a “BE3A Score” based on BMI <25, no Encephalopathy, no Ascites, Albumin >3.5 and ALT >60 IU/L could be used to discriminate the likelihood of reducing the Child-Pugh-Turcotte (CPT) score to class A in patients with hepatitis C virus-associated decompensated cirrhosis who received DAA therapy.  This retrospective  analysis was based on 4 trials of a sofusbuvir-therapy with 502 CPT class B and 120 CPT class C patients.

AH Ali et al. Hepatology 2018; 67: 2338-51.  This study convincingly shows that surveillance for hepatobiliary cancers improves outcomes in patients with primary sclerosing cholangitis.  Among their cohort of 830 patients (Mayo clinic), 79 developed malignancies.  Of those under surveillance (n=40), the 5-year survival was 68% compared to 20% for those who had not been under surveillance.  While the true cynic might ascribe some of the difference to ‘lead-time’ bias, this is unlikely to account for this difference at 5 years.

F Aberg et al. Hepatology 2018; 67: 2141-49.  This Finish-population prospective study, over an 11 year follow-up, using a nationally-representative cohort (n=6771) showed that even moderate alcohol consumption worsened outcomes (eg hepatic decompensation, hepatocellular carcinoma) in patients with nonalcoholic fatty liver disease.  In addition, the authors showed that diabetes the most significant predictor of poor outcome (HR 6.79). In a related commentary, pg 2072-73, the authors state that this article “put an end to the ongoing ddebate whether moderate alcohol drinking (less than 20 g of alcohol/day or 2 drinks per day) could be helpful.”

HCV Treatment and “MELD Purgatory”

A recent study (A Kwong et al. Liver Transplantation 2018; 24: 735-43) and associated editorial (P Martin, pg 727-8) highlight an unintended consequence of HCV therapeutic success –“MELD purgatory.”

The study notes that with the availability of more effective direct-acting antivirals for HCV, there has been a decrease in wait-list mortality and a decrease in disease severity.  This was determined by reviewing 3 timed cohorts (2004 n=2408, 2009 n=2402, and 2014 n=2817) from the Organ Procurement and Transplantation database.

  • For example, the 2014 had a 21% lower risk of wait-list death (HR 0.79) than the 2009 cohort.  This is in contrast to other (non-HCV) disease in which there was no change in mortality.
  • Also, the MELD rate of change was 2.35 per year for the 2009 cohort compared to 1.90 for the 2014 group.
  • In their discussion, the authors note that while patients with HCV can achieve a sustained virologic response, those with advanced liver disease still need liver transplantation.  In these patient, there is a much lower prospect of attaining a high enough MELD score to receive organ offers –“leaving them with persistent complications and a decreased quality of life.”  This situation has been termed “MELD purgatory.”

The editorial notes that in the five years since the introduction of sofosbuvir, HCV has been displaced as the single commonest indication for liver transplantation by nonalcoholic fatty liver disease.  These agents have led to a decrease in advance HCV-related liver disease.  In addition, in the past, HCV infection had near universal recurrence after transplantation and this is no longer the situation.

My take: Undeniably, the advent of DAA have made a huge dent in progressive HCV liver disease. However, those with advanced liver disease may be stuck in a purgatory between good health and poor quality of life even after clearance of HCV infection.

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