If hepatitis C therapy is so great, why isn't everyone doing it?

In this issue of the Journal, Axelrod et al aimed to investigate the impact of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection on liver and kidney transplant outcomes and cost for HCV-positive patients.1 To do this, they integrated 2 large databases, the Scientific Registry of Transplant Recipients (SRTR) with pharmaceutical claims from 2007 to 2016. They divided the periods prior to January 2014, when all-oral DAAs for HCV replaced interferon for HCV treatment, as pre-DAA, and after January 2014 as post-DAA. They also divided the patients into 2 groups based on donor (D) serostatus for HCV as + or –; thus patients could be either D+R+ or D-R+. This is an important analysis because the SRTR uses HCV antibody status only, rather than the presence of HCV RNA, and particularly in the post-DAA era, many of the patients who are recipient HCV-antibody positive (R+) may be HCV RNA negative and thus have little chance of HCV recurrence. However, the majority of D+R+ transplants will be done in patients who have HCV viremia, as the number of organs that are HCV positive that are transplanted into HCV-negative recipients is exceedingly small.

The authors make several important observations. First, in patients in the pre-DAA era, treatment was associated with higher rates of graft loss and death. This is likely not the result of treatment, but rather a selection bias, as treatment with the more toxic interferon therapies was reserved for patients with the most severe disease. Concerns about interferon-induced rejection, particularly in kidney transplantation, low virologic response rates, and high toxicity led to selective HCV therapy in patients with progressive liver disease and worse outcomes independent of the therapy, which improved only a minority of those treated. Conversely, in the post-DAA era, HCV treatment was not associated with mortality or graft failure and did reduce the risk of death in kidney transplant recipients. The lack of benefit in the post-DAA era on liver transplant recipients may have to do with the short duration of follow-up and that DAAs continue to be used preferentially in more advanced liver disease in kidney recipients. These findings are not unexpected. We would expect that early treatment of HCV would lead to a lack of disease progression in both kidney and liver transplant recipients, and HCV has been associated with worse outcome in both groups due to both progression of liver disease as well as recurrent renal disease in renal transplant candidates.

What was extremely surprising and dismaying was the low rate of HCV treatment in both liver and kidney transplant recipients. Treatment in liver transplant recipients occurred in only 19.8% of D+R+ recipients with public insurance and 11% of those with private insurance within 3 years. Only 5-6% of D-R+ recipients received DAA therapy within 3 years. This is lower than what was seen in the pre-DAA era, when 18% of liver recipients were treated with less-effective therapy with no difference between public and private payers. In kidney transplant recipients, similar trends were seen, with only 12.9% of patients being treated in the post-DAA era compared to 5.5% in the pre-DAA era. In kidney transplant recipients, treatment rates did not differ by payer status, perhaps due to the small number of patients treated and the high number of Medicare recipients. In all groups, the rate of treatment plateaued by approximately 1 year, suggesting that patients were either treated early or not at all.

The explanation for these low rates of DAA treatment is likely multifactorial. For kidney transplant recipients, there may be low awareness among transplant nephrologists of newer treatment options for transplant recipients, and physician and patient perception that HCV will not affect long-term outcome. This combined with a reluctance to see another specialist and the perception that DAA therapy is not accessible due to cost barriers may lead to low rates of referral for treatment. I suspect that awareness is a significant part of this issue, since the rate of treatment was substantially higher in D+R+ recipients than in D-R+ recipients. Pretransplant HCV treatment in dialysis patients was extremely uncommon in that era; thus most patients in both groups were likely viremic. Consequently it is likely that the physicians who were using D+ organs were also more likely to treat or recommend treatment for HCV after transplantation.

However, in liver transplant recipients, where awareness of the need for treatment is high and the rates of treatment pre-DAA were higher, the data suggest a strong effect of insurance barriers based on cost. Sofosbuvir plus simeprevir, which was the first all-oral DAA combination available at the end of 2013 (although its use was off-label at that time), had a cost above $150 000 for a 12-week treatment course. The cost decreased to $84 000 in October 2014, when sofosbuvir/ledipasvir combination therapy was approved by the Food and Drug Administration (FDA). Treatment rates may also have been affected by the lack of an available DAA option for genotype 2 and 3 patients; an option did not become available until July 2015 with sofosbuvir plus daclatasvir. The cost of therapy did not decrease substantially until January 2016 with the approval of elbasvir/grazoprevir for genotype 1 and sofosbuvir/velpatasvir for genotypes 2 and 3 in June 2016, and then later in 2017 with glecaprevir/pibrentasvir for all genotypes. The high cost of therapy led to insurance-mandated fibrosis restrictions on treatment with DAA, which was available only for advanced fibrosis/cirrhosis, drug and alcohol screening, and strict per FDA label use requirements by many payers, which had a clear detrimental effect on patient access to DAA therapy. Provider fatigue of payer denials may have led to decreasing future prior authorization requests for drug for subsequent patients. Lack of FDA approval for posttransplant use of some DAA treatment regimens and concern over drug–drug interaction also may have played a role at the level of the provider.

Could this account for this atrociously low level of treatment? I would like to think the authors are wrong—that we as transplant physicians are not that bad. It is possible that their numbers are underestimates. Some of their numbers in the text are higher than the graphs indicate (eg, 35% of D+R+ patients). A quality check of their pharmacy database, for example, looking at calcineurin inhibitor use in their database (which should be close to 100%), would have been helpful to determine if the pharmacy records were complete. It is also unclear what percentage of patients may have received therapy through compassionate-use programs or clinical trials. Although possible, it is unlikely that a lack of viremia accounted for most of the untreated patients, especially in the renal transplant patients, and it could not explain the difference between private and government payers for the liver recipients. So, I am left with a sense of disappointment in our past, hope for our future, and a pressing need to go through my transplant database and get to work on obtaining DAA therapy for those I may have left behind.

Given that hepatitis C therapy is recommended for all patients who do not have a short life expectancy, certainly all transplant recipients should be treated for hepatitis C in the early posttransplant period prior to developing any significant liver disease in the liver allograft or progressive disease in the renal transplant recipient. Early therapy would also prevent any cases of cholestatic hepatitis. Given that hepatitis C therapy is likely cost-effective in the nontransplant setting, it would certainly be cost-effective in the transplant setting. One would hope that we are doing better with pangenotypic lower cost DAA options with the occurrence of fewer drug–drug interactions. Given the World Health Organization's (WHO's) recommendation for HCV elimination by 2030, the fact that the transplant community has not been able to eliminate HCV in our transplant recipients remains a concern. Better education of our providers, advocacy for our patients, and better access to medications are the only solution to this problem. I certainly hope we get there soon.

DISCLOSURE

The author of this manuscript has conflicts of interest to disclose as described by the American Journal of Transplantation. Research grants for research (paid to Institution) and Consulting: Abbvie, Gilead, Merck, Bristol Meyer Squibb.