Tuesday, July 4, 2017

Treatment of HCV with the new DAAs: Part 1

The Burden of Hepatitis C
The estimated global Hepatitis C viral infection (HCV) burden was slashed down to 71 million by the WHO in 2015, from the earlier estimate of 130-150 million, after Rao et all showed that only 51% of patients with positive serology actually carried the virus (detectable RNA by NAT, nucleic acid amplification test). The remaining HCV seropositive have either cleared the virus [spontaneously or after treatment] or have a false positive serology. These NAT negative seropositive patients are considered non-infectious. NAT positive but seronegative individual are always infectious, except for the rare patients with false positive NAT (< 0.2%). NAT is the only reliable way to diagnose HCV in transplant candidates since these patients can be seronegative (due to immunosuppressive state) despite viremia and can have normal liver enzymes despite having liver disease.

Overall, genotypes GT1 followed by GT3 are the most common strains and have a global prevalence compared to GT 2,4 and 6. GT5 is the least common of all having prevalence of <1% and limited to southern Africa. In the United States, approximately 70% of chronic HCV infections are caused by GT1 (55% of 1a, 45% of 1b) followed by GT2 (15 to 20%) and GT3 (10 to 12%). GT 1 is the more aggressive of all and also more resistant to interferon therapy but GT2 has greater risk of CKD progression than GT1.
Serology, NAT and HCV Transmission in the Transplant Setting
Transmission of a virus in eclipse phase (see below) is a well-known phenomenon with HIV and HBV. The eclipse phase is the time lag for the NAT to detect viremia after an acute infection. Even with the new generation HCV PCR tests, there is an eclipse phase of about 5-7 days. 
The first ever report of transmission of HCV from a NAT negative donor was reported in 2015. Notably in all the reported cases, the deceased donors had high risk behavior. The HCV infection being missed in a potential transplant recipient or a live donor in the eclipse phase has not been reported yet but is theoretically possible, especially in centers/countries with high HCV prevalence. 

Direct Anti-Viral Agents (DAAs) and renal disease
DAA in Chronic Kidney Disease
The introduction of DAAs was met with excitement by nephrologists, see previous RFN coverage. The treatment of GT1/4 in CKD is quite straight forward as non-Sofosbuvir regimens are available i.e.  Elbasvir/Grazoprevir (EG) and PrOD (Paritaprevir, ritonovir, Ombitasvir, Dasabuvir +R(ribavirin in GT1a). See here for coverage of the C-SURFER on the blog. These combinations can be used even in CKD4/5D as they are metabolized by the liver.
In contrast Sofosbuvir has renal excretion, accumulates in renal failure (eGFR < 30ml/min/1.73m2) and unfortunately further worsens the renal failure and hence contraindicated in CKD 4/5D. Since a Sofosbuvir-based DAA regimen (Sofosbuvir plus Velpasvir or Ledipasvir or Daclastasvir or Simeprevir) is the only approved treatment for non GT1/4 ,patients with eGFR< 30ml/min/1.73m2  should be treated with pegIFN/ribavirin and those with less severe CKD can be still treated with Sofosbuvir without any dose reduction. This might change after the results of the study looking at effectiveness of low dose Sofosbuvir/Velpatasvir in non GT1/4 HCV patients with CKD5D, are available.
DAA in renal transplantation
Paritaprevir (effect of which is enhanced by ritonavir) inhibits the CYP3A4 enzyme causing 4-6 fold elevation in cyclosporine levels and nearly 60-80 fold elevation in tacrolimus levelsmaking use of the PrOD regimen less desirable in transplant setting. Even though PrOD was effective in liver transplant studies and no rejection reported with CNI dose changes, it has been never used in renal transplant studies. Since there is little direct data in allograft dysfunction, the data from CKD may be extrapolated to the transplant setting.

HCV Positive Donors
D+ donor kidneys are non-inferior
Outcomes of HCV D+/R+ was considered inferior to D-/R+ since the early viral replication with immunosuppression was thought to increase the risk of the liver disease, graft failure and patient mortality. It was even considered that transplantation outcomes with HCV+ donors not different from HCV+ patients remaining on dialysis. In reality, the risk was later found to be very small from 13 year UNOS data published in 2012. The risk of receiving a HCV+ kidney translated to only <1% lower survival at 1 year and a 2% lower survival at 3 years. Also, recently Morales showed that 10 year patient and survival graft survival was not different between D+ and D- to R+ patients.
HCV+ Donor Kidneys are underutilized
Increasing IV drug abuse in the past two decades has increased the prevalence of HCV in the young. Many of these newly infected population are unaware of the infection and so unlikely to get treatment but more likely to die due to drug over-dosage and hence are potential donors of  high quality kidneys. About 300-500 unrealized opportunities exist each year in US and nearly 4100 HCV positive good quality kidneys (with average KDPI 70%) were discarded between 2005- 2014.
In the following post I will deal with treatment issues including whether to treat with DAAs pre or post transplant.

Post by Prabhu Kanchi, Nephrology Fellow, Ottawa

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