Treatment of HCV with the new DAAs: Part 1

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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 levels, making 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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