Treatment of HCV with the new DAAs: Before or After Kidney Transplant?

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In the pre-DAA era, the dogma was to treat
HCV pre-transplant for two reasons: active HCV increases post-transplant
hepatic complications, NODAT, and decreases patient and graft survival and that
IFN cannot be used post-transplant because of higher risk of graft rejection.
The highly effective and safe newer DAA options have literally eliminated both of these problems making the hitherto unfeasible strategy of treating HCV
post-transplant feasible.
Needless to say,
pre-transplant treatment can improve the risk of HCV-related
morbidity, incidence of diabetes and possibly cardiovascular disease in
waitlist candidates but they do have to wait longer (3-5 years) for an HCV
negative kidney post treatment. Instead, if they choose to receive a HCV+
kidney and get treatment post-transplant they just have to wait only for 6
months to 1 year
. The downsides of waiting longer (after successful HCV
treatment) are worsening of their general condition during the wait time and even
never getting transplanted at all. Receiving an HCV+ kidney and treating HCV post-transplant
is safe, shortens waiting time and is cost effective
Purely on a utilitarian basis, it does make
sense to treat HCV post-transplant, unless the wait time is expected to be short i.e. AB
blood group, live donor transplant, centers with short
waiting time or if liver disease is severe enough to warrant early treatment. For live donor transplants planned within 24 weeks, HCV treatment should not
unnecessarily delay the transplant itself as the cure can be obtained with DAAs
post- transplant. If the transplant is expected to be delayed (>24 weeks),
it is wise to treat GT1/4 pre transplant with renal safe
non-sofosbuvir regimens but for non GT1/4, depending on the expected time of
transplant, sensitization and risk of rejection, liver status, general
condition  and patient preference, the treatment can be performed either
pre-transplant with IFN/ribavirin or post- transplant with sofosbuvir based DAA
regimen.
Transplanting
HCV+ve kidneys into HCV-ve Recipients: solves problems raises questions 
The recent THINKER trial reported successful
treatment of HCV in 10 NAT negative recipients transplanted with GT1 positive
kidneys, under ATG induction and triple drug (CNI, MMF, steroid)
immunosuppression. Although all recipients had viremia on day 3, sustained viral response (SVR) at 4 weeks was 100%
with Elbasvir/Grazoprevir. At 6 months none had virological relapse and graft
function was excellent (median eGFR at 6 months was 62.8ml/min/1.73m2). The
only major adverse event observed was sub-nephrotic proteinuria/FSGS in one patient that
occurred after SVR at 12 weeks and so is less likely to be HCV related. Another patient
had a transient increase in the class I DSA without any rejection.
This D+/R- study provided the recipients with high quality donor kidneys
(median KDPI 42%) and significantly reduced the wait time (range between 11
days to maximum of 130 days)Although very
successful, this small pilot study raises many questions:
  • Liver outcomes, patient/graft survival in case a SVR
    does not occur (rare)
  • Cost-benefit ratio if
    second line DAA is required
  • Potentially increased risk of DSA and rejection
  • Treatment options if donor has non
    GT1/4 HCV infection
Current
challenges in HCV treatment and Future of DAA
Growing RAV (resistance associated variants) and
DAA resistance is a threat to HCV treatment. Further DAA treatment for non
GT1/4 in renal failure and allograft dysfunction is still a challenge. Pan-genotypic DAAs which are effective and safe
in renal failure will hopefully soon be a reality. Glecaprevir/Pibrentasvir is
one such DAA now awaiting FDA approval. It has been found to result high SVR
irrespective of genotypes, liver
status
, previous IFN exposure and CKD stage (98% SVR in stage 4/5). The
effectiveness in DAA exposed patients is being currently studied by MEGALLAN part 2 study.
Post by Prabhu Kanchi

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