UPDATE ON MANAGEMENT OF HCV- GENOTYPES 2 & 3

EPIDEMOLOGY:
  • Global Challenge – global impact ,130-170 million chronically infected approximately 2-2.5% of world’s total population.
REGINOL DIFFERENCES:
  • Highest prevalence rates – developing poor countries in Africa & Asia e.g PAKISTAN, INDIA, CHINA. Low prevalence rate in developed countries.
HCV –    Treatment Goals:
  • To reduce virus related complications & achieve SVR, SVR – clearance of virus, SVR 12 & SVR 24.
HCV –    Treatment Principles:
  • Patients with acute HCV should be considered for antiviral therapy in order to prevent progression.
  • Treatment & cure of HCV has been shown to prevent long term risk of complications and is the primary form of management.
  • Not everyone with HCV infection will develop cirrhosis & its complications.
  • An approach involving disease progression .
HCV:

In the past 25 years great progress has been made in elucidating the life cycle. These advances facilitated drug discovery efforts specially DAA & HTA. DAA with better safety profiles & efficacy have been approved. Physicians & HCP & patients should be aware of these improvements & update practice accordingly.

HCV-GENOTYPES:

Comparison of HCV Nucleotide sequences revealed presence of six major genotypes & with large number of subtypes. A very recent study revealed the presence of at least 7 different HCV genotypes & 67 subtypes.

Genotype 2 & 3:

Grouped together in terms of response to treatment. Mounting evidence that SVR rates are higher in HCV-2 patients than in those infected with HCV-3 (80% Vs 70%). Real-life studies have recently reported somewhat lower SVR rates.

Predictions of Response:

Strongest predictors are the degree of fibrosis & RVR at week 4.  Others factors such as low baseline RNA levels, Age, Gender, BMI & genetic polymorphisms IL28 B are less important.  Patients with cirrhosis achieve slightly lower SVR rates particularly in HCV-3-50%.

 

Management:

IFN – based therapy has been SOC treatment for the past 20 years. In 2011 the first generation Protease Inhibitors TVR & BOC became available as triple therapy.  These drugs are limited by emergence of resistance, high rates of SE, less effectiveness in patients with cirrhosis & null responders. Not efficacious for Non-genotype I. Therapy continues to rapidly evolve leading to heightened expectations for universal cure. In Dec 2013 FDA approved sofosbuvir – a potent pangenotypic NA in combination with RBV for the treatment of HCV-2&-3. First oral IFN-Free regimen. New treatment regimens, have higher efficacy, improved tolerability, simplified dosing schedule & shorter duration of treatment. Absence of viral breakthrough during treatment & high barrier to resistance.  Effective in IL28B, CT, TT variants. Much higher cost than the current SOC. Main limitation in future in resource constraint regions. In these transitional times Peg-IFN & RBV continue to the main therapy & best candidates are the patients who achieve RVR. IFN-Free oral therapy must be individualized & tailored care according to resources available.

DRUGS – HCV:

  • NS3/4A Protease Inhibitors (Telaprevir, Boceprevir , Simeprevir, Paritaprevir – ritonavir, Grazoprevir – Broad genotype coverage, Asunaprevir – Japan, ACH – 1625 – all Genotypes,IDX 320,GS – 9256, GS – 9451)
  • NS 5 B – Polymerase Inhibitors ( Nucleoside Analog Inhibitors ; Sofosbuvir, IDX 21437, ACH 3422.Non-Nucleoside Inhibitors ; Dasobuvir, Beclabuvir, Filibuvir, BI-207127,BMS – 791325,VX – 222)
  • NS5A INHIBITORS (Daclatasvir, Ledipasvir, Ombitasvir, Elbasvir, GS-5816, BMS – 824393, PPI – 461)
  • Novel IFN – Free – DAA therapies ; 1. Sofosbuvir based regimens NS5A & NS3-4 A Inhibitors.

SOFOSBUVIR WITH ; Ribavirin, Semiprevir, Daclatasvir, Ledipasvir, GS-5816. Studied in other all – oral regimens – given for 4-24 weeks.

Novel NS5A & NS3-4A based regimens ; 1.Daclatasvir & Asunaprevir  2.Paritaprevir – ombitasvir – dasobuvir  3.Daclates vir – asunaprevir – baclabuvir  4. Grazoprevir – Elbasvir  5. Grazoprevir – Elbasvir – Sofosbuvir  6. Grazoprevir – Elbasvir – IDX 21437

Treatment of HCV GT 2 & 3:

Therapy for GT 2/3 saw a major change in 2014 with the approval of sofosbuvir. SOF is a new NS5B polymerase. Inhibitor Nucleoside with pan genotypic efficacy. Approved as the first IFN free regimen by FDA in Dec 2013 & EMA in early 2014. Given the availability of SOF & the two NS5A inhibitors DCV & LDV, treatment regimens with Peg IFXi seem to be outdated.However treatment with PEG 1 FN/RBV dual therapy may be still considered depending upon health care system & esp. for easy to treat patients.

Treatment of GT 2:

OPTION 1 : Must be treated with daily Weight based Ribavirin( 1000 mg < 75 kg  1200 mg > 75 kg) & Daily Sofosbuvir 400 mg for 12 weeks. Therapy should be prolonged to 16-20 weeks in patients with cirrhosis esp. if they are treatment experienced.

OPTION 2 : Cirrhotics and/or treatment experienced patients can be treated with weekly Peg IFN, daily weight based RBV& daily sofosbuvir 400mg for 12 weeks.

OPTION 3 :   Cirrhotic and/or treatment experienced patients can be treated with an IFN free combination of daily Sofosbuvir 400 mg & daily Daclatasvir – 60 mg for 12 weeks.

OPTION 4 : In settings where these options are not available, the combination of Peg-IFN & Ribavirin remains acceptable for 24 weeks.

GENOTYPE 3:

OPTION 1 : HCV GT3 patients can be treated with a combination of weekly Peg IFN, daily weight based RBV & Sofosbuvir-400 mg for 12 weeks. This combination is a valuable option in patients who – failed to achieve an SVR after Sofosbuvir plus RBV, patients with cirrhosis &previously failed IFN & RBV.

OPTION 2 : Daily sofosbuvir – 400 mg & daily Ribavirin – weight based for 24 weeks. This therapy is suboptimal in treatment experienced cirrhotic patients & Patients failed to achieve on SVR after SOF plus RBV treatment.

OPTION 3 : Patients without cirrhosis can be treated with IFN-free combination of daily SBV-400 mg & daily Daclatasvir for 12 weeks. Patients with cirrhosis (treatment Naïve & treatment experienced) should receive this combination with daily weight based RBV for 24 weeks. (Pending results 12 weeks Vs 24 weeks).

OPTION 4 : In settings where none of these options is available the combination of Peg-IFN  & Ribavirin remains acceptable for 24 weeks.

BENEFITS OF DAA : Improvement in liver function, Improvement of ascites & HE , Improvement in Bilirubin, Albumin, MELD & CPT scores.

NOTE : If patients with cirrhosis achieve SVR, it is important to continue with HCC surveillance because cirrhosis remains & HCC development in reduced but not abolished.

DAA have revolutionized the treatment. As combination therapy with Peg-IFN  RBV and/or other DAAs, resulting in HCV eradication in vast majority of patients with CHC. The Novel, investigational IFN-free regimens may substantially increase future opportunities to treat HCV. Novel all-oral combinations may be superior for the treatment of HCV-GT3 infection. Patients with decompensated cirrhosis & may allow ultrashort treatment durations & decrease costs of antiviral therapy.

On March 30th, 2016, posted in: Blog by
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