HCV; the Rising Concerns and Growing Hopes Figure 3. Retrospective Analysis of pegIFN alfa-2b/RBV Trials (n = 511) Alavian SM et al. help to improve adherence. In IDEAL trial those who were adherent to the advised treatment and received at least 80% of PegIFNα dose and 80% of RBV over 80% of the treat- ment course experienced significant higher SVR rates (20% to30% more SVR compared to those who did not have 80/80/80 adherence) (22). Similarly, a retrospective analysis on PegIFNα-ab/RBV treated patients reported by McHutchison JG. et al., showed a notable rise in SVR (%) when adherence rate had been improved (26) (Figure 3) 3.3. Goals of Treatment in HCV Infection and the Failure Scenarios 0.000 Figure 4. Response Criteria Definition-Patterns of Suboptimal Response When treating chronic hepatitis C, the goal of treat- ment is to eradicate the virus, which is predicted by the McHutchison JG, Manns MP, Patel K, Poynard T, Lindsay KL, Adherence to achievement of an acceptable SVR. The ultimate goal is ar- combination therapy enhances sustained response in genotype-1–infect- riving at “cure” defined as remaining HCV-RNA negative ed patients with chronic hepatitis C, Gastroenterology, John Wiley & Sons Ltd, with permission for at least five years after achieving SVR. Despite using the standard of care regimens for treating of hepatitis C, there are patients who face treatment failure to antiviral therapies. Failure to treatment is categorized into differ- PeglFN alfa and RBV ent entities. These include relapse, non-response, ) 7 NullResponse* response, and viral breakthrough. Relapsers experience undetectable HCV RNA during treatment but have the vi- L6 m rus reappeared after treatment is stopped. Non-respond- /IU5 Partial Non-Response* ers on the other hand fail to have cleared HCV RNA from 1g4 0 their sera after 24 weeks of therapy. The response to o l ( 3 therapy means failure to have decreased HCV RNA by 2 A N2 logs after 24 weeks of therapy. And finally there are pa- R V 1 SVR tients who are categorized to have viral breakthrough. C H0 -8 -4 -2 0 4 8 12 16 20 24 32 40 48 52 60 72 In these patients HCV RNA reemerges after it becomes Wks After Start of Therapy undetectable while on treatment (27, 28) (Figure 4). When patients achieve the SVR, this raises the question wheth- *Subset of Nonresponse er the achieved response is sustained for following years Ghany MG, et al., An Update on Treatment of Genotype 1 Chronic Hepatitis or not. The longer the time with HCV RNA negative after C Virus Infection: 2011 Practice Guideline by the American Association for SVR, the lower the risk of recurrence, and this is the key the Study of Liver Diseases, Hepatology, John Wiley & Sons Ltd, with per- mission factor for the concept of “cure”. With regard to hepati- tis C, the concept of cure achievement is defined under multifaceted response criteria (27). The subcategories of Figure 5. 99% of the Patients Who Achieved SVR Continued to Have Nega- response criteria which may define “cure” achievement tive HCV-RNA Over a five Year Follow Up in HCV patients include virological, clinical, immuno- 1.00 logical, biochemical and histological responses, of which 0.99 virological response is crucial. Virological response lead- 0.98 ing to cure is defined as durability of the SVR over a long edun 00se..9967 term follow up (i.e. five years). SVR rate per se, depends on treatment response criteria during the treatment course i n tn 0op.95 and specific milestones. Early virologic response (EVR) is o s fc 0re.94 when at least a 2 log reduction in HCV RNA (a partial EVR) yo 0ed.93 liitb 0itan.92 or HCV RNA negativity (a complete EVR) occurs by week 12 of treatment. End of treatment response (ETR) is defined rPob a 0su0..9901 s as HCV RNA negativity at the end of treatment. Rapid vi- 52 Yr1 104 Yr2 156Yr3 208 Yr4 260Yr5 312 ≥ Yr5 rologic response (RVR) is when HCV RNA negativity oc- Weeks since previous treatment stop date curs after four weeks of treatment and delayed virologic response means HCV RNA positivity at week 12 but nega- Manns M, Lindsay KL, Gordon SC, et al., Sustained virological response af- tive by week 24 (28) (Figure 4). Today we have evidence de- ter peginterferon alpha 2b and ribavirin predicts long-term clearance of noting that, SVR could be durable and almost all patients HCV at 5 year follow up, J Hepatol, John Wiley & Sons Ltd, with permission who have arrived at SVR should be considered as cured. Hepat Mon. 2012 427