EVALUATION OF DURABILITY OF SUSTAINED VIROLOGICAL RESPONSE (S.V.R.) IN CHRONIC HEPATITIS C TREATED PATIENTS

EVALUATION OF DURABILITY OF SUSTAINED VIROLOGICAL RESPONSE (S.V.R.) IN CHRONIC HEPATITIS C TREATED PATIENTS

By

Fathy Ghamry,  Mahmoud  Bazid,  Ahmed  El- Sawy

and  Wael El-Sehily

Internal Medicine Department - Faculty of Medicine - Al-Azhar University

ABSTRACT

Background: The introduction of direct acting anti virals hase increased sustained virological response (SVR) rates in chronic hepatitis C infection.  At present,  data on long-term durability of viral eradication after successful triple therapy are lacking.

Objective: The predicators of durability of Sustained Virological response (S.V.R.) and its impact as pre-treatment markers.

Patients and Methods: Sixty patients with chronic hepatitis C virus achieved S.V.R. (sustained virological response).   After 12 months of treatment, all patients were subjected to  D.M., H.T.N, any special habits like smoking, clinical examination, PCR for HCV, IL28B genotyping, Liver function tests, CBC and other associated diseases e.g. HIV ,HBV, Serum iorn concentration.

Results: Several factors (host or viral-related factors or treatment related factors)  influenced  response to therapy and durability of S.V.R, advanced fibrosis, cirrhosis and steatosis have a negative impact on S.V.R. Also, IL28B genotyping can influence the durability of S.V.R. Patients with CC genotype were more likely to be cured by Peg-IFN and RBV, or  recent free INF therapy.

Conclusions: Many factors can influence patients response to therapy and durability of SVR and IL28B  C/C genotype play a great role in  clearance of HCV.

Key words: Sustained virological response, Chronic hepatitis, Virus C.

INTRODUCTION

     Hepatitis C is an infectious disease affecting primarily the liver caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure, cancer liver  or life-threatening esophageal and gastric varices.Chronic  infection after several years may cause cirrhosis or cancer liver .  Fatty changes to the liver occur in about half of those infected patients and are development of usually present before cirrhosis. (Paradis and Bedossa, 2008).

     Several factors have been implicated in predicting the response to the treatment and it may be used as pretreatment markers for selection of the patient (Lee  et al., 2011).

     Both host and viral factors can influence patient response to therapy & durability of (SVR) including age, sex, degree of activity, degree of liver fibrosis or cirrhosis, pretreatment viral load, type of interferon, genetic variation of IL₂₈B, HCV genotype, response pattern to previous antiviral therapy (Maylin et al.,  2009).

    SVR is defined by the absence of detectable HCV RNA in the serum as shown by a qualitative HCV RNA assay with lower limit of detection of 15 Iu/mL or less at week 24 after the end of treatment (Shiratori et al., 2012).

    SVR rates for genotype 1-infected patients ranged from 41%-52% after 48 weeks of PEG IFN / RBV and Interferon free therapy  as opposed to 76%-84% in genotypes 2 and 3 (Hadziyannis et al., 2014).

     Over the past years, interferon (IFN) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response (SVR), short treatment and improved tolerability, INF- free treatment  represents the paradigm for both treatment-naive and exprienced patients. (Zeuzem  et al.,  2014).

    The present work aimed to evaluate to S.V.R. and its impact as pre-treatment markers.

PATIENTS AND METHODS

     Sixty patients with chronic hepatitis C virus achieved S.V.R. (sustained virologi-cal response) after 6 months of treatment completion were selected from patients admitted to Internal  Medicine Depart-ment, Kobri-El-Koba Military Hospital.

     All patients were subjected to careful and detailed history, thorough clinical examination, laboratory investigations including PCR,liver function test and CBC, other associated diseases, e.g.  HIV, HBV, Serum iorn concentration, IL28B genotyping by sequencing mechanism to detect type of IL28B polymorphism, and Fibrotest to determine the severity of liver disease (degree of liver fibrosis and cirrhosis).

    The patients were evaluated after 12 months from the end of treatment,  and were classified into two equal groups.

     Group (A) were -ve HCV RNA PCR with durable S.V.R. at 12 months after the end of treatment, and Group (B) were +ve HCV RNA PCR 12 months after the end of treatment.

RESULTS

    A total of 60 patients (females were equal to males, age 59.6+6.8  years) with a sustained virological response (SVR) were evaluated.  The SVR in smokers was significantly lower than in nonsmokers.  There was a highly significant difference in IL28B genotyping. Percentage of CC genotype were high among group(A) than group (B).    The percentage of CT genotype and TT genotype were high among group (B) than group(A)(Table 1).

Table (1): Characteristics of patients.

There was a significant difference as regard associated diseases (D.M, H.T.N, D.M and H.T.N Hepatic steatosis) between the two studied groups of patients (Table 2).

Table (2): Comparison between the two studied groups of patients as regard different associated disease.

The difference in degree of disease severity (liver fibrosis) was highly significant (P value <0.01) between group (A) and group (B).  The percentage of severity of liver fibrosis by (fibrotest) was high among group (B) than group (A) (Table 3).

Table (3): Comparison between the two studied groups of patients as regard disease severity

    There were highly significant difference between group (A) and group (B) as regard pretreatment viral load   The range of pretreatment viral load was high among group (B) than group (A) (Table 4).

Table (4): Comparison between the two studied groups of patients as regard the pretreatment viral load.

DISCUSSION

     This  study confirms that  SVR  equals permanent HCV eradication by whatever interferon-based anti-viral treatment it was achieved. Our data indicate that the Favourable  long-term outcome reported after peg-interferon/ ribavirin combination therapy seems to hold true for patients treated with a triple therapy with peg-interferon/ ribavirin in combination with a direct anti-viral agent. To the best of our knowledge, this is the study reporting long-term virological outcomes in patients with hepatitis C after successful anti-viral triple therapy . (De Marcol et al ., 2012).

     There are the oretical concerns regard-ing the durability of HCV eradication after successful direct-acting anti viral-based triple therapy. During direct-acting anti-viral treatment resistance-associated variants with reduced rep-lication fitness compared with the wild type virus may emerge. If these resistance-associated  variants  cannot be eliminated  by  the required peginterferon/ribavirin backbone,  strains with reduced replication fitness may  persist in low concentration and  may account for  late  relapses (Nelson  DR et al., 2012).

     In  our study,  30 patients with a sustained  virological  response (SVR24) experienced a relapse  12 months later. Both patients completed a full course of  anti-viral treatment without dose  modifications  or  discontinuations of medications with peg-interferon/ ribavirin and free- interferon therapy . The serum samples of both patients (taken at base line and after relapse) revealed no viral resistance and showed viral homology to samples collected at screening.   the relapsed patients showed a risk  behavior  regarding HCV  infection before  reappearance of  HCV.

      Thus, in  patients a late relapse rather than a newly acquired infection seems to be the reason for reappearance  of  hepatitis C virus. Obviously, an ongoing  occult  HCV infection  cannot  be excluded  with certainty (De Marcol et al., 2012).

     Overall, our data show that it seems appropriate to extrapolate the encouraging long-term data of dual combination therapy to triple therapy with direct-acting ant virals.  The laterel apserate was 1.9%  (95%CI:0.24–6.8) as compared to 0.18% (0.004-1.01) in a much larger cohort of patients with SVR after dual therapy.  As all patients treated with direct-acting anti-viral in combination with PEGIFN/RBV achieving similar rates of SVR were followed prospectively, a potential selection bias is unlikely.(Ruller et al., 2013).

     However, in parallel to reported late relapses after successful dual therapy, late relapses  after triple therapy although a rare event - seem to occur within the first months after SVR like in the cases in our cohort .The fact that both relapses were observed in patients receiving free- interferon therapy occurred possibly just by chance, as the mode of action and the efficacy of the protease inhibitors are  similar. Never theless, it seems advisable to confirm  a successful HCV eradication within the first year of follow-up after achieving a sustained virological response. From our  data , no impact  on the durability of SVR after interferon- free treatments can be inferred.( Lawitz EPF et al., 2012).

CONCLUSION

     Our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To  assess the long-term clinical benefit of triple therapy,  studies with a longer follow-up and larger patient numbers are needed. And that there are several factors related to the virus and patient releated factors can affect the patients treatment response and durability of SVR. It was clear from the study that the full advanced fibrosis and cirrhosis  have a negative effect on the response of viral steady. And that the genetic factor for IL28B  has an effect on SVR. And patients who have genotype cc were the most responsive to treatment.

REFERENCES

1. De MarcoL, Manzini P ,Trevisan M (2012). Prevalence and follow-up of occult HCV infection in an Italian population free of clinically detectable infectious liver disease. plosone 2012; 7 :e43541.

2. Hadziyannis S, Sette J and Morgan T (2014): Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C. A randomized study of treatment duration and ribavirin dose. Ann Int Med; 140: 346-355.

3. Lawitz EPF, Kowdley  KV,Jensen D, Cohen  DE, Siggelkow S (2012). A12-week interferon-free  regimen of ABT-450/r, ABT-072  , and ribavirin was well  Tolerated and achieved  sustained Virologic response in 91%  treatment- Naïve HCV  IL28B-CC genotype-1- Infected subjects. JHepatol  2012; 56(Suppl.2 ): S7.

4. Lee JE, Yoon NR, Kim JD and Song MJ (2011):Durability of sustained virologycal response in chronic hepatitis C: Analysis of factors related to relapse after virological response  with peginterferon plus ribavirin combination therapy. Korean J . Gastroentrology 57:173-179.

5. Maylin S,Martinot-Peignoux M and Ripault M(2009): Sustained virological response is associated with clearance of hepatitis C virus antibody. Liver Int. 29:511-517.

6. Nelson  DR,  Zeuzem  S,  Andreone  (2012): Balapiravir  plus  peginterferon alfa-2a (40KD) /  ribavirinin a randomized  trial  of hepatitis C genotype 1 patients.  Ann Hepatol  2012;

7. Paradis V and Bedossa P (2008): Definition and natural history of metabolic steatosis. Histology and Cellular Aspects; 34: 638-642.

8. Rutter K, Stätter mayer AF, Ferenci P(2013). Successful HCV eradication due to antiviral therapy is associated with improved long term outcome of  patients with chronic hepatitis C. JHepatol 2013;58(Suppl.1):S369.

9. Shiratori V and Imazeki F (2012): Histologi-cal improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med; 132: 517-524.

10. Zeuzem S (2014): Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med, Mar 2; 140(5): 370-381.