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Prolonged Pegasys+RBV Therapy to 72 Weeks May Improve SVR in Patients Who were HCV RNA+ after 4 weeks & slow responders
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Reported by Jules Levin
There were two studies presented at AASLD examining the potential benefits of extending treatment from 48 to 72 weeks with Pegasys plus ribavirin. One study found that patients with detectable HCV RNA after 4 weeks of therapy could benefit from extending therapy from 48 to 72 weeks. The second study found that in patients with 'slow viral response' (positive HCV RNA at week 12 with between 50 to 5,000 IU/mL, but negative HCV RNA ayt week 24) could reduce relapse rates and improve sustained response rates. Read details of both studies below.
"Longer Treatment Duration With Peginterferon alfa-2a (40KD) PEGASYS and Ribavirin (COPEGUS) in Naïve Patients with Chronic Hepatitis C and Detectable HCV RNA After 4 Weeks of therapy"
--The SVR rate was significantly higher in patients treated for a total of 72 vs 48 weeks, including those with genotype 1 and high baseline viral loads.
-Prolonged therapy reduced the relapse rate in this study
--there was not an increase in incidence or severity of adverse events, but there was an increase in the number of patients who voluntarily stopped treatment
Data from viral kinetic and pilot studies suggest that treatment for longer than 48 weeks may increase sustained virological response (SVR) rates in patients who do not have a rapid decrease in HCV RNA after the start of treatment. The TeraViC-4 study is focused on such patients. Those without a rapid virological response (nonRVR) at week 4 (ie patients with detectable serum HCV RNA, >50 IU/mL by PCR) to Pegasys plus Copegus were randomized to a total duration of 48 or 72 weeks of treatment. JM Sanchez-Tapias and the TeraVIC-4 Study group reported results from this study in an oral session at AASLD (October 2004). There was some criticism from researchers/doctors at the microphone after the presentation regarding the study design, but at these meetings there is frequently disagreement between researchers regarding the significance of study results.
Extended treatment beyond 48 weeks may also be potentially helpful for individuals with negative predictive factors such as HIV, previous nonresponders, cirrhotics, but this study did not specifically examine these questions.
Sanchez-Tapias provided this background. HCV kinetic analyses during antiviral therapy indicate that sustained virologic response: inversely correlates with the time of therapy necessary to clear serum HCV RNA; and directly correlates with the time on therapy after clearance of HCV RNA. Extension of treatment may increase the efficacy of therapy in patients who do not show virological response early during therapy.
On a personal note, I completed 18 months (72 weeks) therapy with peginterferon plus 800 mg ribavirin (I weigh 140 lbs) about two years ago. I did the extended 18 months therapy because there was data back then from a study suggesting that extended therapy might be helpful in achieving a sustained viral response and in preventing relapse. I felt and other key thought leaders also felt that people like myself with negative predictive factos might do better with 18 rather than 12 months therapy. My doctor, a leading researcher who also knew of this data and theory, agreed with me. I had previously been treated with standard IFN plus RBV but had no viral response, so I was a nonresponder. I have HIV, people with HIV have less SVR rates than HCV monoinfected, I had cirrhosis. So I had several important negative predictive factors. Within 5 weeks after starting pegIFN+RBV I had a complete viral response, my viral load was undetectable. It may have gone to undetectable sooner but my first test was at 5 weeks. It's two years since I completed 18 months therapy and I test my viral load every few months and it's still undetectable. I consider myself "cured". There is no way to be sure if the 18 months was more effective for me. Perhaps my outcome would've been the same with 12 months therapy. But in retrospect I'm glad I did the 18 months. If I hadn't I might have regretted it.
Back to the study. The aim of the study was to compare the efficacy and the safety of treatment with PEG-IFN alfa-2a (40KD) plus ribavirin administered during 48 or 72 weeks in patients who did not have a rapid virological response (RVR).
RVR was defined as undetectable serum HCV RNA at week 4 of therapy (COBAS AMPLICOR HCV Test v2.0, <50 IU/mL).
PATIENT STUDY POPULATION. Adults with chronic HCV; elevated ALT; HCV RNA >600 IUmL; liver biopsy proven; treatment-naïve; compensated liver disease; no contraindications for study drugs; no significant co-morbidity.
517 patients started the study. At week 4 a PCR HCV RNA was performed. 36% (n=184) of patients had negative HCV RNA and went on to treatment for 24 or 48 weeks depending on their genotype, 24 weeks for genotype 2/3 & 48 weeks for genotype 1.
326 (64%) patients had positive HCV RNA at week 4 and were randomized to 48 or 72 weeks of therapy with Pegasys and ribavirin 800 mg/day.
CHARACTERISTICS of the patients with positive HCV RNA at week 4: 65% men; 43 yrs old; 75 kg weight; 1.0 HCV RNA x 105 (IU/mL); 39-46% >800x 103 IU/mL. 94% genotype 1; ALT 2.5 x ULN.
RESULTS
The SVR rate was significantly higher in patients treated for a total of 72 vs 48 weeks, including those with genotype 1 and high baseline viral loads. As you can see patients with 72 weeks therapy had better sustained viral response rate (45% vs 32%), but also they had less relapses, presumably due to the longer treatment. (EOT=end of treatment response rate).
72 WEEKS THERAPY:
EOT 52%
SVR 45% (n=161)
ITT
48 WEEKS THERAPY:
EOT 61%
SVR 32%
ITT
P=0.014
RELAPSE RATE
The relapse rate was significantly less for patients taking 72 vs 48 weeks therapy (48% vs 13%, p=0.05).
SUSTAINED VIRAL RESPONSE IN GENOTYPE 1 PATIENTS
ITT
SVR was 28% for 48 weeks therapy vs 44% for 72 weeks (p<0.001).
ADVERSE EVENTS
The rates of commonly reported adverse events were the similar for patients whether they received 48 or 72 weeks therapy. Serious adverse events were 5% for 48 weeks & 8% for 72 weeks. There were no previously unreported AEs.
TREATMENT DISCONTINUATION
At week 24, disct was 12% in 72 week grp & 11% in the 48 week grp, the same. At week 48, disct was 18% in the 48 week grp 7 27% in the 72 week grp. And at week 72 the disct rate was 36%.
REASONS FOR DISCONTINUATION
adverse events: 10.3% in 48 wk grp, 13.0% in 72 wk grp
lab abnormalities: 0% in 48 wk grp, 1.2% in 72 wk grp
patient's own decision: 4.8% in 48 wk grp, 18.0% in 72 wk group
other reasons: 1.8% in 48 wk grp, 4.3% in 72 wk grp
SLOW VIRAL RESPONDERS MAY BENEFIT FROM 72 WEEKS THERAPY
"Reduction of Relative Relapse Rates by Prolongation of the Duration of Therapy with Peginterferon alfa-2a (Pegasys) plus Ribavirin up to 72 Weeks in Patients with HCV Genotype 1 Infection"
--Early viral responders (week 12 negative) achieved high SVR (75-80%) regardless of treatment duration (72 or 48 weeks)
--Slow viral responders (week 12 positive & week 24 negative) showed significantly improved SVR rates when treated for 72 weeks as a result of reduced relapse rates
--About 18% of the genotype 1 patients in this study were slow viral responders
--Authors said: our data do not support the concept of generally extending treatment duration to achieve higher SVR rates in patients with HCV genotype 1, BUT in the small significant sub-group of patients with slow viral response extension of treatment to 72 weeks may represent a strategy to improve sustained viral response rates in this difficult to treatment patient population
Thomas Berg presented these study findings at the AASLD meeting in the same oral session as the study above. The reasons for the relatively high virological relapse rates after antiviral combination therapy in patients with HCV genotype 1 are unknown. Slower turnover of hepatocytes infected with HCV type 1 could be a reason. A prolongation of the duration of the therapy could represent a strategy for reducing relapse rates in this difficult-to-treat patient group.
In a German multicentre study 453 treatment-naïve patients with histologically proven chronic HCV type 1-infection were treated with 180 µg peginterferon alfa-2a per week plus 800 mg ribavirin per day for either 48 weeks (n=231) or 72 weeks (n=222).
Patients had elevated ALT & compensated liver disease (Child Pugh A). Liver biopsy findings were consistent with chronic HCV. All patients had genotype 1 and HCV RNA >1000 IU/mL. 55% males; 97% Caucasian; 75 kg weight; 25.3-25.6 kg/m2 BMI; ALT 2.5 x ULN; HCV RNA 5,7 IU/mL; 7.4-9.0% had cirrhosis.
RESULTS
VIROLOGIC RESPONSE RATES
(ITT)
The intention to-treat analysis presented at AASLD 2003 didn't show a significant difference in the sustained virological response rate between the two treatment groups (52% vs 53% SVR; EOT 72% 48 wks, 67% 72 wks). In this study we examined the influence of the duration of therapy on the relative relapse rate in relation to viral kinetics.
RELAPSE RATES
Overall the relative relapse rate (related to the number of patients with negative HCV RNA at the end of therapy) was 23% (72/314). In patients treated for 48 or 72 weeks, the relapse rates were 26% (44/165) and 19% (28/149) (p=0.09), respectively.
SVR IN RELATION TO EARLY VIRAL RESPONSE
No significant difference was evident for sustained virological response in patients who were HCV RNA negative at week 4 or 12.
For patients with HCV RNA <50 IU/mL at week 4 there was no difference in SVR rates whether they were treated for 48 weeks (84%) or 72 weeks (77%). And also at week 12, patients with <50 IU/mL, 80% treated for 48 wks & 75% treated for 72 wks had SVR.
30% of patients with >50 IU/mL at week 12 receiving 72 weeks vs 18% receiving 48 weeks therapy had SVR, but this was not significant (p=0.08). For patients with detectable HCV RNA at week 4 SVR rates were similar (44% for 48 wks & 50% for 72 wks).
REFINED ANALYSIS OF THE STUDY; GOAL
Whether there is a difference in the relapse rates between type 1 infected patients treated either for 48 or 72 weeks in relation to the early viral response
Early viral response defined; HCV RNA >=2 log decline or undetectable at treatment week 12 by qualitative PCR (Roche Amplicor).
Slow viral response; HCV RNA <2 log decline or detectable at week 12 by qualitative PCR but becoming undetectable at week 24.
RELAPSE RATES in EARLY VIRAL RESPONDERS
In patients with >2 log decline in HCV RNA SVR was the same whether treated for 48 or 72 wks: 22% for 48 wks, 17% for 72 wks.
In patients with <50 IU/mL at week 12, SVR rate was also the same: 13% for 48 weeks, 12% for 72 wks.
BUT...
RELAPSE RATES IN SLOW VIRAL RESPONDERS
For patients with <2 log decline at week 12, 90% (9/10) had relapse with 48 wks therapy but only 57% relapse (4/7) with 72 weeks therapy (p=0.14). For patients with >50 IU/mL at week 12 34% with 72 weeks therapy had relapse vs 60% taking 48 weeks therapy (p=0.028).
RELAPSE RATES LOWER IF VIRAL LOAD WAS LOW AT WEEK 12
Patients with <50 IU/ml at week 12 had 13% (48 wks) & 12% (72 wks) relapse rates. BUT, for patients with 50-5,000 IU/mL (mean 1049) at week 12, the length of therapy mattered: 50% receiving 48 wks had relapse & 24% receiving 72 weeks had relapse (p=0.037). Patients with >5000 IU/mL at week 12 (mean 44,113) had similar relapse rates regardless of length of therapy (90% for 48 wks, 75% for 72 wks).
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