Individualized tx duration, RVR and tx duration, first dose predictions, nitazoxanide resistance. ..

[jmjm530]

Check out the Journal Options Hepatitis - Volume 3, Issue 1 at the Clinical Care Options Web site. Free registration required.

http://www.clinicaloptions.com/Hepatitis/Journal%20Options/Collections/Volume%203%20Issue%201/Pages/Page%205.aspx

Articles of interest:

Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF

Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial Donald M. Jensen, MD

Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response  Mark S. Sulkowski, MD

Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alfa-2a and ribavirin Hari S. Conjeevaram, MD, MSc

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C
K. Rajender Reddy, MD

Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide Tarek Hassanein, MD

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I will try do do some copy and paste's later but anyone with access please jump right in. At first glance looks like some very interesting and infomative reads.

-- Jim

[orleans]

Hey, I've run across all of these studies in the past couple of months "googleing". They can be found w/out having to sign up. Just a note, It is recommended that one have several PCRs prior to treatment to CONFIRM low baseline VL. As jim said, some might have low VL then highVL. This result does not qualifiy as low VL when considering 24 wks for G1s. jerry

[FlGuy]

"Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alfa-2a and ribavirin "

This one makes so much sense.

However, I don't think that the article touches on all the elements which define 'difficult to treat';  things like age, liver damage, prior treatment history, race, IR etc.

Maybe someday there will be a 'check off'' treatment calculator that can better assess the needs of the treating patient that is proliferated to all treating docs.  It seems that a patient needs to get to a very specialized and experienced liverhead in order to get customized tx magic.  And, then there's the problem of insurance companies getting in the game.  Too much wasted treatment, in my opinion, following the dusty road of SOC when there are possibilities to increase effectiveness the first time around..

[jmjm530]

Sure, all these articles are available to anyone. You can access them for a fee on the internet and some of them for free in a public medical hospital.

And hey, I was going to direct you to where you could order the first article but it turns out that full-text is offered for free here: http://www3.interscience.wiley.com/cgi-bin/fulltext/117861050/HTMLSTART

Just "google" the titles and a link should take you to one of the larger databases usually with a link to "full text" which either will turn out to be a fee based service or if lucky you will get the full-text free like in this instance.

-- Jim

[MYS]

Can the study by Dr. Mangia in "Hepatology" be read by people who are not in the medical profession?  
Is this Dr. Mangia from Italy?
Thanks,
MYS

[jmjm530]

Max: Is such a low viral load common (in geno 1's)?
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The proportion of patients infected with genotype 1 and low viral load seems to be around 33% for patients infected with genotype 1.

Source: http://www3.interscience.wiley.com/cgi-bin/fulltext/117987860/HTMLSTART
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From observation here, the 33% figure does seem high although personally my viral load was around 150,000 IU/ml three months  prior to treatment although 1.5 million the day before tx.

An interesting area of study since pre-tx vl does seem such an important predictor of SVR would be mechanisms to lower pre-tx viral load which in theory would then enhance SVR rates. The other thought is a "timing" tx strategy that might take advantage of the natural ebb and flow of vl with the aim of treating in a trough.

-- Jim

[Max60]

What were the characteristics of these “superresponders,” and could they be identified before or early in therapy, thereby decreasing the burden of treatment? Zeuzem and colleagues[2] subsequently demonstrated that 89% of patients with genotype 1 HCV with low baseline HCV RNA (≤ 600,000 IU/mL) and who had undetectable HCV RNA at Week 4 (ie, a rapid virologic response [RVR]) could anticipate an SVR with only 24 weeks of peginterferon/ribavirin therapy.

--------------------------------------

I'm a believer in RVR being a major indicator of gaining SVR. I guess I've just not run across many geno 1's who had a viral load less than or equal to 600K.

Is such a low viral load common?

[burned74]

Thanks Jim

The info that we get from you is always first rate.

I am really anxious to see the Alinia results on GT 1. If i was stage 4 now i would be treating and adding Alinia.

The Riba plasma level is something you have talked about in the past

[jmjm530]

Yeah, lots of good stuff. Only have skimmed the articles, but keep an eye out for the concept of RVR trumping all pre-tx predictors. It appears to be questioned in special cases in the context of shorter treatment protocols.

-- Jim

[jmjm530]

It is important to note that this study was investigator initiated and driven and was not sponsored by a pharmaceutical company, which perhaps limits any concerns about potential biases regarding the reported results."

Implying that a study sponsored by a pharmaceutical company......

I thought this kind of concept was conveyed by a wink and a nod, not by understandable words.
------------------------------------
It is important to note that this study was investigator initiated and driven and was not sponsored by a pharmaceutical company, which perhaps limits any concerns about potential biases regarding the reported results."

Implying that a study sponsored by a pharmaceutical company......

I thought this kind of concept was conveyed by a wink and a nod, not by understandable words.
---------------------
Word has it that Dr.  K*wdl*y was recently transferred to the podiatry section of the hospital's farm animal division.

[geterdone]

There is a lot of info here to digest and the same as FlGuy picked up on that the first read, Lots of good info jim.

[FlGuy]

This jumped out at me...(from the first one)
"It is important to note that this study was investigator initiated and driven and was not sponsored by a pharmaceutical company, which perhaps limits any concerns about potential biases regarding the reported results."

Implying that a study sponsored by a pharmaceutical company......

I thought this kind of concept was conveyed by a wink and a nod, not by understandable words.

[jmjm530]

Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide
Tarek Hassanein, MD

The current report by Korba and colleagues[1] is an in vitro study evaluating the activities of nitazoxanide and tizoxanide on hepatitis C virus (HCV) replication in HCV replicon-containing cell lines and exploring the development of resistance to these agents in the HCV genome (Capsule Summary). Nitazoxanide is a thiazolide with anti-infectious activities against some anaerobic bacteria, protozoa, and some viruses. Tizoxanide is its active metabolite and is secreted in urine and bile. Nitazoxanide has been approved as an antiprotozoan agent for the treatment of diarrhea caused by Giardia lamblia and by Cryptosporidium parvum in HIV-infected children. In this setting, it is administered twice daily for 3 days and produces minimal adverse events.

Nitazoxanide was recently studied in combination with peginterferon in a phase II study to treat HCV-infected patients, most of whom had HCV genotype 4 (Capsule Summary).[2] In this study, nitazoxanide was administered for a 4-week lead-in phase before starting peginterferon for 36 weeks. The study reported an 80% sustained virologic response rate compared with a 50% sustained virologic response rate in the historic control group which received peginterferon/ribavirin for 48 weeks. In addition, the previous Studies to Evaluate Alinia for the Treatment of Hepatitis C (STEALTH C-1) trial showed that nitazoxanide in combination with peginterferon alfa-2a, with or without ribavirin, resulted in sustained virologic response rates of 79% in the triple-therapy arm vs 61% in the nitazoxanide/peginterferon arm vs 50% in the control peginterferon/ribavirin arm (Capsule Summary).[3] These clinical trials confirm the synergistic activity of nitazoxanide and peginterferon in genotype 4 HCV–infected patients.

In the present study, although reduced susceptibility to both nitazoxanide and tizoxanide were observed in HCV replicons after serial passage, no resistance within the HCV genome was detected. These results are in contrast to the known mutations that develop in the HCV genome in the presence of NS3 protease and NS5B polymerase inhibitors. Furthermore, in these nitazoxanide- and tizoxanide-resistant cell lines, the anti-HCV effects of ribavirin remained constant and susceptibility to interferon was increased several-fold. The mechanism of interaction between tizoxanide and interferon alfa is still under investigation, but it is proposed that nitazoxanide and tizoxanide inhibit HCV replication by a cell-mediated mechanism and not via a virus-specific mechanism. These results suggest that nitazoxanide might be a viable addition to standard treatment by increasing the antiviral efficacy of interferon, without inducing viral mutations and resistance.

A recent presentation at the 2008 American Association for the Study of Liver Diseases meeting showed that nitazoxanide and tizoxanide in vitro increase the intracellular levels of phosphorylated protein kinase R and eukaryotic translation initiation factor 2-alfa, which serves to potentiate the effect of interferon alfa on inducing cell-mediated antiviral activity.[4] These findings, in conjunction with those of the current study by Korba and colleagues, support ongoing clinical trials of nitazoxanide in combination with peginterferon-based therapy.

In summary, although the Korba study adds to the logic of exploring the potential use of nitazoxanide in combination with peginterferon/ribavirin, these data are still very preliminary and are not yet sufficient to change the current treatment landscape. Currently, clinical trials are under way that may further address this issue.

References

1. Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS. Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069-4071.

2. Rossignol JF, Keeffe EG. Evaluation of a 4 week lead-in phase with nitazoxanide (NTZ) prior to peginterferon (PegIFN) plus NTZ for treatment of chronic hepatitis C: final report. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 87.

3. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Randomized controlled trial of nitazoxanide-peginterferon-ribavirin, nitazoxanide-peginterferon and peginterferon-ribavirin in the treatment of patients with chronic hepatitis C genotype 4. Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy. Abstract 68.

4. Elazar M, Liu M, Liu P, et al. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR phosphorylation. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 1881.

[jmjm530]

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C
K. Rajender Reddy, MD

The current proof-of-concept, exploratory pharmacokinetic-pharmacodynamic study by Loustaud-Ratti and colleagues[1] showed that early ribavirin plasma levels, as a marker of exposure, correlate with sustained virologic response (SVR) in patients with hepatitis C virus (HCV) genotype 1 receiving treatment with peginterferon/ribavirin (Capsule Summary). The most significant challenge with ribavirin-containing therapy for hepatitis C is the dosing, both initially and during the course of treatment. Inadequate ribavirin dosing has been shown to be a negative predictor for SVR, in addition to an HCV genotype other than 2/3 and a high baseline HCV RNA.[2] As a consequence, previous clinical trials have suggested that it would be beneficial to adjust the dose of ribavirin based on body weight to ensure that adequate ribavirin dosing is achieved.[2,3] Yet, determining whether a given patient is indeed attaining optimal ribavirin levels has been difficult. In the past, it was suggested that anemia might be a surrogate marker of adequate dose. Investigators have also discussed monitoring ribavirin levels to assess the adequacy of dose. However, such assays are currently not readily available and have interuser variability.

The investigators of this study determined that patients who attained an SVR had significantly higher levels of ribavirin plasma levels over the first 4 and 12 hours after ribavirin dosing compared with those who did not attain an SVR. More specifically, ribavirin exposure was independently associated with an SVR at a threshold level of 1755 µg/hour/L within the first 4 hours of the first ribavirin dose and a threshold level of 3014 µg/hour/L within the first 12 hours of the first ribavirin dose. Based on these findings, the researchers suggest that the dose of ribavirin should be augmented to achieve these threshold levels to offer patients the best chance of attaining an SVR.

The basic finding that higher concentrations of plasma ribavirin correlate with the probability of achieving an SVR corroborates what has been demonstrated clinically.[2-5] For example, in a clinical study conducted by Hadziyannis and colleagues,[4] the SVR rate was nearly 12% higher for patients with HCV genotype 1 who received standard-dose ribavirin (1000/1200 mg/day) vs low-dose ribavirin (800 mg/day). In another study, SVR rates in HCV genotype 1 patients were shown to be significantly higher when ribavirin dosing was based on weight rather than a flat dose (34% vs 29%, respectively; P = .008).[5]

The results of this study suggest that more ribavirin appears to be better for achieving response, but where is the balance between efficacy and safety? Practically speaking, there are limitations to administering high doses of ribavirin. Anemia, cough, rash, and shortness of breath are all ribavirin-associated adverse events that may occur more frequently at high drug doses. One weakness of this study is the fact that the small proportion of patients (3 out of 27) who experienced severe adverse events were removed from the statistical analysis of the exposure-efficacy (area under the concentration time curve-SVR) relationship. Therefore, if the dose of ribavirin were to be augmented to achieve the suggested 1755 µg/hour/L threshold level over the first 4 hours after initial ribavirin dosing, patients would need to be closely monitored for ribavirin-associated adverse events.

In this interesting study, the investigators used a validated high-performance liquid chromatography–tandem mass spectrometry assay carried out in a central laboratory to assess ribavirin plasma exposure. Although it makes sense to use such an assay to determine ribavirin pharmacokinetics, putting this method into practice in a clinical setting would be a challenge. Aside from the limitations of being able to access such an assay, the method would first have to be validated across multiple sites and in various patient populations—for example, according to race, body mass index, HCV genotype, and the presence or absence of renal failure—before becoming readily accepted. In addition, insufficient data currently exist on the ability of therapeutic drug monitoring to improve outcomes. Although this paper presents some intriguing and perhaps useful findings regarding the adequacy of ribavirin dosing, the applicability to clinical practice remains to be seen in the future.

References

1. Loustaud-Ratti V, Alain S, Rousseau A, et al. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology. 2008;47:1453-1461.

2. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-65.

3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

4. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355.

5. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971-981.

[jmjm530]

Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alfa-2a and ribavirin
Hari S. Conjeevaram, MD, MSc

Fried and colleagues[1] conducted a prospective randomized study to assess the impact of higher doses of peginterferon alfa-2a and ribavirin on viral kinetics and virologic outcomes in genotype 1 hepatitis C virus (HCV)–infected patients with difficult-to-treat baseline profiles (with HCV RNA level > 800,000 IU/mL, body weight > 85 kg) (Capsule Summary). Four 48-week treatment arms were compared: standard doses of peginterferon alfa-2a 180 µg/week and ribavirin 1200 mg/day, higher-dose peginterferon 270 µg/week plus ribavirin 1200 mg/day, peginterferon 180 µg/week plus higher-dose ribavirin 1600 mg/day, and higher doses of both peginterferon 270 µg/week and ribavirin 1600 mg/day.

In these difficult-to-treat patients, the investigators found that the use of a higher dose of peginterferon and ribavirin improved the kinetics of viral suppression, with the greatest declines in HCV RNA at 24 weeks in the groups receiving peginterferon 270 µg/week along with ribavirin 1600 mg/day. There was an incremental increase in the rates of sustained virologic response (SVR), with the lowest SVR rate seen in the group that received standard treatment with peginterferon 180 µg/week and ribavirin 1200 mg/day and the highest rate in the group that received higher-dose treatment with peginterferon 270 µg/week and ribavirin 1600 mg/day, although the difference between these groups was not statistically significant (28% vs 47%, respectively; P = .09). The rate of relapse was significantly lower in the group that received higher doses of both medications compared with the standard-dose group (19% vs 40%, respectively; P < .0001). Taken together, this study shows that higher doses of peginterferon and ribavirin can improve viral kinetics and SVR rates and markedly decrease relapse rates.

In conjunction with these findings, the frequencies of adverse events, dose reductions, and discontinuations were higher in the group receiving higher doses of both drugs, as expected. Indeed, the group receiving peginterferon 270 µg/week plus ribavirin 1600 mg/day had the highest withdrawal rate, the highest rate of grade 3/4 neutropenia, and the greatest use of growth factor support compared with the other treatment groups. However, the frequency of serious adverse events was similar across all 4 groups.

The strength of this randomized study is that it prospectively addressed the important issue of maximizing response in patients known to have difficult-to-treat baseline characteristics (ie, a high HCV RNA, overweight/obesity) by using higher doses of both peginterferon and ribavirin. In practice, it is important for all physicians treating HCV-infected individuals to offer the best chance of success with first-line treatment, as this is the best opportunity to achieve a maximal response to therapy. This study shows that it is possible to achieve higher rates of virologic response, including SVR, in difficult-to-treat genotype 1 HCV–infected patients by using higher doses of peginterferon and ribavirin, thereby improving the chance of successful eradication of HCV infection. As expected, the greater efficacy of using higher doses of these 2 medications comes at a price regarding adverse events and tolerability, although serious adverse events were similar in all groups.

As the authors identified, a limitation of this study is that it was not powered to compare differences in virologic response among the 4 arms. However, the trends seen regarding virologic response favor the use of higher doses of both drugs in this patient population, especially in individuals who are motivated and able to tolerate the higher doses. In addition, as the authors also recognize, a cost-effectiveness analysis was not performed. It is important to balance the net gain in virologic response with the cost of using higher drug doses, patient tolerability, and the need for adjuvant therapy to treat hematologic adverse events.
Reference

1. Fried MW, Jensen DM, Rodriguez-Torres M, et al. Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology. 2008;48:1033-1043.
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[jmjm530]

Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response
Mark S. Sulkowski, MD

The study of patients infected with genotype 1 or 4 hepatitis C virus (HCV) conducted by Ferenci and colleagues[1] tested the hypothesis that an individualized duration of treatment based on patients’ on-treatment virologic response may improve treatment outcomes (Capsule Summary). Previous studies of peginterferon/ribavirin demonstrated that the rapidity of HCV RNA suppression is closely linked to the likelihood of sustained virologic response (SVR) and viral relapse.[2-4] For example, in a retrospective analysis of a large clinical trial[2] examining the duration of HCV treatment, Jensen and colleagues[3] reported that 90% of patients with genotype 1 HCV treated with peginterferon alfa-2a/ribavirin who achieved a rapid virologic response (RVR) (defined as HCV RNA < 50 IU/mL after 4 weeks of treatment) went on to achieve an SVR, independent of treatment duration (24 or 48 weeks). Similarly, in an uncontrolled prospective study, Zeuzem and colleagues[4] observed that 89% of genotype 1 HCV–infected patients who achieved an RVR subsequently attained SVR with 24 weeks of peginterferon alfa-2b/ribavirin treatment.

The current analysis reports efficacy, tolerability, and safety data for 150 patients with genotype 1 (n = 120) and 4 (n = 30) HCV who achieved an RVR and were assigned to receive 24 weeks of peginterferon/ribavirin. The primary finding was a relatively high SVR rate (80%) in this subset of patients, which confirms the results of previous retrospective and prospective studies. However, the majority of patients who achieved an RVR had relatively low baseline HCV RNA levels (< 400,000 IU/mL or < 800,000 IU/mL) and mild hepatic fibrosis (METAVIR 0-2). Patients with a high baseline HCV RNA level were more likely to experience relapse, although this difference was not statistically significant in this small sample size. Therefore, the generalizability of the observations from this relatively small, uncontrolled cohort to patients with “hard-to-treat” characteristics is limited. Interestingly, the data also suggest that genotype 4 HCV–infected patients may be more likely than those with genotype 1 to achieve an RVR (45% vs 27%)—and, among those with an RVR who completed 24 weeks of therapy, more likely to achieve an SVR (87% vs 79%).

Not surprisingly, the safety and tolerability profiles observed for the 24-week cohort were typical of the profiles observed with peginterferon/ribavirin in other studies. Because this study did not randomize patients with an RVR to 24 vs 48 weeks of therapy, and because data from those without an RVR who were treated for longer durations were not presented in this partial publication of the trial, the investigators were unable to directly compare the safety findings to those of a control group. Nonetheless, one would anticipate that the impact of clinical and laboratory events would be markedly reduced with 24 weeks of treatment compared with the standard 48 weeks. Another interesting, albeit uncontrolled, observation was the report of adequate safety and tolerability of a modified ribavirin dose-reduction scheme (200 mg/day compared with the standard 400 mg/day or 600 mg/day) in patients with treatment-related anemia (hemoglobin < 10 g/dL). Therapy with erythropoietin was permitted, but no data were provided on the role, if any, of this adjuvant therapy in the management of anemic patients.

Taken together, this study supports the use of a short 24-week course of therapy for genotype 1/4 HCV–infected patients with “low” HCV RNA (< 800,000 IU/mL) who achieve an RVR, thereby potentially limiting the adverse events and the overall cost of treatment. Of note, the European Medicines Agency previously approved a similar short-course regimen for patients with genotype 1 HCV and low baseline HCV RNA who achieve an RVR with peginterferon alfa-2b/ribavirin treatment.[5] Although data from the current study suggest that 24 weeks of therapy is sufficient for most genotype 1/4 HCV–infected patients who have an RVR, one important caveat is that the small number of “hard-to-treat“ patients (eg, high baseline HCV RNA, presence of advanced fibrosis, black race) with RVR in this and other studies limit the implementation of short treatment in such patients. Further research is needed to rigorously assess the efficacy of short-duration therapy for such persons, including the rate of relapse, before routine application in clinical practice.
References

1. Ferenci P, Laferl H, Scherzer TM, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology. 2008;135:451-458.

2. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355.

3. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology. 2006;43:954-960.

4. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006;44:97-103.

5. Schering-Plough Web site. Shorter course of PEG-INTRON and REBETOL combination therapy approved in European Union for certain hepatitis C patients with genotype 1 and low viral load. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=89839&p=irol-newsArticle&ID=764488&highlight=. Accessed December 19, 2008.

[jmjm530]

Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial
Donald M. Jensen, MD

Standard treatment for genotype 1 hepatitis C virus (HCV) infection is 48 weeks of peginterferon/ribavirin. However, the desire to reduce treatment costs and the incidence of adverse events has prompted many researchers to investigate whether individuals infected with genotype 1 HCV might be able to achieve a sustained virologic response (SVR) with only 24 weeks of peginterferon/ribavirin. Hadziyannis and colleagues[1] conducted a randomized, double-blind trial that compared 24 vs 48 weeks of peginterferon/ribavirin in HCV-infected patients, approximately one half of whom had genotype 1 HCV. Approximately 36% of patients with genotype 1 achieved an SVR with only 24 weeks of therapy, some of whom received only 800 mg/day of ribavirin. What were the characteristics of these “superresponders,” and could they be identified before or early in therapy, thereby decreasing the burden of treatment? Zeuzem and colleagues[2] subsequently demonstrated that 89% of patients with genotype 1 HCV with low baseline HCV RNA (≤ 600,000 IU/mL) and who had undetectable HCV RNA at Week 4 (ie, a rapid virologic response [RVR]) could anticipate an SVR with only 24 weeks of peginterferon/ribavirin therapy. Although this trial was prospective, it used a historical control group rather than randomized, prospectively studied controls for comparison. My colleagues and I expanded this observation in a retrospective review of the Hadziyannis database, which included all genotype 1 subjects, and again confirmed that 89% of those achieving an RVR could anticipate an SVR with only 24 weeks of treatment.[3] However, the vast majority of patients achieving an RVR were those with low baseline HCV RNA. In addition, this was not a prospective, controlled study, limiting the strength of the findings.

The current study by Yu and colleagues[4] is important because it tested—in a prospective and controlled fashion—whether genotype 1 patients with an RVR could benefit from a shortened duration of peginterferon/ribavirin treatment (Capsule Summary). The investigators demonstrated that 24 weeks of peginterferon/ribavirin was inferior to 48 weeks of treatment, even if patients attained an RVR. That said, both 24 and 48 weeks of peginterferon/ribavirin produced high SVR rates (> 96%) in genotype 1 HCV–infected patients with a low baseline HCV RNA ( 400,000 IU/mL) and/or suboptimal ribavirin exposure had a higher likelihood of relapse with 24 vs 48 weeks of treatment, which may compromise the response to shorter therapy for genotype 1 HCV–infected patients.

These findings suggest that there is some risk in shortening therapy in genotype 1 patients who have high baseline HCV RNA or in whom suboptimal ribavirin dosing is used, even if they attain an RVR, as these patients may anticipate a higher relapse rate. However, for patients with low baseline HCV RNA and an RVR, 24 weeks of peginterferon/ribavirin is not inferior to 48 weeks of therapy.

This represents a well-designed trial that addresses an important observation in the HCV field. However, several questions still remain:

    * How definitive are the findings? The investigators assert that patients infected with genotype 1 HCV attain significantly higher SVR rates with 48 vs 24 weeks of treatment, even if they attain an RVR. Although the SVR values are quantitatively higher with 48 vs 24 weeks of treatment (100% vs 89%, respectively), the P value listed for this difference is .056, which falls outside the predefined P < .05 significance level. The message that 48 weeks of treatment is superior to 24 weeks of treatment may be valid, but the conclusion is less clear given that the difference failed to meet statistical significance and given the very high SVR rates in each treatment arm. The benefit of longer treatment was clearly demonstrated in patients with high baseline HCV RNA (≥ 400,000 IU/mL), and the difference in SVR rates between the 48-week and 24-week treatment arms did reach statistical significance in this subgroup of patients (100% vs 76.5%, respectively; P = .045).

    * Since the trial was conducted in Taiwan, are the results transferable to other populations? Differences between Asian and Western populations seem to favor SVR in Asians. This is partly attributed to a higher prevalence of genotype 1b in Asians, which appears to be more responsive to therapy, as well as to a lower body weight in Asians. That said, the fact that a difference in SVR was observed in patients with high baseline HCV RNA probably does signal that the difference in outcome based on the length of therapy is significant.

    * If weight-based doses of ribavirin had been used, might that have improved SVR rates in patients with high baseline HCV RNA? The authors suggest that it might have done so.

The overall take-home message is that we cannot necessarily assume that all patients infected with genotype 1 HCV who have an RVR can successfully shorten their treatment duration from 48 to 24 weeks. Careful patient monitoring and individualized treatment decisions are the keys to successful HCV therapy.
References

1. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355.

2. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006;44:97-103.

3. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology. 2006;43:954-960.

4. Yu ML, Dai CY, Huang JF, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology. 2008;47:1884-1893.

[jmjm530]

Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF

The prospective, randomized, controlled study by Mangia and colleagues[1] sought to test the concept of an individualized duration of peginterferon/ribavirin treatment in patients infected with genotype 1 hepatitis C virus (HCV) (Capsule Summary). Clinicians have learned over the past several years that tailoring therapy for individual patients infected with HCV may be associated with better clinical outcomes and could result in fewer adverse events. Information gleaned from studies of viral kinetics suggest that a faster rate of viral decline and a longer duration of time that a patient maintains undetectable HCV RNA while receiving peginterferon/ribavirin treatment might be associated with a higher likelihood of achieving a sustained virologic response (SVR).

The investigators of this study aimed to determine whether it is possible to 1) truncate the duration of peginterferon/ribavirin from 48 to 24 weeks for patients who have a very early response to treatment at 4 weeks (ie, a rapid virologic response [RVR]) and 2) prolong the duration of peginterferon/ribavirin from 48 to 72 weeks to improve outcomes in patients who demonstrate a delayed response to treatment (ie, first undetectable HCV RNA measurement at Week 12). Patients were randomized to receive standard-duration treatment (48 weeks) or variable-duration treatment (24, 48, or 72 weeks based on undetectable HCV RNA at Week 4, 8, or 12, respectively) in a 1:2 fashion and were further assigned by the investigator to receive either peginterferon alfa-2a or peginterferon alfa-2b on a 1:1 basis, in combination with ribavirin.

The overall results identified no significant difference in SVR rate between patients treated with standard-duration vs variable-duration therapy (45.1% vs 48.8%, respectively; P = .37). Although still not significant, the SVR rate for patients who achieved undetectable HCV RNA at Week 12 was 38.1% with standard therapy compared with 63.5% with variable therapy—a difference that showed a trend toward significance (P = .068). This trend may support the idea of prolonging treatment duration in this select group of patients in whom undetectable HCV RNA is not achieved until Week 12 of therapy.

One of the key findings was that patients with a low baseline HCV RNA ( 2 log reduction in HCV RNA at Week 12 but who remained HCV RNA positive; the SVR rates in this cohort were 0% in the standard treatment group and 7.5% in the variable treatment group. These data may suggest that Week 12 could be used as a potential treatment management decision point for slow responders.

The adverse events typically associated with peginterferon/ribavirin were observed in both the standard and variable study groups at generally similar frequencies. The rates of treatment discontinuation were also not significantly different between the standard and variable groups (10.1% and 12.9%, respectively; P = .19). In addition, there was no statistically significant difference in the rate of treatment discontinuation due to adverse events for the standard and variable treatment groups (66.6% [16/24] vs 51.0% [30/59], respectively).

It is important to note that this study was investigator initiated and driven and was not sponsored by a pharmaceutical company, which perhaps limits any concerns about potential biases regarding the reported results. The patient population was well diversified and represents the range of patients typically seen in clinical practice, except regarding race. Because the study was conducted in Italy, no Hispanic or black individuals were included—individuals typically considered harder to treat—which might limit the applicability of the findings to those racial groups.

In summary, this study adds to the accumulating data that support tailoring therapy for the individual patient with genotype 1 HCV based on pretreatment and on-treatment virologic data, as well as patient variables, such as the degree of hepatic fibrosis. The most important factors to consider when individualizing therapy include a patient’s baseline HCV RNA, HCV genotype, on-treatment viral kinetic data (ie, how quickly the patient responds to treatment), and the needs of the patient from the standpoint of the tolerability and safety of therapy. The clinical implications of these findings are that genotype 1 HCV–infected patients who achieve an RVR with peginterferon/ribavirin treatment might be well served with only 24 vs 48 weeks of therapy, especially if they are younger in age and have baseline HCV RNA  2 log reduction in HCV RNA at Week 12, alternative management strategies should be considered. For patients who first attain a virologic response somewhere between 4 and 12 weeks, the best treatment duration probably lies somewhere between 24 and 72 weeks and should be based on individual patient factors, although it may be prudent to offer such patients a full 48 weeks of therapy.
Reference

1. Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology. 2008;47:43-50.