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Reducing Riba
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Reducing Riba

I am on one of the trial drugs, does anyone know when it is safe to reduce riba?
I went undectable by week two. Geno 1a, vl 4.7 million, stage o
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179856_tn?1333550962
Honestly Dr. Jacoboson told me one of the most important things was NEVER to reduce meds, at all.  But if you had to I would assume (although I am sure someone will post more scientific speak) that not until after week 12, because this is all the most crucial time period in the "hit it hard" logic that seems to work.

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183955_tn?1296407045
Why are you wanting to reduce the riba???
Are you not feeling well??
Just curious....

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Avatar_f_tn
Have you lost a lot of weight? Rebetol is weight based therapy. And I was allowed to reduce it from 5 pills to 4 a day recently. I lost 14 lbs. They don't want you to reduce it at all for the first 12 weeks. Also geno 1A. Week 34/51. You have to as the people in charge of the trial. You don't want to do anything to invalidate the trial results.
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Avatar_n_tn
No, not to bad yet, hemo down to 11.6 after two weeks. Just curious how important the riba is once you go undectable
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Avatar_m_tn
Not sure what is the focus of your post.  I do recall the article you reference and found it interesting at the time of publication.  But as your excerpt identifies, it seemed to only be the begining of understanding how ribavirin truly works and only provides additional evidence that the stated hypothesis and theory might actually have a level of credence to them.

Their following conclusion seemed to reflect that their findings are interesting but still preliminary thus requiring further research:

"The field of viral kinetics has provided important insights into the life cycle of HCV and the mechanisms of antiviral therapy. Further research is needed to develop models to predict nonresponse at early time points. Additional studies should focus on special populations, such as liver transplant recipients and patients co-infected with HIV. Finally, as newer antiviral therapies are introduced, viral kinetic models will provide a means to study the mechanisms of action and antiviral efficacies of these agents."

I also found it quite interesting to also note that the study is being solely funded by Roche Labs, Inc..  I've always been a bit skeptical of studies funded by pharmacutical companies which have a stake in the derived findings, not that it really means anything here.
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Avatar_m_tn

UND to what level?  Keep in mind, that the possibility does exist for false positive UND readings, hence the rate of relapes being seen, so despite UND in blood stream, virus could still be hanging out in organs.

As the virus itself has a very short lifespan, ~48 hours if I recall correctly, it thus relies heavily upon replication to retain an infectious level in the body.  Thus the importance on maintaining a Riba level which keeps it in check to allow Peg-Ifn to actually kill the little buggers faster than they can reproduce.

I can not positively say, but I strongly believe that it was the reduction of Riba early in my tx which compromised it and allowed the virus to become resistant to the Riba, as evidenced by the measured increase while on tx meds after a substantial decrease (72 million to 1.8 million in 6 wks)  at the start of tx.

I would have never agreed to Riba reduction if I had known then about Procrit, and still wonder why my doctor did not know and discuss it as an alternative to Riba reduction, unless she of course did not know, in which case I think it borders on incompetance.
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Avatar_m_tn
From: Viral Kinetics in the Treatment of Chronic Hepatitis C
Posted 08/30/2006
http://www.medscape.com/viewarticle/543530_1

"....A recent study that modeled the impact of ribavirin on IFN therapy has provided further insight into the mechanism of action of ribavirin.[45] This study tested the hypothesis that ribavirin acts by causing lethal mutagenesis to the virus, and the traditional model was, therefore, extended to incorporate a term accounting for these effects. The results fit well into this revised model. Moreover, findings from this study indicated that ribavirin enhances the second-phase viral decline, but that its enhancement was substantial only when IFN effectiveness was low. Figure 4 shows theoretic decay profiles for high and low IFN effectiveness. In patients with high IFN effectiveness, the second-phase viral decline is not significantly affected by increasing the effectiveness of ribavirin. In contrast, when IFN effectiveness is low, increasing ribavirin effectiveness has a greater impact on the second-phase viral decline. The authors of this study also theorized on what ETR and SVR rates should be, based on the addition of ribavirin. In general, predictions from this model were in agreement with the response rates from previous clinical trials....."
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Avatar_f_tn
I always wondered about that, too.  IMO, there's a lot left to find out about these drugs.  A lot they don't know.  Like, why 24, 48, 72 weeks, and not 36?  I'm curious about that, too.

Good earlier advice, if it's the trial, hang in there.  You're one of our 'helpers' regarding tx and whatever it is they're looking for.

Go SVR!
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132578_tn?1189759437
First ,ask your doc. dont act on any information other than what comes from him , her , them . (i'm sorry for stating the obvious , and I'm sure you already no that). In my "exit" analysis of the combo treatment of why my treatment failed , I felt as though it failed because of my size (  270 lbs), and that I could not take enough RBV to keep the virus from
continuing to replacate.
I know that sounds simplistic , but I do feel like I have a grasp of the role of the RBV is playing in the treatment protocol and I think its important that you continue for as long as possible without disrupting the continuous assault with the RBV , regardless of pcr results.
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Avatar_m_tn
I understood your post as suggesting that you believe that your ribavirin dose reduction allowed the "virus to become resistant to the Riba". I didn't think that fit with the viral kinetics models and theories that I have seen. While the action of ribavirin is still somewhat of a mystery it appears that it causes lethal mutagenesis to the virus and I have never seen anything that suggests that a ribavirin resistance can develop. If you have something supporting that premise I would appreciate seeing it. Mike
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Avatar_m_tn
Mutation Rate of the Hepatitis C Virus NS5B in Patients Undergoing Treatment With Ribavirin Monotherapy.

Lutchman G, Danehower S, Song BC, Liang TJ, Hoofnagle JH, Thomson M, Ghany MG.

Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Background & Aims: Error catastrophe from an increase in mutation rate may be a possible mechanism of action of ribavirin in chronic hepatitis C (CHC). We sought to evaluate the mutagenic potential of ribavirin in vivo and to determine if conserved regions of hepatitis C virus (HCV) NS5B are mutated during ribavirin therapy. Methods: Thirty-one patients with CHC genotype 1 who participated in a randomized, placebo-controlled trial of ribavirin for 48 weeks were studied. After 48 weeks, patients on placebo were crossed-over to open-label ribavirin for 48 weeks. Viral RNA was extracted from paired, stored sera at day 0 and week 24 during the randomized phase and weeks 48, 52, and 72 during the cross-over phase. The entire NS5B region was sequenced and the mutation rates were calculated. Results: An increase in mutation rate was observed after 4 weeks (4.4 x 10(-2) vs 2.1 x 10(-3) per site/y, P = .02) but not after 24 weeks (4.0 x 10(-3) vs. 5.5 x 10(-3) per site/y, P = .1) in patients who crossed over to ribavirin. Similarly, during the randomized phase no increase in the number of mutations or the mutation rate was observed at week 24 between the ribavirin- and placebo-treated patients 6.6 vs 4.3 x 10(-3) per site/y, respectively (P = .4). No mutations were observed in conserved regions of NS5B. Conclusions: Ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV. Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for CHC.

Mike
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Avatar_m_tn
Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C.

Asahina Y, Izumi N, Enomoto N, Uchihara M, Kurosaki M, Onuki Y, Nishimura Y, Ueda K, Tsuchiya K, Nakanishi H, Kitamura T, Miyake S.
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan.

BACKGROUND/AIMS: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. METHODS: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. RESULTS: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. CONCLUSIONS: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.

PMID: 16098627 [PubMed - indexed for MEDLINE]
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Avatar_m_tn
Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy.

Young KC, Lindsay KL, Lee KJ, Liu WC, He JW, Milstein SL, Lai MM.
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90089-9094, USA.

Ribavirin (RBV), a guanosine analogue, has been suggested to exert an antiviral action against hepatitis C virus (HCV) by causing lethal mutations and suppressing RNA polymerase in vitro, but the mechanism of its clinical therapeutic effects is currently unknown. To test the hypothesis that RBV could act both as an RNA mutagen and inhibit viral RNA synthesis in vivo, we studied the evolution of the nucleotide sequences of HCV RNA at the nonstructural (NS) 5B region in patients receiving RBV, placebo, or interferon alfa (IFN-alpha) monotherapy. The RBV group showed a slightly more accelerated evolution rate of HCV RNA quasispecies than either the IFN-alpha or placebo group. RBV caused preferentially A-to-G and U-to-A mutations. Interestingly, an NS5B amino acid 415 Phe-to-Tyr (F415Y) mutation emerged in all (5 of 5) patients infected with HCV genotype 1a during the RBV treatment. Subsequently, the parental 415F strain reemerged in some patients after the treatment was discontinued. The effect of the amino acid substitution at NS5B415 on HCV RNA replication was then investigated using an HCV subgenomic replicon in Huh7 cells. We showed that treatment of replicon cells with RBV reduced the HCV RNA level of NS5B415F replicon, but not NS5B415Y, in a dose-dependent manner. Thus, NS5B F415Y mutation represents an RBV-resistant variant. The 3-dimensional modeling and structure analysis of NS5B protein revealed that the 415th amino acid is located at the P helix region of the thumb subdomain, which may interact with the minor groove of the template-primer duplex in the putative RNA-binding cleft. In conclusion, RBV could work as a weak mutagen for HCV RNA in HCV-infected patients. Furthermore, the selection of an RBV-resistant variant with a single amino acid substitution in NS5B suggested that RBV may directly interact with HCV RNA polymerase, thus interfering with its enzymatic activity.

PMID: 14512874 [PubMed - indexed for MEDLINE]
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Avatar_m_tn
Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy.

Hofmann WP, Polta A, Herrmann E, Mihm U, Kronenberger B, Sonntag T, Lohmann V, Schonberger B, Zeuzem S, Sarrazin C.
Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany.

BACKGROUND AND AIMS: Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial. METHODS: The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control. RESULTS: Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable. CONCLUSIONS: Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.

PMID: 17383421 [PubMed - indexed for MEDLINE]
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Avatar_m_tn
Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy.

Arataki K, Kumada H, Toyota K, Ohishi W, Takahashi S, Tazuma S, Chayama K.
Department of Internal Medicine, Kure Medical Association Hospital, Kure-shi, and Department of Medicine and Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Japan.

OBJECTIVE: Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy. METHODS: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B. RESULTS: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy. CONCLUSION: Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy. Copyright (c) 2006 S. Karger AG, Basel.

PMID: 16926548 [PubMed - indexed for MEDLINE]
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Avatar_m_tn
Thank you, Mike
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Avatar_m_tn
No problem.
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