This blog is all about current FDA approved drugs to treat the hepatitis C virus (HCV) with a focus on treating HCV according to genotype, using information extracted from peer-reviewed journals, liver meetings/conferences, and interactive learning activities.
Risk Of Developing Liver Cancer After HCV Treatment
1) I think the guidelines are fine. I do have a question as to follow up of a Genotype 1 patient who does not want treatment and also the Genotype 1 patient who fails triple therapy?
Response: Monitoring of patients with all genotypes who do not warrant or want treatment was not addressed in the guidelines. Frequency of monitoring should be based on underlying disease severity. Patients with mild disease could be seen every six months while those with more advanced disease should be seen every three to four months; this recommendation is based on expert opinion. Patients with cirrhosis need to be considered for periodic surveillance for esophageal varices and hepatocellular carcinoma as per AASLD guidelines on Management of Esophageal Varices and Hepatocellular Carcinoma.
2) There is no consideration for IL28B testing to determine if some patients are good candidates for double therapy with Pegylated Interferon with Ribavirin vs. triple therapy. Since, compliance is a major issue with the triple therapy, providing an option with double therapy to patients who would respond well based on IL28B should be addressed.
Response: The advantages of using PI-based treatment even in persons with IL28B genotype CC are that more persons will qualify for abbreviated therapy with telaprevir and possibly boceprevir, and there are higher SVR rates than double therapy. The advantages of treating IL28B genotype CC patients with peginterferon and ribavirin alone are fewer side effects, fewer drug-drug interactions, and lower cost. However, until cost effectiveness studies are published, we recommend the PI-based approach in most patients.
3) I am surprised there is so little commentary on which patients warrant treatment. This is a significant omission. Future guidelines and commentary should include a balanced discussion framing the pros and cons of treatment according to typical patient scenarios. These therapies are still prone to many side effects, and many patients have little urgency to treat, yet are feeling pressured to participate.
Response: This question was beyond the scope of our mandate and will be reconsidered in the next full update to the guidelines. The issue is a highly controversial one with many different opinions. Many factors go into the decision regarding whom to treat including disease severity, likelihood of response, benefits and risks of treatment, as well as the likelihood of new therapeutic options. As efficacy and safety of therapy improves many of these factors may become less important and it is likely that most patients will become candidates for therapy.
4) The #16 recommendation of the guideline is somewhat contradictory to the #9 recommendation: In #9, the futility rule is described as the following: "telaprevir, peginterferon alfa and ribavirin should be stopped if the HCVRNA level is >1,000 IU/ml at treatment weeks 4 or 12". But in #16 it says that "the protease inhibitor should be discontinued if virological breakthrough (>1 log increase in serum HCVRNA above nadir) is observed". If telaprevir was used, there are occasions HCVRNA measured 10 times higher from nadir (e.g. Around 10 IU/ml to the hundreds but well within 1000 IU/ml futility limit) during telaprevir dosing period. If the clinician follows #9, telaprevir should be continued but if #16 was followed, telaprevir needs to be stopped. Therefore, this inconsistency needs to be addressed.
Response: The two statements are not contradictory. To clarify, the stopping rule in #9 applies to patients who reach a virological plateau after which continued therapy would significantly increase the risk for antiviral resistance. Recommendation #16 deals with compliant patients who experience virological breakthrough signifying the emergence of antiviral resistance. Although the author is correct, among the patients with virological breakthrough, their HCV RNA may increase from undetected to 100 IU/ml and still be under the 1,000 IU/ml rule; the important point is the change from a negative to a positive test.
These evidence-based guidelines are developed and updated regularly by a committee of hepatology experts and include recommendations of preferred approaches to the diagnostic, therapeutic, and preventive aspects of care.
The slides from the below ePOSTER along with other abstracts, webcasts, and video podcasts from the AASLD November meeting are available online@ the "LiverLearning" portal. Free registration is required, it's quick and painless folks, start the process by clicking here.Once that is accomplished, sign in and come back to this post and click this link, after landing on the page click on "VIEW ePOSTER" to view the 8 slides .
Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care.
Hamish A Innes1,2, Sharon J Hutchinson1,2, Samuel Allen3, Diptendu Bhattacharyya4, Peter Bramley5, Toby E S Delahooke6,7, John F Dillon8, Ewan Forrest9, Andrew Fraser10, Ruth Gillespie9, David J Goldberg2, Nicholas Kennedy11, Scott McDonald1,2, Allan McLeod2, Peter R Mills12, Judith Morris13 and Peter Hayes7, on behalf of the Hepatitis C Clinical Database Monitoring Committee. 1 Department of Mathematics and Statistics, University of Strathclyde, Glasgow G1 1XH, Scotland, UK; 2 Health Protection Scotland, Glasgow G2 6QE, Scotland, UK; 3 Crosshouse Hospital, Kilmarnock KA2 OBE, Scotland, UK; 4 Victoria Hospital, Kirkcaldy KY2 5AH, Scotland, UK; 5 Stirling Royal Infirmary, Stirling FK8 2AU, Scotland, UK; 6 Leicester Royal Infirmary, Leicester LE1 5EW,England, UK; 7 Royal Infirmary Edinburgh, Edinburgh, EH16 4SA, Scotland, UK ; 8 Ninewells Hospital & Medical School, Dundee DD 9SY, Scotland, UK; 9 Glasgow Royal Infirmary, Glasgow G4 0SF, Scotland, UK; 10 Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, Scotland, UK; 11 Monklands Hospital, Airdrie ML6 0JS, Scotland, UK; 12 Gartnavel General Hospital, Glasgow G12 0YN, Scotland, UK; 13 Southern General Hospital, Glasgow G51 4TF, Scotland, UK
Premise
With an estimated worldwide prevalence of 2.35%1 the hepatitis C virus (HCV) presents a global public health challenge. In cohorts of HCV patients, up to 24% develop liver cirrhosis within 20 years of infection.2 Chronic HCV infection can however be treated (and the virus eradicated),through interferon based therapy. However, current treatment options are far from ideal,particularly with respect to frequent adverse effects,3 and substantial cost.4 Thus, when justifying the resourcing and widespread use of treatment, these drawbacks must be considered in the context of the improvement in prognosis that treatment induced viral eradication can confer.
Despite this, there is a lack of robust data in the literature quantifying the benefit of this improvement in prognosis, particularly in terms of all-cause, and non liver-related outcomes.
Further, although SVR patients without cirrhosis tend to be discharged from care without further follow-up (FU), liver-related morbidity in this population, relative to the general population, until now, remains entirely unexplored. In this study, we thus attempted to address these shortfalls in the HCV knowledge base.
Methods A retrospective cohort of treatment naïve HCV patients commencing antiviral therapy (initiated 1996-2007, N=1215) was derived from clinical data bases installed in Scottish HCV treatment clinics. The records of these treatment patients were then linked to national hospital admission and mortality data(both current to December 2009).
The two outcomes of primary interest were liver-related mortality, and liver-related hospital episodes (outcomes determined on the basis of ICD 9/10 codes5, 6). The primary exposure variable of interest for treatment patients was a SVR (SVR is the optimum virological outcome of treatment).
Other exposure variables considered in these analyses were: gender, age at study entry, ethnicity, ever injected drugs, genotype, diagnosed cirrhotic at study entry, alcohol-related hospitalisation (alcohol-related hospitalisation determined on the basis of ICD 9/10 codes; according to previously documented methods6), and mean post-treatment alanine aminotransferase (ALT).Each treatment patients’ FU time began six months from being administered their final treatment dose(ensuring consistent comparability between SVR and non-SVR treatment groups) and ended at the dateof outcome, or censoring date.
FU time was censored for: (i) reaching the right censor date (December2009), or (ii) mortality (i.e. all-cause mortality for models with liver-related hospitalisation outcomes,and non liver-related mortality for models with liver-related mortality outcomes).
Cox regression was used to determine the association between a SVR and the risk of liver-related mortality and hospitalisation, after adjustment for confounders. Hospital episodes (unlike mortality data) can occur recurrently (i.e. can be experienced multiple times during FU). Thus, to account for within patient clustering in the likelihood of a hospital episode, an Andersen-Gill model for recurrent events, with robust variance estimation was used.
Further, we compared rates of: (a) liver-related hospital episodes, (b) non liver-related hospital episodes, (c) alcohol-related hospital episodes, and (d) all-cause hospital episodes, in subgroups of our treatment cohort (subgroups were: (i) non-cirrhotic SVR patients, (ii) all SVR patients, and (iii) all non-SVR patients), to that of the general population after adjustment for age, sex and calendar year, via the calculation of standardised morbidity ratios (N.B. only results relating to liver-related, and alcohol-related hospital episodes are presented in this poster).
In order to roughly gauge the contribution of chronic HCV per se (i.e. independent of lifestyle factors) on excess liver-related morbidity in our treatment subgroups, we chose a priori to similarly calculate SMRs for spontaneous resolvers of HCV; i.e. persons diagnosed with HCV antibodies in Scotland between 1 January 1996 and 31 December 2008, who were subsequently tested at least once for viral RNA (but never tested positive) and were never interferon treated. (N=3690).
Results SVR was attained in 46% (650/1215) of persons in our cohort. Patients were followed-up for a total of 6,462 person years (mean duration of 5.3 years). During follow-up, 2,962 hospital episodes were observed. (Of these 1005 (34%) were liver-related), and 88 patients died (of which 55 deaths(63%) were liver-related). Fig 1-2 illustrates the results of Cox regression analyses, whilst Fig 3 presents standardised morbidity ratios for treatment subgroups (and spontaneous resolvers of HCV).
Conclusions
(1) Treatment naïve patients who attain a SVR, have a better prognosis than those who do not (i.e. SVR patients are more than four times less likely to die a liver related death, or be hospitalised for a liver-related cause).
(2) Despite this improved prognosis, SVR patients without cirrhosis (a group, who in the main tend to be discharged without further follow-up) still harbour an increased risk of liver-related morbidity (liver related hospitalisations are six times that of the general population).
(3) Further, liver-related morbidity in spontaneous resolvers of HCV is considerably higher (27 times) that of the general population. Because (i) spontaneous resolvers of HCV typically harbour viral RNA for less than 1 year,7 and (ii) the median duration of HCV infection for progression to cirrhosis is 30 years8, HCV induced liver damage in this population should be negligible, thus any liver damage that is apparent, should be largely attributable to lifestyle factors (and not past HCV infection).
Therefore our data suggests that lifestyle factors contribute substantially to liver disease in HCV infected patients, and could thus account for the excess liver-related morbidity observed in non-cirrhotic SVR patients.
References
1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17:107-115. 2. Freeman AJ, Dore GJ, Law MG, Thorpe M, Von Overbeck J, Lloyd AR, Marinos G, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001;34:809-816. 3. Tine F, Graviano D, Giannuoli G, Madonia S, Malizia G, Patti S, et al. An open-safety study of dual antiviral therapy in real-world patients with chronic hepatitis C. Pharmacoepidemiol Drug Saf. 2010;19:1113-23. 4. Joint Formulary Committee; London: British Medical Association and Royal Pharamceutical Society of Great Britain. British National Formulary;9AD. No.58. 5. McDonald SA, Hutchinson SJ, Bird SM, Mills PR, Hayes P, Dillon JF, Goldberg DJ. Excess morbidity in the hepatitis C-diagnosed population in Scotland, 1991-2006. Epidemiol Infect;139:344-353. 6. McDonald SA, Hutchinson SJ, Bird SM, Graham L, Robertson C, Mills PR, Hayes P, et al. Association of selfreported alcohol use and hospitalization for an alcohol-related cause in Scotland: a record-linkage study of 23,183 individuals. Addiction 2009;104:593-602. Acknowledgements We are grateful to the Scottish Government for funding the Scottish Hepatitis C Clinical Database. 7. Amin J, Law MG, Micallef J, Jauncey M, Van Beek I, Kaldor JM, et al. Potential biases in estimates of hepatitis C RNA clearance in newly acquired hepatitis C infection among a cohort of injecting drug users. Epidemiol Infect 2007;135:144-150. 8. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-832.
The slides from the below ePOSTER along with other abstracts, webcasts, and video podcasts from the AASLD November meeting are available online@ the "LiverLearning" portal. Free registration is required, it's quick and painless folks, start the process by clicking Here.
Once that is accomplished, sign in and come back to this post and click this link, after landing on the page click on "VIEW ePOSTER" to view the 12 slides .
Impact of age more then 65 years on svr and relapse in chronic hepatitis c (chc) patients (pts) treated with peginterferon alfa-2a (40kd) (pegifn?2a[40kd]) plus ribavirin (rbv): final analysis from the large multinational real-world prophesys cohorts A. Aronsohn,1 I. Ancuta,2 F. Caruntu,3 C. Coppola,4 D. Delic,5 A. Digiacomo,6 G.M. Dusheiko,7 G. Lengyel,8 P. Marcellin,9 A. Orlandini,10 J. Pruthi,11 G.F. Silva,12 L. Tallarico,13 M. Schmitz,14 F. Hamzeh,15 H. Cheinquer16 1University of Chicago Medical Center, Chicago, IL, United States; 2Dr l. Cantacuzino Clinical Hospital, Bucharest, Romania; 3Matei Bals Infectious Diseases Institute, Bucharest, Romania; 4Unità Operativa Epatologia ed Ecografia Interventistica Ospedale Gragnano, Naples, Italy; 5Clinic for Infectious Disease, Clinical Center Serbia, Belgrade, Serbia; 6Divisione di Medicina Interna, Ospedale Regina Margherita, Comiso, Italy; 7Royal Free and University College School of Medicine, London, United Kingdom; 8Semmelweis University, 2nd Dept. of Medicine, Budapest, Hungary; 9Hôpital Beaujon, Clichy, France; 10Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; 11High Desert Gastroenterology Suite B, Lancaster, CA, United States; 12Botucatu School of Medicine, Botucatu, Brazil; 13Divisione di Medicina , Ospedale Elena D’Aosta, Napoli, Italy; 14IST GmbH, Mannheim, Germany; 15Genentech, South San Francisco, CA, United States; 16Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
INTRODUCTION
Several mostly retrospective analyses have suggested that older patients with chronic hepatitis C are less likely than younger patients to achieve an SVR after treatment with peginterferon plus ribavirin.[1–4] This hypothesis is difficult to validate because randomized clinical trials generally enroll few patients aged more then 65 years.
Possible reasons for reduced SVR rates in the elderly include a higher incidence of advanced fibrosis, more frequent dose modifications, higher discontinuation rates, and poorer tolerability.[1–3, 5]
The large multinational, non-interventional PROPHESYS cohorts enrolled a diverse population of patients with chronic hepatitis C and thus provide an excellent opportunity to examine the effect of patient age on the outcome of treatment with peginterferon alfa plus ribavirin.
The objective of this analysis was to examine the association between patient age (less then 65 vs. more then 65 years), on-treatment virologic response (HCV RNA less then 50 IU/mL), and SVR in patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin in accordance with local labels.
METHODS
PROPHESYS comprised three separate cohort studies of patients receiving treatment for chronic hepatitis C in accordance with the local label.
The prescribed treatment was at the sole discretion of the physician and eligibility for inclusion in PROPHESYS was determined only after the choice of treatment had been made.
According to country-specific requirements, PROPHESYS 1 included patients prescribed peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin, while patients included in PROPHESYS 2 and 3 received either peginterferon alfa-2a (40KD) or peginterferon alfa-2b (12KD) (PegIntron®) plus ribavirin.
This analysis was restricted to naive HCV mono-infected patients who were assigned to treatment with peginterferon alfa-2a (40KD) plus ribavirin.
Patients included in the analysis were stratified by age at enrollment
(less then 65 vs. more then 65 years).
Outcomes of interest included on-treatment virologic responses (undetectable HCV RNA, less then 50 IU/mL) by week 2, 4 (rapid virologic response; RVR), 12 and the end of treatment, and SVR, defined as undetectable HCV RNA after 24 weeks of untreated follow-up.
The percentage of patients with more then 80% exposure to both study drugs was calculated for the two age groups.
A multiple logistic regression analysis was conducted to examine associations between baseline factors and SVR. Age was entered as a dichotomous variable (less then 65 vs. more then 65 years).
RESULTS
A total of 6625 patients were enrolled in PROPHESYS and treated with peginterferon alfa-2a (40KD) plus ribavirin including 6276 individuals who were aged less then 65 years and 349 who were aged more then 65 years.
Of the 349 patients aged more then 65 years, 208, 109 and 15 individuals, respectively, were infected with HCV genotype 1, 2 and 3 (Table 1).
Across HCV genotypes 1, 2 and 3 a higher proportion of patients aged more then 65 years were of non-white race/ethnicity compared with patients aged less then 65 years (Table 1).
Compared with younger patients a higher proportion of patients aged more then 65 years had transition to cirrhosis or cirrhosis, numerically higher serum aspartate aminotransferase (AST) levels and lower mean platelet counts. The percentage of patients with platelet counts less then 140 x 109/L was also consistently higher in patients aged more then 65 years (Table 1).
Virologic response
In general, rates of on-treatment virologic response, defined as undetectable HCV RNA (less then 50 IU/mL), were lower in patients aged more then 65 years compared with those aged less then 65 years (Figure 1). In particular, RVR rates at week 4 were numerically lower in older patients across genotypes.
SVR rates were significantly lower and relapse rates were significantly higher in older genotype 1 patients compared with those individuals aged less then 65 years (both p=0.0002) (Figure 2).
In contrast to findings in genotype 1 patients, SVR and relapse rates were generally similar in genotype 2 and 3 patients aged more then 65 years and less then 65 years (Figure 2).
Of patients with an end of treatment response, 15% (714/4692) and 9% (23/243) of those aged less then 65 and more then 65 years, respectively, were imputed as treatment failures due to incomplete follow-up data.
The positive predictive value (PPV) of RVR for SVR was comparable between the two age groups in genotype 1 patients (less then 65 years: 68.6%; more then 65 years: 66.7%; Table 2). Among genotype 2 and 3 patients the
PPV of an RVR for SVR was higher in older patients compared with younger patients.
In general, HCV genotype 1 and 3 patients aged more then 65 years had shorter mean treatment duration compared with patients aged less then 65 years (Table 3).
Across all genotypes premature treatment discontinuations due to adverse events were about two times higher in patients aged more then 65 years (14.9%) compared with patients aged less then 65 years (7.4%), and ribavirin dose modifications due to anemia were reported in 31.5% of the patients aged more then 65 years compared with 13.4% in younger patients.
Fewer older patients had ribavirin exposure of more then 80% of the planned dosage compared with younger patients (Table 3). This was in spite of much higher rate of usage of erythropoietin in older individuals (102/349, 29.2% vs 706/6276, 11.2% among patients aged less then 65 years). The frequency of granulocyte colony stimulating factor usage was similar in older (19/349, 5.4%) and younger (273/6276, 4.3%) patients.
Although less pronounced than seen for ribavirin, generally fewer older patients had peginterferon alfa-2a (40KD) exposure more then 80% (Table 3).
Multiple logistic regression analysis in genotype 1 patients confirmed that older age was significantly associated with lower SVR rates in genotype 1 patients (Figure 3). Other factors that were significantly associated with higher SVR rates included well-established predictors of SVR such as ethnicity (Asian vs. White, White vs. Black and vs. Hispanic), lower HCV RNA level, higher ALT ratio, and no cirrhosis. Indicators of advanced fibrosis such as low platelets and high AST ratio, as well as injection drug use as the mode of infection, were negatively associated with SVR.
CONCLUSIONS
This analysis of data from the PROPHESYS cohorts suggests that patients aged more then 65 years tended to have inferior virologic responses compared with patients aged less then 65 years.
Older patients tended to have lower RVR rates regardless of HCV genotype.
Older patients with HCV genotype 1 infection (but not genotype 2 or 3 infection) had significantly lower SVR rates and significantly higher relapse rates. However, results for patients infected with HCV genotype 3 should be interpreted with caution since relatively few such patients were aged over 65 years.
RVR remains a reliable positive predictor of SVR in older patients.
In addition to well-established baseline predictors of SVR, age more then 65 years was significantly and negatively associated with SVR in patients with HCV genotype 1 infection.
Shorter treatment duration due to adverse events and lower exposure to ribavirin due to anemia may have contributed to the significantly lower SVR rates in older genotype 1 patients.
REFERENCE LIST
1. Antonucci G, Longo MA, Angeletti C, et al. The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr. Am J Gastroenterol 2007; 102(7): 1383–1391.
2. Reddy KR, Messinger D, Popescu M, et al. Peginterferon alpha-2a (40 kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients. J Viral Hepat 2009; 16(10): 724–731.
3. Honda T, Katano Y, Shimizu J, et al. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int 2010; 30(4): 527–537.
4. Oze T, Hiramatsu N, Yakushijin T, et al. Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. J Hepatol 2011; 54(4): 604–611.
5. Nudo CG, Wong P, Hilzenrat N, et al. Elderly patients are at greater risk of cytopenia duringPresented at The Liver Meeting® 2011 [62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)]
November 4–8, San Francisco, USA
This research was funded by Roche
Disclosure information: GD – Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott, Beohringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Anchillion; Board Membership: Gilead Sciences ; PM – Consulting: Roche, Schering- Plough, Gilead, BMS, Vertex, MSD, Novartis, Tibotec, Boehringer, Abbott, Pfizer; Grant/ Research Support: Roche, Schering Plough, Gilead, Echosens; Speaking and Teaching: Roche, Schering- Plough, Gilead, BMS, Vertex, Novartis, Pharmasset, Tibotec, MSD, Abbott, Pfizer ; HC – Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche; Grant/Research Support: Bristol-Myers Squibb, Roche; Speaking and Teaching: Bristol-Myers Squibb, Roche ; JP – Speaking and Teaching: Roche ; GFS – Grant/Research Support: Roche, Shering Plough; Speaking and Teaching: Roche, Shering Plough, Bristol-Myers Squibb, Bayer ; MS - Employed by IST GmbH and provides statistical consultancy and analysis for Roche; FH is an employee of Roche; AA, IA, FC, CC, DD, AD, GL, AO, LT have nothing to disclose.
Support for third-party writing assistance for this presentation was provided
by F.Hoffmann-La Roche Ltd
On the blog today requested by a reader is an abstract from the November meeting available @ "LiverLearning" on the AASLD web site. In this study researchers found that temperature increase *fever after the initial injection of PEG-IFN is closely associated with interferon responsiveness, and IL28B genotype. The study included 60 naive patients treating with peginterferon and ribavirin with various genotypes. 67% were genotype 1/4/6, 33% were genotype 2/3.
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Once that is accomplished, sign in and come back to this post and click this link , after landing on the page click on "VIEW ePOSTER" to view the 9 slides .
BACKGROUND: During the first 24 hours after the initial dose of peginterferon alfa-2a (PEG-IFN), patients have variable degrees of non-specific symptoms including fever. The significance of these side effects in reflecting the antiviral actions of PEG-IFN is unknown.
PURPOSE: To assess whether temperature change reflects interferon responsiveness as assessed by viral kinetics, serum cytokines and treatment response in patients with chronic hepatitis C.
METHODS: Previously untreated patients with chronic hepatitis C were admitted to start standard combination therapy with PEG-IFN and ribavirin. Temperatures were measured via infrared tympanic electronic thermometers in oral mode, before the first injection of PEG-IFN, and at 8, 16 and 24 hours.
Maximum temperature increase from baseline within the first 24 hours (Tmax) was determined for each patient.
Serum HCV levels were measured at baseline, 6, 24, 48, 72 hours, and weekly for the first 4 weeks of treatment. 1st phase decline of viral levels and 2nd phase slope were calculated. In a subset of patients, levels of serum interferon-gamma-inducible protein-10 (IP10) were measured by cytokine bead array assay at baseline, 6 and 24 hours after treatment initiation. The IL28B single nucleotide polymorphism, rs12979860, was genotyped using TaqMan assay.
RESULTS: Among the 60 patients enrolled (67% genotype 1/4/6, 33% genotype 2/3), oral temperature rose by 1.1± 0.8°C, reaching an average peak of 37.9±0.7°C, and rising above 38.0°C in 20 patients (33.3%). There was a strong positive correlation between Tmax and 1st phase virological decline (r2=0.35, p<0.0001), and between Tmax and IP10 fold-induction at 6 hours (n=39, r2=0.25, p=0.001) and at 24 hours (n=39, r2=0.20, p=0.004). Tmax did not correlate with 2nd phase slope. The correlation between Tmax and 1st phase decline was similar for genotype 1 (n=34, r2=0.38) and genotype 2/3 (n=20, r2=0.38) and there was no difference in Tmax between viral genotypes (p=0.38). Average Tmax was higher for patients with rs129790860 CC (1.43°C) vs. CT/TT (0.84°C, p=0.036). Tmax predicted virological response at weeks 4 (RVR, AUC=0.60) or 12 (EVR, AUC=0.61), albeit weakly.
DISCUSSION: Temperature increase after the initial injection of PEG-IFN is closely associated with interferon responsiveness, reflected by the correlation with serum IP10 increase, virological decline and IL28B genotype. The lack of difference between genotypes pinpoints its association with host-responsiveness factors. An easily measurable marker, temperature may be incorporated as a surrogate of more expensive and elaborate tests in future models of responsiveness to interferon-based treatment.
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December 6, 2011 (San Francisco, California) — Adding the recently approved protease inhibitor telaprevir to pegylated interferon (peginterferon) plus ribavirin therapy achieved a 47% sustained viral response (SVR) in hard-to-treat patients with hepatitis C virus (HCV) infection and cirrhosis who had previously failed the standard 2-drug regimen. This finding comes from a subset analysis of the phase 3 REALIZE trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
The REALIZE investigators originally looked at telaprevir in combination with peginterferon plus ribavirin in patients with HCV genotype 1 who had had a previous null or partial response, or who had relapsed after treatment with the 2-drug regimen. REALIZE had 3 treatment groups — 2 with different schedules of triple therapy and a third with placebo plus the 2-drug regimen.
Stanislas Pol, MD, PhD, from the Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, and Assistance Publique-Hôpitaux de Paris, Cochin Hospital, France, and colleagues performed the subanalysis of the REALIZE trial to gauge the effect of triple therapy on a subset of patients with Child class A cirrhosis who had responded poorly to the 2-drug regimen. "For this analysis, we pooled the 2 telaprevir arms since there was no difference in safety and efficacy" between the 2, he explained.
The REALIZE study population consisted of 169 patients with cirrhosis (stage F4) and 493 patients without cirrhosis (stages F0 to F3). For the entire cohort, median age was 52 years, 93% was white, 88% had an HCV RNA level of at least 800,000 IU/mL, and median body mass index was 28 kg/m². Just more than half of the patients were infected with HCV genotype 1a.
There were more null responders in the group with cirrhosis (36% vs 25%), but fewer relapsers (43% vs 57%).
Results showed that in patients with no, minimal, or portal fibrosis (F0 to F2), SVR was achieved in 75% of patients receiving telaprevir and in 22% of those receiving placebo.
"If we consider SVR according to fibrosis stage and prior response, we see no clear impact of fibrosis stage on the overall SVR rate of around 85%. For prior partial responders, there was a significant impact by fibrosis stage, with a decrease in SVR rate from 77% to 56% in patients with mild fibrosis, declining to 34% in those patients with cirrhosis," Dr. Pol told Medscape Medical News.
In previous null responders, the SVR rate after triple therapy was 41% in the patients without cirrhosis, 42% in those with mild fibrosis, and 14% in those with cirrhosis.
More than half (53%) of these previously treated patients with cirrhosis did not achieve an SVR with the addition of telaprevir, compared with 27% of patients without cirrhosis.
Regarding safety, the prevalence of rash was higher in patients with than without cirrhosis (67% vs 53%), but other rates for common adverse events were similar. For hematologic events, anemia was more frequent in patients with cirrhosis (42% vs 34%). In addition, neutropenia was higher (25% vs 17%) and, "as might be expected, platelet counts were lower in the cirrhotic subset," Dr. Pol noted.
Can Early Responders Stop Treatment?
The relatively high response rate in patients with cirrhosis and HCV who had failed previous treatment with peginterferon and ribavirin raises the question of whether treatment can be stopped early with triple therapy.
Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, asked: "If they had an extended RVR [rapid virologic response], if they were negative for virus at week 4 and again at week 12, for which there was evidence in REALIZE, then perhaps they could get just 24 weeks of treatment. That's called response-guided therapy."
Dr. Bernstein's reasoning is that in patients without cirrhosis, an extended RVR is indicative of a greater than 90% SVR rate.
"The current recommendation is to treat these patients for 48 weeks, whether they have an extended RVR or not. In this study, this is a special subgroup of patients — even a sub-subgroup — because it is not just cirrhotics, but cirrhotics who have not responded previously to treatment.... It may be feasible to stop [treatment] at 24 weeks if they have this very favorable RVR," he told Medscape Medical News. As phase 4 data accrue, evidence might support doing so.
Dr. Pol reports being a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Novartis, and Gilead; and receiving grants for research from Bristol-Meyers Squibb, Gilead, Roche, and Schering-Plough/Merck. Dr. Bernstein has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 31. Presented November 6, 2011.
December 5, 2011 (San Francisco, California) — Patients coinfected with hepatitis C virus (HCV) and HIV have only a 55% chance of survival 5 years after liver transplantation, according to results from a study performed at a French transplant center and reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting. The study authors concede that improvements in care might depend on the near-term availability of new HCV therapies.
Liver disease progression to cirrhosis is rapid in HIV-infected patients, and liver transplantation is now an accepted therapeutic option for those with end-stage liver disease. "However, everyone knows that the mortality in HIV/HCV coinfected patients is very high," said principal investigator Jean-Charles Duclos-Vallée, MD, Centre Hépato-Biliaire, Hôpital Paul-Brousse, Villejuif, France. "A paper from 2005 puts the figure at just 25% 5 years after the first episode of decompensation, compared with 44% for HCV patients without HIV."
This reference aside, there are limited data overall regarding the survival of coinfected patients who undergo liver transplantation, he said. However, the increasing frequency of HIV-positive patients undergoing transplantation and the severity of recurrence of HCV infection in the liver grafts in transplanted patients is of growing concern.
Dr. Duclos-Valle and colleagues looked at survival rates and the degree of recurrence of HCV infection in 105 transplant patients at their center. The patient cohort was 83% male, 61% had HCV genotype 1, median MELD score was 16.0, and waiting time to transplantation was 4.9 months. All patients were using highly active antiretroviral therapy (HAART) at the time of transplantation. Reasons for transplant included HCV-related cirrhosis (56%), hepatocellular carcinoma (HCC; 19%), hepatitis B virus (HBV)-related cirrhosis (7.6%), HBV/HCV-related cirrhosis (4.7%), and other (14%).
"The overall survival rate for the entire cohort was 55% at 5 years posttransplant," said Dr. Duclos-Valle.
The 5-year survival rate for patients with HCV-related cirrhosis was 45%, with HCC was 49%, and with HBV-related cirrhosis was 100%. Nine patients have undergone retransplantation. Of the 40 deaths, 20 were due to HCV recurrence, 5 were due to HCC, 5 were due to sepsis, and 2 were due to myocardial infarction; the remaining patients died for other reasons.
After transplantation, anti-HCV therapy (pegylated interferon alfa-2a plus ribavirin) was given to 36 of 58 patients who had a recurrence of HCV infection in the new liver graft. The response rates were as follows: no response in 24 patients, partial response in 6, and sustained viral response in 6.
"For response to treatment after recurrence, we had [a sustained viral response] of 16.6%, with 64% nonresponders and 1 relapse," said Dr. Duclos-Valle. Given the dismal survival outcomes 5 years after transplantation and the less-than-optimal response rates to retreatment after HCV recurrence, Dr. Duclos-Valle said he is doubly concerned. Transplant organ resources are already strained, and with the success of HAART treatment, the number of HIV-infected individuals that will require transplantation in the future will only increase.
Race Against Demographics
"We are going to be seeing more of these patients," noted Jay H. Hoofnagle, MD, director of the Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Maryland. "They're living longer so they're going to have other health issues."
Dr. Hoofnagle said he is seeing an increase in complications from chronic conditions such as heart disease. "As HAART therapy extends lives, you're going to see these complications. That is particularly true with hepatitis C because of the common modes of transmission."
Dr. Hoofnagle is optimistic, however, about the overall prognosis for the situation. "The treatments for hepatitis C are improving so fast that what looks bad now is just going to improve with new drugs. This will be particularly helpful for the coinfected group, when you get the chance to get these patients away from interferon, which is very hard to take." Dr. Hoofnagle expects to see critical improvements in HCV treatment within the next 5 years.
Dr. Duclos-Valle and Dr. Hoofnagle have disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 4. Presented November 6, 2011.
November 30, 2011 (San Francisco, California) — Patients with hepatitis C virus (HCV) infection who previously failed combination treatment with pegylated interferon alfa-2a (peginterferon) and ribavirin achieved up to a 50% sustained viral response (SVR) with the recently approved protease inhibitor boceprevir. This finding, from the preliminary results of the ongoing PROVIDE study, was reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
"This study was designed to give boceprevir treatment to patients who were null responders in the control arms of our previous pivotal trials," said Michelle Treitel, PhD, from Merck Research Laboratories in Kenilworth, New Jersey.
Patients were rolled over from the SPRINT-1, SPRINT-2, RESPOND-2, and PEG 2a/BOC studies into PROVIDE. "These are patients who had either met the futility rule or who had relapsed after the end of treatment with peginterferon and ribavirin. After failure, they were immediately started on 44 weeks of boceprevir/peginterferon/ribavirin triple therapy." The aim of the study was to assess SVR after boceprevir, peginterferon, and ribavirin treatment in nonresponders.
Overall, 168 patients from the 4 studies were enrolled in PROVIDE. Patients were eligible if they received 12 or more weeks of peginterferon plus ribavirin treatment and failed to achieve a SVR (HCV RNA levels below the lower limit of detection of +9.3 IU/mL at treatment week 12 in treatment-experienced patients or at treatment week 24 in treatment-naïve patients), had a virologic breakthrough, or relapsed after the end of treatment (undetectable HCV RNA at the end of treatment but no SVR).
The subanalysis presented by Dr. Treitel involved 48 patients from the SPRINT-2 and RESPOND trials.
Patients were treated with boceprevir 800 mg orally twice daily, peginterferon 1.5 µg/kg subcutaneously once daily, and ribavirin 600 to 1400 mg/day (based on weight) orally in 2 divided doses. All patients received 4 weeks of peginterferon plus ribavirin induction therapy prior to receiving boceprevir. Patients received the boceprevir, peginterferon, ribavirin combination for up to 44 weeks, and were followed for an additional 24 weeks to determine SVR.
The PROVIDE cohort was 64.6% male, 68.8% white, had mean age of 51.0 years, and had a mean body mass index of 26.8 kg/m². Among the patients, 87.5% had a baseline viral load greater than 800,000 IU/mL, 64.6% were infected with HCV genotype 1a, and 4.2% had detectable cirrhosis.
The primary end point of PROVIDE was undetectable HCV RNA 24 weeks after therapy.
In this nonresponder subpopulation, 38% of patients treated with the triple combination achieved a SVR. The achievement of SVR differed by race (27% of black subjects and 42% of nonblack subjects), age (50% of those younger than 50 years and 29% of those older than 50 years), alanine transaminase levels (50% of those with normal levels and 34% of those with elevated levels), and genotype (41% of those infected with genotype 1a and 33% of those with genotype 1b).
"The difference by genotype is the reverse of what you would expect," said Dr. Treitel. "That most likely has to do with the small sample size."
The magnitude of decline in HCV RNA after 4 weeks of peginterferon plus ribavirin induction therapy was positively related to the rate of SVR. Dr. Treitel reported a 50% SVR for patients who experienced a reduction of at least 1 log in HCV RNA, compared with 34% SVR for patients who experienced a reduction of less than 1 log.
"This null group has not been specifically studied for boceprevir before, and these patients are really poor interferon responders," said Dr. Treitel. "In these traditionally very hard-to-treat subjects, we're still showing that you can get a 38% SVR."
Taking It to the Street
"I was very interested to see the rate of response to triple therapy in patients who have previously failed treatment or who were nonresponders," said Abu Hamour, MBBS, MSc, FRCP, from the University Hospital of Northern British Columbia in Prince George, Canada.
The lack of patients with cirrhosis in the study was a sticking point for Dr. Hamour. Although this does not reflect the population of patients he sees in his practice, the conclusions give him something valuable to take home.
"I have this information that I can give to my patients — a prognosis," he said. After treatment with this triple therapy, I can tell patients "who failed treatment with peginterferon/ribavirin or who were nonresponders...[that] if you have a more than a 1 log drop, you have a 50% chance of response; if you have less than a 1 log drop, then your response is much lower, around 35%. Patients can then make choices based on that information."
Dr. Treitel is an employee of Merck Research Laboratory. Dr. Hamour has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 931. Presented November 7, 2011.
If you haven't yet explored the "LiverLearning" section available @ the AASLD web site you're missing out on the November meeting webcasts, video podcasts, abstracts and more. Free registration is required, it's quick and painless folks, start the process by clicking Here. Once that is accomplished, check out some of the topics and programs available below .
View Complete list of selected sessions by clicking here
Repeated doses of slightly too much acetaminophen (known as paracetamol in the United Kingdom and elsewhere in Europe) can be fatal, according to the results of a large, single-center cohort study published online November 22 in the British Journal of Clinical Pharmacology."On admission, these staggered overdose patients were more likely to have liver and brain problems, require kidney dialysis or help with breathing and were at a greater risk of dying than people who had taken single overdoses," senior author Kenneth J. Simpson, MBChB (Hons), MD, FRCP (Edin), from the University of Edinburgh and Scottish Liver Transplant Unit in the United Kingdom, said in a news release."They haven't taken the sort of single-moment, one-off massive overdoses taken by people who try to commit suicide, but over time the damage builds up, and the effect can be fatal," he adds.
In the United Kingdom, acetaminophen hepatotoxicity is the leading cause of acute liver failure (ALF).
However, the effect of a staggered overdose pattern or delayed hospital presentation on mortality or need for emergency liver transplantation was previously unknown.
Of 663 patients admitted with acetaminophen-induced severe liver injury between 1992 and 2008, 161 (24.3%) had taken a staggered overdose. Compared with patients who took an overdose at a single time, patients with staggered overdose were significantly older and more likely to abuse alcohol.When asked why they repeatedly ingested more than the recommended dose of acetaminophen, patients with staggered overdose most often cited pain relief as their rationale (58.2%).
Compared with patients who took an overdose at a single time, those who took staggered overdoses had lower total ingested doses and lower serum alanine aminotransferase (ALT) levels on admission. Nonetheless, they were more likely to be encephalopathic and to require renal replacement therapy or mechanical ventilation.
Although mortality was higher in staggered overdoses than in single-time overdoses (37.3% vs 27.8%; P = .025), the staggered overdose pattern was not an independent predictor of mortality.
For staggered overdoses, sensitivity of the King's College poor prognostic criteria was reduced (77.6%; 95% confidence interval [CI], 70.8% - 81.5%).
Delayed presentation to medical services more than 24 hours after single-time overdose occurred in 44.9% of those in whom accurate timings could be determined, and was independently associated with death or liver transplantation (odds ratio [OR], 2.25; 95% CI, 1.23 - 4.12; P = .009).
In their logistic regression analysis, the investigators controlled for signs and symptoms, such as hepatic encephalopathy and prothrombin time, as well as various demographic factors."Staggered overdoses or patients presenting late after an overdose need to be closely monitored and considered for the paracetamol antidote, N-acetylcysteine [NAC], irrespective of the concentration of paracetamol in their blood," Dr. Simpson said.Because both these groups are at increased risk of developing multiorgan failure, they should be considered for early transfer to specialist liver centers.
Limitations of this study include reliance on patient recall regarding the time of last ingestion, total paracetamol dose, and suicidal intent; limited data regarding the use of concomitant P450 enzyme inducers or recent fasting; and selection bias for the more severe cases of acetaminophen toxicity in Scotland."[T]his large cohort study demonstrates the deleterious effects of delayed presentation and staggered overdose pattern upon outcome following paracetamol-induced acute liver injury," the study authors conclude. "Both delayed presentation more then 24 hours and staggered overdoses are strongly associated with multiorgan injury and the need for [liver transplantation].
Patients presenting with these overdose patterns should be treated as high risk for progression to ALF, and should receive NAC in their presenting hospital whilst awaiting serial ALT and PT levels."This study received no external funding. The authors have disclosed no relevant financial relationships. Br J Clin Pharmacol. Published online November 22, 2011.
University launches iphone app for hepatitis treatment The University of Liverpool has launched an iphone app, HEP i-chart, that provides Hepatitis C (HCV) patients with quick and easy access to the latest information about drug interactions. Hepatitis C was first discovered in the 1980s when it became apparent that there was a new virus (not the already known hepatitis A or B) causing liver damage. Hepatitis C causes inflammation and swelling of the liver. It is estimated that over 170million individuals – representing 3% of the world's population – are chronically infected with the Hepatitis C virus (HCV). Statistically, as many people are infected with HCV as are with HIV. Since its identification, drug treatment to eradicate the virus has advanced greatly, especially in the last few years. Two new drugs have recently been licensed for treatment of HCV, and there are more drugs in development.
HEP i-chart is based on the website (http://www.hep-druginteractions.org/) developed at the University by Professor David Back and Professor Saye Khoo which provides a comprehensive online guide to the interactions between anti-hepatitis drugs and other drugs. It is a tool that provides Hepatitis C patients and healthcare professionals with immediate access to up-to-date information on potential drug interactions between HCV drugs, and other drugs that the patient may be prescribed as well as over-the-counter, recreational or herbal medications. Existing HCV drugs, newly licensed drugs and drugs in development can have interactions with each other and with other drugs which can impact on their effectiveness – sometimes with serious consequences. For this reason, some drug combinations must not be used, whilst others must be given with caution, possibly requiring adjustment or monitoring.
Professor of Pharmacology, David Back, said: "We are delighted to launch with our partners – KnowledgePoint360, MSD and Janssen- this new i-phone application that provides Hepatitis C patients and healthcare professionals with instant and easy access to information about HCV drug interactions which is relevant and reliable and up-to-date. This resource is especially important as new HCV drug treatments are approved and come into use."
Professor Graham Foster, President of the British Association for the Study of the Liver (BASL) said: "This new app, HEP i-chart, is a timely and much-needed resource for HCV patients as the number of new drugs which are available to treat Hepatitis C increases."
Hepatitis Screening Offered With Routine Colonoscopy Accepted by 75% ATIONAL HARBOR, MD. – A screening colonoscopy can provide a convenient opportunity to simultaneously test older adults for hepatitis, based on a study of 500 patients, 75% of whom agreed to blood tests for hepatitis A, B, and C.
Adults aged 50-65 years (the "baby boomers") represent a high-risk population for hepatitis, and hepatitis C in particular, because of possible exposure to high-risk activities in their teens and twenties, said Dr. Dawn Sears of Scott & White Hospital in Temple, Tex. The findings were presented at the annual meeting of the American College of Gastroenterology.
Men make up 70% of chronic hepatitis cases, and they are less likely to see a doctor regularly than women, she noted. "Colorectal cancer screenings are often the only physician encounter for men aged 50 to 60 years," she said.
To increase hepatitis screening in older adults, Dr. Sears and her colleagues tested whether combining hepatitis testing with routine colonoscopy appointments would be effective. Patients were mailed information about hepatitis along with their instructions for colonoscopy preparation. On the day of their colonoscopies, patients met with a research nurse, signed a consent form, and completed a patient risk form. Blood was drawn for hepatitis screening when the IV was placed prior to the colonoscopy.
A total of 376 of 500 patients (75%) undergoing colonoscopies agreed to hepatitis testing. The study population was 42% male and 58% female. Risk factors in the patients’ histories included high-risk sexual activity, getting a tattoo prior to the year 2000, injecting or snorting drugs, having a blood transfusion before 1992, having a sexual partner with known hepatitis, being a health care worker who had been stuck with a needle, and spending at least 2 days in jail. None of the patients had hepatitis B surface antigens, and 77% did not have antibodies against hepatitis A and B. Four patients had results suggesting previously undiagnosed hepatitis C, and all four complied with the recommended follow-up polymerase chain reaction (PCR) testing. One patient had a positive PCR follow-up, and that patient is beginning triple therapy, Dr. Sears said. All patients who were found to have hepatitis C antibodies had risk factors for hepatitis C infection, she noted.
"We should ask about risk factors and consider screening for hepatitis B and C," Dr. Sears said. "Gastroenterologists see most baby boomers at least once. We understand the [test] results, and this provides the highest quality, most efficient health care for our patients." Dr. Sears said she had no financial conflicts to disclose.
Cost issues in liver transplantation have received increasing attention, but the cost-utility is rarely calculated.
Dr Fredrik Åberg and colleagues from Finland compared costs per quality-adjusted life year from the time of placement on the liver transplant waiting list to 1 year after transplantation for 252 liver transplant patients, and to 5 years after transplantation for 81 patients. The researchers performed separate calculations for chronic liver disease, acute liver failure, and different Model for End-Stage Liver Disease (MELD) scores.
For the estimation of quality-adjusted life years, the health-related quality of life was measured with the 15D instrument.
The team found that the median costs, and quality-adjusted life years after liver transplantation were €141,768 and 0.9 for 1 year, and €177,618 and 4 for 5 years, respectively. MELD scores more than 25 demonstrated higher 5-year costs
Liver Transplantation The research team noted that costs of the first year were 80% of the 5-year costs. The researchers observed that main cost during years 2 to 5 was immunosuppression drugs. The cost/quality-adjusted life year ratio improved from €158,400/quality-adjusted life year at 1 year to €44,854/quality-adjusted life year at 5 years, and the ratio was more beneficial for chronic liver disease patients versus acute liver failure patients, and for patients with low MELD scores versus patients with high MELD scores.
Although patients with chronic liver disease and MELD scores more than 25 demonstrated markedly higher 5-year costs than patients with MELD scores less than 15, the cost/quality-adjusted life year difference was less pronounced.
Dr Åberg's team concluded, "Cost/quality-adjusted life year ratio for liver transplantation appears favorable, but it is dependent on the assessed time period and the severity of the liver disease."
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Life is not always fair, or easy, but it’s wondrous — a gift that comes somehow from the vast everything and is bestowed upon small, silly, frightened, cartoonish creatures with foolish wants, petty greed, and occasional moments of stunning beauty, generosity and love that can be as pure as starlight.
It is a gift to be treasured, a gift to be thankful for. Breathe in the slightly chill fall air, see the blue of the morning sky, the clear dark of the November night. Appreciate it. Give thanks. Thanks for that collection of strivers, lay-abouts, fools and heroes that are your family and friends. Thanks for a meal to share with them, and a home to share it in — however humble, overmortgaged or in need of a good cleaning.
And since, even in tough times, there is so much for American suburbanites to be thankful for — warm and well fed and watching TV — consider giving something back to life.
There is a gift, a commitment, a donation each person may offer. Consider signing up to be an organ donor. Notify the motor vehicle department and get a new driver’s license with the small heart symbol of the organ donor on it. Tell family so they know. Talk about it to other people who might consider signing up themselves.
There are some 112,000 Americans awaiting organs, according to the national Organ Procurement Transplant Network. From January to August this year, fewer than 19,000 organ transplant operations were performed. Most of those were either organs donated by people who’d died or living donors who shared organs such as kidneys with relatives in need.
To sign up as a donor doesn’t cost a thing. And what donors are offering to give — to share with another human being in desperate need — is what they’re most thankful for on holidays like this themselves: days of work and relaxation, nights of dinner and family and love, the breathtaking beauty and miraculous wonder of life itself.
Hepatocellular carcinoma patients who underwent radio frequency ablation (RFA) had a similar survival rate to those who had a surgical resection in a new study from China.
There was no difference in survival even for tumors up to 4cm in diameter, researchers reported November 7th at the annual meeting of the American Association for the Study of Liver Diseases in San Francisco.
The abstract was one of 10 that Dr. Jake Liang, president of the AASLD, singled out to present to the media from among 2300 abstracts at the conference. But at least one expert said the study can't definitively answer the question of whether ablation is as good as surgery for this kind of cancer.
The trial was headed by Dr. Ma Kuansheng at Southwest Hospital in Chongqing. The researchers randomly assigned 168 patients with early-stage hepatoma to either surgery or RFA. Each patient had no more than two tumors less than 4cm in diameter.
Survival rates were similar: 96% in the surgery group and 93.1% in the RFA group at one year, 87.6% with surgery and 83.2% with RFA at two years, and 74.8% and 67.6%, respectively, at three years.
Predictors of survival after ablation included multiple tumors (relative risk 3.85, p = 0.018) and preoperative indocyanine green clearance (RR 3.544, p = 0.002).
Dr. Yuman Fong, a hepatobiliary surgeon at Memorial Sloan-Kettering Cancer Center in New York City who was not involved in the research, pointed to a growing body of research suggesting that ablation compares to surgery for small carcinomas. In that context, the finding is not surprising, but welcome, he told Reuters Health.
"This is an important finding because most patients with HCC have cirrhosis and cannot have a liver resection," Dr. Fong said. "Ablation therefore becomes a life saving, safe and effective therapy for these patients."
But Dr. Myron Schwartz, a surgical oncologist at the Mount Sinai Hospital in New York City, warned of flaws in the study's design.
He told Reuters Health that as a reviewer for the AASLD he had read the abstract when it was first submitted. Among the study's problems, he said, is that it appears to contradict a larger body of evidence suggesting that the failure rate for ablation increases with the size of the tumor.
"It is well-documented that local failure of RFA increases rapidly with increasing tumor diameter," he wrote in an email. "Failure at 2cm is around 5%, whereas at 4cm it's as high as 40%."
Also, he suspects that some of the patients randomized to surgery may not have been good candidates for the procedure.
Resection patients should have normal liver function (including normal ICG clearance) and no portal hypertension, he said. "The fact that impaired ICG clearance was an independent risk factor for poor outcome in this study allows one to conclude that patients with impaired ICG clearance were allowed to enter the study."
Furthermore, according to Dr. Schwartz, patients with multiple tumors are not optimal resection candidates "since multiple tumors imply intrahepatic dissemination and a high likelihood of remote recurrence regardless of how the index tumors are treated."
"The bottom line is that this trial adds nothing," Dr. Schwartz said.
"The real question," he added, "which hasn't been answered directly by a randomized trial but on which a consensus seems to be building, is whether ablation is equivalent to resection even for optimal resection candidates when there is a solitary hepatocellular carcinoma of 2cm or less in diameter."
"The answer seems more and more to be, Yes," Dr. Schwartz said. He added that guidelines are starting to reflect that agreement, "and it's what we do these days."
OAKLAND, Calif., November 22, 2011 – HIV-infected patients are at increased risk for cancer as a result of both their impaired immune system and lifestyle factors, such as smoking, according to researchers at Kaiser Permanente.
The study, which appears in the current issue of Cancer Epidemiology, Biomarkers and Prevention, is among the first to directly compare the risk of cancer in HIV-infected patients with a comparison group without HIV infection, while accounting for major cancer risk factors.
Of the 10 cancer types studied, six were more common in HIV patients, compared with patients without HIV infection — including, Kaposi's sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, melanoma, anal cancer and liver cancer, while prostate cancer was less common. Lung and oral-cavity cancers also occurred more frequently in HIV patients, although most of the risk appeared to be due to risk factors such as smoking, according to the investigators.
Further analysis suggested that immunodeficiency — as measured by CD4 count (a measure of the strength of the immune system) — was positively associated with the risk of all studied cancer types, except prostate cancer. The amount of HIV virus in the blood, however, was only associated with two cancers, Kaposi sarcoma and non-Hodgkin lymphoma, they said.
Most cancers found to be associated with immunodeficiency had a known infectious cause, suggesting a mechanism in which an impaired immune system cannot adequately suppress certain cancer-causing viral infections such as human papillomavirus or hepatitis, investigators explained . They also acknowledged that for some cancers, such as lung and oral-cavity cancers, the elevated risk was multifactorial and likely resulted from both an impaired immune system and risk factors such as smoking.
"Taken together, we believe our results support cancer prevention strategies that combine routine prevention activities, such as smoking cessation, with earlier HIV treatment to help maintain a patient's immune system," said study lead author Dr. Michael Silverberg, PhD, MPH, a research scientist with the Kaiser Permanente Division of Research in Oakland, Calif. The main goal of the study, he added, was to determine how much of the increased cancer risk in HIV patients resulted from their disease, and how much was due to risk factors. To accomplish this goal, they performed a cohort study from 1996-2008 of adult HIV-infected and demographically similar HIV-uninfected individuals from Kaiser Permanente Northern and Southern California. The risk for 10 cancer types were compared between groups, while adjusting for cancer risk factors including smoking, alcohol/drug abuse, and overweight/obesity. They also evaluated the effect of CD4 and HIV virus levels, both of which are markers for HIV disease severity.
"After adjusting for risk factors, the incidence rates of six of 10 cancers were markedly elevated in HIV patients. When we looked more closely we discovered that for most cancers studied — eight of 10 — HIV patients with the lowest CD4 had higher rates compared with those without HIV," said Dr. Silverberg. "These findings need confirmation in other settings, particularly colorectal cancer, which has not been previously linked to immunodeficiency."
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Additional researchers on the study include: Chun Chao, PhD and Lanfang Xu, MS, with Kaiser Permanente Department of Research & Evaluation in Pasadena, Calif.; Wendy A. Leyden, MPH, Charles Quesenberry, Jr., PhD, and Romain S. Neugebauer, PhD, with Kaiser Permanente Northern California Division of Research; Michael Horberg, MD, with the Mid-Atlantic Permanente Research Institute; William J. Towner, MD, with Kaiser Permanente Los Angeles Medical Center; Daniel Klein, MD, with Kaiser Permanente Hayward Medical Center; Robert Dubrow, MD, PhD, with the Yale School of Public Health; and Donald I. Abrams, MD, with the University of California at San Francisco.
Funding was provided by grants from the National Institutes of Health, the Garfield Memorial Research Fund and Pfizer Pharmaceuticals.
About the Kaiser Permanente Division of Research (http://www.dor.kaiser.org/)
The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and the society at large. It seeks to understand the determinants of illness and well-being and to improve the quality and cost-effectiveness of health care. Currently, DOR's 400-plus staff is working on more than 250 epidemiological and health services research projects.
About the Kaiser Permanente Department of Research & Evaluation (http://www.kp-scalresearch.org)
The mission of the Department of Research & Evaluation is to initiate and conduct high-quality, public-sector health services, epidemiologic, behavioral and clinical research that has a demonstrable positive impact on the health and well-being of Kaiser Permanente Southern California members and the general population.
About Kaiser Permanente
Kaiser Permanente is committed to helping shape the future of health care. We are recognized as one of America's leading health care providers and not-for-profit health plans. Founded in 1945, our mission is to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We serve approximately 8.9 million members in nine states and the District of Columbia. Care for members and patients is focused on their total health and guided by their personal physicians, specialists and team of caregivers. Our expert and caring medical teams are empowered and supported by industry-leading technology advances and tools for health promotion, disease prevention, state-of-the art care delivery and world-class chronic disease management. Kaiser Permanente is dedicated to care innovations, clinical research, health education and the support of community health. For more information, go to: www.kp.org/newscenter.
Over two-thirds of HIV-positive military veterans in the US have a mental health disorder, according to research published in the online edition of AIDS. The presence of certain mental health problems was associated with an increased risk of death and HIV disease progression.
“Our results reflect ‘the real world’ of clinical practice, where challenging patients with complex comorbidities are much more common than in the clinical trial setting,” comment the investigators.
Improvements in treatment and care mean that many HIV-positive patients have a near-normal prognosis. However, the impact of mental health disorders on the outcomes of patients taking antiretroviral therapy is poorly understood.
Earlier research has shown that HIV-positive military veterans in the US have high rates of substance abuse and mental health problems. Therefore investigators from the Department of Veterans Affairs conducted a retrospective study to see if a number of psychiatric disorders hastened HIV disease progression and time to death.......Continue Reading..
Nurutdinova D et al. Mental health disorders and the risk of AIDS-defining illness and death in HIV-infected veterans. AIDS 25, online edition, doi: 10.1097/QAD.0b013e32834e1404, 2011 (click here for the free abstract).
15 to 20 percent of all human cancers are caused by viruses
New evidence links virus to brain cancer (Medical Xpress) -- Tilting the scales in an ongoing debate, University of Wisconsin-Madison researchers have found new evidence that human cytomegalovirus (HCMV) is associated with glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy.
The findings confirm what only a handful of scientists have found, but in a manner that University of Wisconsin School of Medicine and Public Health researchers believe enhances the scientific rigor of earlier studies. The study, published in the advanced online edition (Nov. 16, 2011) of the Journal of Virology, hints for the first time that HCMV may work differently than other cancer-related viruses - possibly by affecting only tumor stem cells, self-renewing cells that keep the tumor growing.
The new research may place HCMV in an expanding group of viruses associated with cancer.
"As many as 15 to 20 percent of all human cancers are caused by viruses, and the number is growing," says HCMV expert Dr. Robert Kalejta, associate professor of oncology at the UW School of Medicine and Public Health (SMPH). "The viruses may not cause cancer on their own, but they play a critical role in the process." Among others, human papilloma virus (HPV) causes cervical cancer, Epstein-Barr virus (EBV) causes lymphoma and hepatitis C virus (HCV) causes liver cancer.
HCMV's role in GBM has been debated, with many scientists and clinicians remaining skeptical. Oncologist Dr. Charles Cobbs of California Pacific Medical Center has been the main proponent of the theory that HCMV contributes to GBM. Dr. John Kuo, assistant professor of neurological surgery and human oncology and a cancer stem cell scientist at the School of Medicine and Public Health, was one of the skeptical ones, but he says he's now convinced that HCMV is associated with human GBM specimens. Still, the association does not prove a causal relationship between HCMV and the development of GBM, he says.
"This study may open up a new unexplored area of research for this incurable disease," says Kuo, who is director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics. He also coordinates clinical trials as chair of the brain tumor group at the Carbone Cancer Center. Kuo and colleagues on the UW brain tumor team currently treat GBM patients with the standard regimen of surgery, followed by radiation and chemotherapy. More research is needed before anti-viral drugs against HCMV could be considered for clinical trials, says Kuo, whose group contributed to the Journal of Virology paper.
Two years ago, Kalejta's team added support to Cobb's position when it showed that two HCMV proteins shut down a key protein that restricts tumor growth in general.
"HCMV can also do every one of the things that are generally considered the 10 hallmarks of cancer," says Kalejta, a member of the McArdle Laboratory for Cancer Research, Carbone Cancer Center, Stem Cell and Regenerative Medicine Center and Institute for Molecular Virology at UW-Madison.
The problem with studying HCMV is that the virus is present in a harmless way in almost everyone, so scientists can't ask if HCMV-positive people are more likely to get cancer than people without HCMV. Kalejta's postdoctoral fellow Dr. Padhma Ranganatan used a standard laboratory test, rather than the ultra-sensitive test Cobb has used, to see if HCMV was present in 75 GBM samples. The UW-Madison researchers also looked to see if the entire virus genome - all of its DNA - rather than just a portion of it was present in the tissues. Finally, they wanted to learn if all cells within the tumor or just some of them were infected.
The analysis showed that HCMV is statistically more likely to be present in GBM sample tissues than in other brain tumor and epileptic brain tissues. The whole virus genome, not a portion of it, was present in GBM samples. And the data suggested that a minority of GBM cells were infected with HCMV. "We hypothesize that HCMV may be infecting only tumor stem cells, unlike other viruses, which infect every single tumor cell," says Kalejta. "This leads us to predict that HCMV functions by a unique mechanism that no other virus uses."
Kalejta hopes to begin looking for the new mechanism soon. If there is such a mechanism, it could open a new door in cancer biology. It would also convert many more people to the idea that HCMV plays a key role in GBM. "But I think the tide is now turning on the debate," Kalejta says. Provided by University of Wisconsin-Madison (news : web)
Hall Of Shame
Province pressured to pay up for dirty doctor By JON WILLING, QMI AGENCY Posted -22 second ago OTTAWA -- It's time to put the heat on the province to pay for Ottawa's $750,000 response to the dirty lab investigation, the city health board says. Ottawa public health is on the hook for the money to pay for its prevention program, which is contacting nearly 7,000 former patients of Dr. Christiane Farazli, suggesting they get tested for infectious diseases.
The College of Physicians and Surgeons of Ontario discovered Farazli's clinic wasn't always cleaning endoscopy equipment properly between procedures.
The fai led inspect ion prompted an investigation by the college and a campaign by public health to warn patients there is a very low risk they were exposed to Hepatitis B, C or HIV. During a health-board meeting Monday night, Coun. Maria McRae emphatically called for the board to insist the province provide money to the health unit. Otherwise, the whole Farazli response would come out of the pockets of city taxpayers.
It would be "despicable" if the city had to pay because a clinic, regulated by the college, failed an inspection, McRae said.
"I don't like this cat-and-mouse game," she said. McRae likened it to her time on the police services board when police begged the feds for money to help maintain law and order in the nation's capital. The board agreed public health should pressure the province for cash. The city's legal department said it's premature to talk about pursuing the costs through legal channels.
The college said this week its investigation into Farazli is ongoing.
Big Pharma
Vertex Pharmaceuticals Announces Webcast of its Presentation at the 23rd Annual Piper Jaffray Health Care Conference
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it will webcast its corporate presentation at the 23rd Annual Piper Jaffray Health Care Conference on Tuesday, November 29, 2011 at 11:00 a.m. EST. The presentation will be webcast live and may be accessed from ‘Events & Presentations' on the home page of Vertex's website at www.vrtx.com. A replay of the webcast will also be available on the Company's website for two weeks following the presentation. To ensure a timely connection, it is recommended that users register at least 15 minutes prior to the scheduled webcast.
About Vertex Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives. Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 1,900 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences. Vertex's press releases are available at www.vrtx.com.
By Katherine Hobson Vioxx Settlement: The U.S. Justice Department said Merck agreed to pay $950 million and plead guilty to a criminal misdemeanor charge to resolve allegations that the company promoted its now-defunct pain drug Vioxx for rheumatoid arthritis before the FDA approved it for that use, the WSJ reports. Merck had reserved that amount last year to cover the settlement. The settlement includes a payment of about $628 million to settle civil allegations that Merck representatives made inaccurate statements about Vioxx’s cardiovascular safety to boost sales, but Merck denies those allegations and is admitting no wrongdoing or liability, the paper says.
The manufacturing problems engulfing the troubled Boehringer Ingelheim unit have just grown worse. The European Medicines Agency has just issued a ‘precautionary’ recall for the remaining batches of three cancer meds - Busilvex, Velcade and Vidaza - that were manufactured at its Ben Venue Laborartories facility in Ohio. And no new patients are to be treated with yet another med, Doxil.
FDA
Mylan Is Warned Over Plant In Puerto Rico As the FDA attempts to toughen its oversight of manufacturing facilities in far away lands, plants in Puerto Rico are also undergoing added scrutiny. The latest example is a San Juan plant operated by Mylan Laboratories, the generic drugmaker, which received a warning letter last month for significant violations of good manufacturing practices.
For Your Reading Pleasure
Grand Rounds Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.
By AmyT on November 22, 2011 Welcome to Grand Rounds, Vol. 8, No. 9, the 2011 Thanksgiving edition of the weekly summary of the best health and medical blog posts on the web. Many thanks to the organizers at Get Better Health for inviting us to host!
In a world where major economies are imploding and a climate catastrophe seems impending, there is still much to be thankful for — especially in the arena of health and medicine, where technology is empowering a revolution of sorts in hospitals, clinics and doctors’ offices, and in patients’ everyday lives.
A few submissions from grand rounds, to read more click here
What We’re Collectively Thankful for, from all around the med-blogosphere:
Last week’s host, Alvaro Fernandez at Sharp Brains, is thankful that everyone contributing to and reading Grand Rounds has a human brain (no bots, we hope!), and thankful that the human brain is not fully pre-wired.
Jenni Prokopy, Editrix at the amazing site Chronic Babe, just published a great patient blog carnival about “Gettin’ Our Gratitude On.” A must-read!
Preparing for surgery, White Turk at SrubsIsReal is thankful for a newfound transparency in medicine: “you have to understand bullshit and be comfortable enough with it to strip a legal document down to what it’s really saying.” Amen!
Elaine Schattner, both a doctor and a patient at Medical Lessons, is hoping physicians will keep things personal, remembering that their patients are fellow human beings, and not just digital images for the files.
Jessie Gruman, president and founder of the Center for Advancing Health and blogger at the Prepared Patient Forum, is hoping for improved survivorship care in the years to come, i.e. Who Will Help Cancer Survivors Stay Healthy When Treatment is Over? A great question.
Mount Sinai Medical Center Launches Initiative to Erase the Stigma of Hepatitis C
Uploaded by MarketwireNews Video on Nov 10, 2011
Along with shattering the stigma surrounding the Hepatitis C virus, Dr. Dieterich wants patients to understand that testing positive for the virus is not a death sentence if caught early.
The Mount Sinai Medical Center Launches Initiative to Erase the Stigma of Hepatitis C and Encourage Everyone to Get Tested
NEW YORK, NY--(Marketwire - Nov 16, 2011) - The Mount Sinai Medical Center has embarked on a new mission to educate the public about Hepatitis C and urge more Americans to be tested for this "silent killer." While two million people in the US suffer from Hepatitis C, an additional two million are undiagnosed, putting them at risk for devastating long-term effects. Through an important video program, The Mount Sinai Medical Center's Dr. Douglas Dieterich, Professor of Medicine in the Division of Liver Diseases and former Hepatitis C patient, urges people to take charge of their health by getting tested for the virus, even if no symptoms are present.
Did you know?
Not all patients are IV drug or intranasal cocaine users. Other ways to contract the virus include: body piercings, tattoos, manicures, pedicures, or even while playing sports such as boxing and rugby
The virus can creep along very silently, presenting no symptoms or abnormal liver test results for 30-40 years
Hepatitis C is spread by blood-to-blood contact
If left undetected, the virus can lead to advanced scarring of the liver, or a condition known as cirrhosis, and eventually cause liver failure or other major complications including liver cancer
About 4 times as many people will die in 2020 from Hepatitis C then in 2010
"Many people around the world, probably the majority got it, through the fault of the health care system. They got infected needles from vaccines or other medical devices when they were in the medical world," says Dr. Dieterich.
Along with shattering the stigma surrounding the Hepatitis C virus, Dr. Dieterich wants patients to understand that testing positive for the virus is not a death sentence if caught early. Dr. Dieterich himself contracted the virus in 1977 while attending medical school. He accidentally stuck himself with a needle infected with Hepatitis C and suffered from a rare, but acute reaction. Frustrated with his diagnosis and lack of options to treat it, Dr. Dieterich dedicated his career to studying Hepatitis C and finding effective treatment options for those diagnosed. He was cured in 1998 after an 18-month regimen of daily interferon injections and Ribavirin -- an anti-viral drug that was unavailable at the time of his diagnosis. While he was lucky, he knew there was much more work to be done.
Thanks in part to Dr. Dieterich's commitment to better understanding and treating this virus, we have come much closer to a cure for this disease. Today patients have access to new, FDA-approved protease inhibitors that bring the cure rate to 80 percent.
"If we can treat you, we can cure you almost all of the time. So go get tested before it's too late," Dr. Dieterich says.
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and US News & World Report and whose hospital is on the US News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
Patients may ask about a study suggesting that eating canned soup leads to spikes in urinary excretion of bisphenol A (BPA), a chemical found in the linings of many canned goods. The small randomized crossover trial was reported in a research letter in JAMA.
Some 75 adults ate 12 ounces of either fresh or canned soup for 5 days, and then crossed over to the other soup for another 5 days. Urine samples, collected on days 4 and 5 of each phase, were positive for BPA in 77% of participants after eating fresh soup and in 100% after eating canned soup. Average urinary BPA concentration was roughly 23 μg/L higher after consuming canned versus fresh soup.
The authors note that elevated urinary BPA concentrations have previously been linked to cardiovascular disease and diabetes, and conclude that the increase observed here "may be important."
