Despite Poor Interferon Response in Advanced Hepatitis C Virus Infection, Models of Protease Inhibitor Treatment Predict Maximum Treatment Benefit

From Alimentary Pharmacology & Therapeutics

I. A. Rowe; D. D. Houlihan; D. J. Mutimer

Posted: 09/28/2012; Aliment Pharmacol Ther. 2012;36(7):670-679. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Background Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy.
Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin.
Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches.
Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period.
Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

Introduction

Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality.^[1] Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).^{[2, 3]} Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.^[4]

In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.^{[5, 6]} This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in).^[7] Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.^[8]

In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.^[8–10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.^[11–13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making.^[14] This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.

The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.

Methods

Treatment Strategy

All patients who had previously failed treatment with interferon and ribavirin were considered suitable for treatment. The proportions of subjects with previous null response (<2log₁₀ decline in plasma HCV RNA during 12 weeks of dual therapy), partial response (>2log₁₀ decline in plasma HCV RNA but without achieving plasma HCV RNA PCR negativity) and relapse (PCR negativity at end of antiviral treatment, but subsequent relapse) were estimated at 45%, 20%, 35% respectively.^[15–17] There is no head-to-head comparison of boceprevir and telaprevir, and treatment responses appear comparable.^{[8–10, 18]} As patients with prior null response to dual therapy were not included in the registration studies of boceprevir we planned treatment using a prototypic protease inhibitor modelled on telaprevir. Sustained virological response rates were estimated from studies in previously treated subjects and their subgroup analyses (Table 1, and supplementary information).^{[9, 19]} The utility of treating subjects with advanced fibrosis (defined as METAVIR F3/F4) was first determined using these SVR estimates and by comparison with treatment of subjects with all stages of fibrosis.

Treatment regimens with and without a stopping rule after the 4-week pegylated interferon and ribavirin lead-in phase (<1log₁₀ reduction in HCV RNA) in subjects with advanced fibrosis were then assessed. The variables included in this analysis are shown in Table 2 (and are summarised in Supplementary Figure S1). Standard stopping rules to avoid futile treatment were left in place (i.e. HCV RNA greater than 1000 IU/mL at either 4 weeks or 12 weeks after the start of triple therapy^[20]) but were not explicitly modelled. In each case, analyses were done containing only those showing previous partial or null response since it was considered likely that previous relapsers would receive full treatment regardless of response to lead-in pegylated interferon and ribavirin (SVR rates in this population are very high regardless of baseline fibrosis stage).^[9] Frequency of poor interferon response was extracted from a subgroup analysis of the REALIZE trial.^{[9, 19]}

Outcomes After Treatment

Estimations of the rates of liver-related mortality, hepatic decompensation, and for the development of HCC were reported in a meta-analysis of previously treated patients,^[21] and more recently in a prospective study of patients entered into clinical trials in a single centre.^[22] These data allow the calculation of the absolute risk reduction (ARR) for each of these clinical events with successful treatment. For instance in the meta-analysis,^[21] in previously treated subjects with advanced fibrosis and who do not achieve SVR the annual risk of liver-related mortality is estimated at 2.7%. For individuals with SVR the annual risk reduction is estimated at 0.19, or an annual mortality risk of 0.5% thus giving an ARR of liver-related mortality of 2.2% in those with SVR. The ARR for each outcome is given inTable 2. Adverse outcomes were calculated considering a follow-up duration of 5 years as it is unlikely that additional classes of DAAs will be licensed in that timeframe, and since it is interferon failure in this group that governs poor treatment response this is likely the minimum time until interferon-free regimens are licensed.

Comparison of Treatment Regimens

Calculations were based on hypothetical cohorts of 1000 subjects, and were compared using a decision analysis and comparative effectiveness approach.^[23–25] These cohorts were assigned to receive treatment according to the regimens defined above. Treatment benefit was estimated using a number needed to treat (NNT) approach.^[26] The NNT was calculated using the formula below accounting both for the ARR associated with successful treatment (i.e. the SVR) and also the relative probability of that success.

Since the ARR is expressed per annum, to account for 5-year follow-up, the NNT was divided by 5 to give a 5-year NNT for each outcome.

The rate of clinical events in each cohort was then calculated using the NNT and compared by treatment regimen. The rate of the treatment related serious adverse events of hepatic decompensation (2%) and death (1%)^[27–29] were also compared using this approach.

Sensitivity Analyses

Selected parameters in the base case analysis were varied within plausible limits (Table 2). For instance, rates of ARR for liver-related mortality and HCC varied from 2% to 4%, and 2% to 5%, respectively, in line with recently published data.^{[21, 22]} As relatively few subjects with advanced fibrosis were included in the phase III studies, and those that were had well-preserved liver function, SVR rates varied from 10% to 20% in previous null responders and from 40% to 60% in partial responders. The proportion of subjects not achieving a 1log₁₀ reduction at 4 weeks also varied from 32% to 45% in partial responders and from 55% to 70% in null responders. The relative proportion of null and partial responders included varied from 80/20 to 60/40 splits. Finally, the rate of treatment emergent adverse events varied between 1% and 3% for hepatic decompensation and 0.5% and 2% for treatment-related death.

Results

Mortality Reduction After Treatment

The effect of antiviral treatment on mortality has been assessed in relatively few studies due to the slowly progressive nature of HCV infection and the consequent use of SVR as a surrogate endpoint. To assess the treatment benefit of protease inhibitor containing triple therapy in previously treated subjects, we calculated the 5-year NNT for two groups: those with any stage of liver disease, and those with advanced fibrosis.^[30] For those treated with a protease inhibitor, the 5-year NNT for those with any stage of liver disease is 60 to prevent one liver-related death whereas it is 18 when considering those with advanced fibrosis, despite a reduced SVR (Table 3). The impact of the NNT is highlighted when the number of deaths prevented in each treatment strategy is calculated in hypothetical patient cohorts: more than threefold more deaths are prevented when treating only subjects with advanced disease. These data highlight the importance of considering treatment in this high-risk group and indicate that this group should be prioritised for treatment on the basis of need.

Comparative Effectiveness of Including a Stopping Rule After the 4-week Lead-in

The outcomes of subjects treated with protease inhibitor containing triple therapy are shown in Figure 1. The strategy of treating all patients regardless of response after the 4-week lead-in with pegylated interferon and ribavirin results in the maximal prevention of death (Figure 1a). Employing the virological response to a 4-week lead-in with dual therapy as a stopping rule (Figure 1b) allows treatment to be stopped in the majority of this difficult-to-treat population thus reducing protease inhibitor exposure, and reducing the total number of treatment emergent adverse events. However, there is a notable increase in the efficacy of protease inhibitor containing therapy if treatment is stopped in subjects not achieving a >1log₁₀ reduction in HCV RNA. As those with unfavourable responses are excluded from protease inhibitor containing treatment SVR rates for subjects treated with triple therapy are increased from 37.9% in the treat all strategy to 56.1% when the 4-week stopping rule is applied (Figure 1a,b).

Figure 1. Flow diagram of the hypothetical 1000 subject cohort based on two strategies. (a) All 1000 subjects were treated with protease inhibitor containing triple therapy regardless of initial interferon response, and (b) after a 4-week lead-in treatment was stopped in subjects not achieving >1log₁₀ reduction in HCV RNA. The number needed to treat for each scenario of completed treatment was calculated. After 5-year follow-up the number of deaths prevented was also assessed. F/U, follow-up; NNT, number needed to treat; P/R, pegylated interferon and ribavirin; SVR, sustained virological response.

There is however a significant reduction in overall clinical effectiveness associated with using the 4-week stopping rule. The number of patients achieving SVR is reduced by 37% as a result of excluding those subjects who would otherwise have been cured by continued treatment (SVR 'missed', Figure 1b). As this is a high-risk group and subjects who are not cured remain at significant risk of liver related morbidity and mortality we calculated the effects of the 4-week stopping rule on these parameters (Table 4). For subjects treated with triple therapy but without a stopping rule at week 4, 42 deaths are prevented over 5-year follow-up. However, only 28 deaths are prevented when the 4-week stopping rule is applied, a reduction of 33%. This indicates that by using the 4-week stopping rule 14 premature deaths occur that would have otherwise have been prevented by treating in the absence of the stopping rule.

The Impact of Treatment Emergent Adverse Effects on Outcome

This difficult to treat population is at risk of treatment emergent adverse effects that can negatively impact on the outcome of treatment. In similar studies of dual therapy hepatic decompensation occurs in approximately 2% of those treated and death occurs in approximately 1%.^{[28, 29]} These data are supported by the initial safety data reported in the early expanded access to protease inhibitor programmes in France.^[27] The impact on these episodes is summarised in Table 4. For instance, treatment emergent hepatic decompensation (i.e. decompensation precipitated by treatment) decreases overall treatment effectiveness. In effect there is an approximately 40% reduction in the net number of decopmensation episodes prevented by treatment in the treat-all strategy. When the 4-week stopping rule is employed there is a reduction in treatment-related decompensation episodes, but the advantage of treating all subjects regardless of response at week 4 of treatment remains. The impact on death is similar and these data indicate that the development of treatment emergent adverse effects does not significantly reduce the comparative benefit that is achieved by treating subjects regardless of virological response at treatment week 4.

Sensitivity Analyses

In sensitivity analyses, the overall benefit of continued treatment despite poor virological response at treatment week 4 was maintained despite variation in the proportion of null and partial responders, low SVR rates to protease inhibitor containing treatment, and also in cohorts containing an increased frequency of subjects not achieving >1log₁₀ reductions at treatment week 4. However, in scenarios where there was greater mortality associated with treatment, and particularly where this was associated with low treatment efficacy, there was no difference in overall mortality between those treated regardless of virological response and those treated according to the 4-week stopping rule (Table 5). These analyses support not using the 4-week lead-in as a universal stopping rule but rather individualising treatment where subjects at high risk of on-treatment mortality due to the presence of advanced cirrhosis and portal hypertension^{[28, 29]} should have interferon sensitivity considered in treatment planning.

Discussion

The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.^{[5, 6]} There are however a number of questions regarding how, and in whom, these agents should be used.^{[13, 14, 31]} This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates^[32] and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.

Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment.^[33] Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.^{[9, 21]} Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.

The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.^[11–13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.^{[28, 29]} Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs),^[27] there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment^[7] and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.

This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log₁₀ reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.

This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry^[34] and fibrosis stage,^{[35, 36]} the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR.^[21] A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered^[22] suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.^{[37, 38]} Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.

These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar^[39] these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.

In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.

References

1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558–67.
2. Seeff LB. Natural history of hepatitis C. Am J Med 1999; 107: 10S–5S.
3. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011; 140: 1182–8.
4. Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ 2011; 343: d7995.
5. Rowe IA, Mutimer DJ. Protease inhibitors for treatment of genotype 1 hepatitis C virus infection. BMJ 2011; 343: d6972.
6. Lange CM, Sarrazin C, Zeuzem S. Review article: specifically targeted antiviral therapy for hepatitis C – a new era in therapy. Aliment Pharmacol Ther 2010; 32: 14–28.
7. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology 2011; 53: 1742–51.
8. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–17.
9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–28.
10. Poordad F, McCone JJ, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–206.
11. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56(Suppl.): S88–100.
12. Bacon BR, Khalid O. Triple therapy with boceprevir for HCV genotype 1 infection: phase III results in relapsers and nonresponders. Liver Int 2012; 32(Suppl. 1): 51–3.
13. Ramachandran P, Fraser A, Agarwal K, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012; 35: 647–62.
14. Jacobson IM, Pawlotsky JM, Afdhal NH, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat 2012; 19(Suppl. 2): 1–26.
15. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa- 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.
16. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645–52.
17. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa- 2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–93.
18. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.
19. Foster GR, Zeuzem S, Andreone P, et al. Subanalyses of the trlaprevir leadin arm in the REALIZE study: response at week 4 is not a substitute for prior null response categorisation. J Hepatol 2011; 54: S3.
20. Telaprevir (Incivo) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/25038/spc. Accessed June 2, 2012.
21. Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010; 8: 280–8.
22. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010; 52: 652–7.
23. Pauker SG, Kassirer JP. Decision analysis. N Engl J Med 1987; 316: 250–8.
24. Plevritis SK. Decision analysis and simulation modeling for evaluating diagnostic tests on the basis of patient outcomes. AJR Am J Roentgenol 2005; 185: 581–90.
25. El-Serag HB, Talwalkar J, Kim WR. Efficacy, effectiveness, and comparative effectiveness in liver disease. Hepatology 2010; 52: 403–7.
26. Moore A, McQuay H. Numbers needed to treat derived from meta analysis. NNT is a tool, to be used appropriately. BMJ 1999; 319: 1200.
27. Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non-responders. First results of the French early access program (ANRS CO20-CUPIC) in reallife setting. GAJ 2011; 7: 54.
28. Massoumi H, Elsiesy H, Khaitova V, et al. An escalating dose regimen of pegylated interferon and ribavirin in HCV cirrhotic patients referred for liver transplant. Transplantation 2009; 88: 729–35.
29. Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005; 42: 255–62.
30. Rowe IA, Armstrong M, Houlihan D. Prioritising treatment experienced patients with hepatitis C infection for treatment with telaprevir. A number needed to treat approach. Hepatology 2012; 55: 1644–5.
31. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 1433–44.
32. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 513–21.
33. AASLD. AASLD: Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection. Available at: http://www.aasldorg/practiceguidelines/Pages/hepccomments. Accessed June 20, 2012.
34. Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial. Aliment Pharmacol Ther 2009; 29: 589–601.
35. Everson GT, Balart L, Lee SS, et al. Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis. Aliment Pharmacol Ther 2008; 27: 542–51.
36. Hezode C, Castera L, Roudot-Thoraval F, et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther 2011; 34: 656–63.
37. DiBonaventura M, Wagner JS, Yuan Y, L'Italien G, Langley P, Ray Kim W. The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities. J Med Econ 2011; 14: 253–61.
38. Su J, Brook RA, Kleinman NL, Corey-Lisle P. The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs. Hepatology 2010; 52: 436–42.
39. Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010; 32: 344–55.

Source

The patient, the doctor, and the system: Underdiagnosis and undertreatment of hepatitis B

Download the PDF here

Tram T. Tran M.D.1,2,
Luis H. Ocampo Jr M.D.2

Hepatology August 2012

Cohen C, Holmberg SD, McMahon BJ, Block JM, Brosgart CL, Gish RG, et al. Is chronic hepatitis B being undertreated in the United States? J Viral Hepat 2011;18:377-383. (Reprinted with permission

Hepatitis B in the united states: a major health disparity affecting many foreign-born populations - (06/03/12)

Abstract

Chronic infection with the hepatitis B virus (HBV) is a major risk factor for the development of end-stage liver disease, including cirrhosis, liver failure, and primary liver cancer. There are now 7 antiviral agents approved by the US Food and Drug Administration for the management of chronic HBV infection. Despite the fact that there are between 1.4 and 2 million chronic HBV infections in the United States, fewer than 50,000 people per year receive prescriptions for HBV antiviral medications. This report discusses possible explanations for the disparity between the number of people who are chronically infected and the number of people who receive treatment. Explanations for this incongruence include the potentially large number of infected persons who are unscreened and thus remain undiagnosed, and lack of access, including insurance, education, and referral to appropriate medical care, particularly for disproportionately infected populations.

Comment

The incidence of acute hepatitis B (HBV) infection has decreased since the implementation of universal screening of pregnant women and vaccination of newborns.1 However, there still exists a substantial number of Asian Americans, Africans, and other groups immigrating from areas of high prevalence, men who have sex with men (MSM), and IV injection drug users (IVDU) who are already infected or are at risk of infection. Once chronic, HBV increases the risk of cirrhosis, as well as hepatocellular carcinoma (HCC). Unfortunately, even with the success of preventative strategies there still exist 730,000 to 2 million people in the United States who are already chronically infected with HBV,2 with the largest proportion being MSM, IVDU, and Asian Americans. Of the chronically infected, Cohen et al. suggest only 50,000 patients are receiving antiviral treatment.3 Although not all infected persons require therapy, understanding why this large disparity exists requires understanding the individual, specific community, health care provider-related, and health care systems-based barriers that may exist.

One group affected by HBV infection is the Asian American/Pacific Islanders (AAPI), who comprise approximately 4% of the US population and are expected to be 9.2% of the population by 2050.1 This group is disproportionately affected by chronic HBV compared to the rest of the US population as an estimated 1 in 10 AAPIs have chronic HBV. Of new cases of chronic HBV diagnosed in the United States, approximately 24% of those cases are found in AAPIs.4 This is in contrast to the prevalence of chronic HBV among whites, which is estimated at 0.2%.5 Many of these chronically infected AAPIs are immigrants from countries where the prevalence of hepatitis B surface antigen positivity may be as high as 10% to 20% of the population, which is seen in many parts of Southeast Asia.5 Contributing to the issue is that two-thirds of immigrants from high-prevalence areas such as Southeast Asia do not know they are infected.1 Many of the countries with the highest prevalence of HBV worldwide are also countries with limited resources for mandatory screening programs; therefore, increasing opportunities for screening this population are critical to decreasing the impact of chronic HBV infection.

Other populations at risk include MSM and intravenous drug abusers. These 2 groups have the highest incidence of acute HBV infection in the United States,6 which equates to an annual incidence of chronic HBV infection within these groups of 1.1% and ~2.4% to 11%,7 respectively. Although some of these individuals may have access to the health care system, studies have shown that these groups may also be underscreened for HBV.

The reasons for the lack of screening and treatment in high-risk groups often involve a patient's educational status, belief systems, and cultural barriers to screening. These factors can influence the willingness of an individual to seek screening or comply with screening recommendations. Philbin et al. recently surveyed immigrant and native-born Chinese, Vietnamese, and Korean individuals about their knowledge of hepatitis and associated liver diseases. In this study, the responses showed that many individuals felt that lack of education about the disease, as well as limited access to health care were barriers to screening.8 Studies among AAPIs who have lower levels of education and socioeconomical status revealed that they were the least likely to be vaccinated and screened.1, 9 These patients were asked about their health care in a questionnaire, which showed that health care provider recommendations as well as family suggestion were the leading reasons for a person to seek screening.9 Overcoming these barriers as well as the social stigma of infection and treatment will be essential in improving screening and treatment acceptance.

The MSM community is often perceived as having a higher socioeconomic status than AAPIs; however, when this community was studied by the Young Men's Survey Phase II, Weinbaum et al. reported the prevalence of immunization at only 17.2% among MSM surveyed. Many of these individuals had access to health care or had been screened for HIV, another commonly associated disease among MSM, but many had no knowledge they were susceptible to HBV or that a vaccine existed.6

Aside from individual patient factors, the health care practitioner's role in screening, diagnosis, and treatment of HBV is of obvious importance. With the expansion of the treatment armamentarium and the effectiveness of vaccination, it would be expected that physicians would be highly proactive in screening and treating those meeting treatment guidelines. Unfortunately, this has not been the case as data published on physicians' adherence to The Centers for Disease Control and Prevention guidelines for screening showed that only 60% of physicians correctly screened at-risk patients.10 In fact, many physicians who practice in areas with large at-risk populations such as AAPIs actually underestimate the impact of HBV on this population. Misidentifying the population to screen was determined to be the main reason for lack of screening among physicians in a recent survey.1 Many clinicians feel they only need to screen those with abnormal liver tests, such as transaminitis or when presenting with symptoms, when in fact many patients may not have symptoms or abnormal lab tests.

The approval of new first-line oral therapies have shown effective viral suppression, low resistance, and good safety profiles with evidence of biochemical normalization and moderate rates of hepatitis B e antigen seroconversion.11 The result of decreasing disease activity with antiviral suppressive therapy is decreased risk of cirrhosis and theoretical decrease of HCC risk as well.12, 13 Despite the availability of these medications, recent interviews with physicians who treat patients in AAPI populations show that close to 60% of these physicians are not aware of current treatments.14

In the article by Cohen et al.-"Is Chronic Hepatitis B Being Undertreated in the United States?"3-the authors show how patients, doctors, and health care systems are the primary factors for the lack of screening and treatment of HBV. Screening is cost effective even in population centers with as little as 0.3% prevalence when the expense of hospitalizations for cirrhosis and transplantation are considered.15 The authors make the case that only 4% to 5% of chronic HBV-infected patients are screened, enter into a health care system, and obtain treatment. So what can we do? One large AAPI community intervention in San Francisco using a comprehensive citywide program utilizing HBV education, screening, and treatment showed that within 1 year of being screened, the individual diagnosed with chronic HBV (67%) had accessed health care, and many (78%) have encouraged family members to undergo screening.1 This article makes a point that we probably all know: that hepatitis B is underdiagnosed and undertreated. The more difficult task will be how to mobilize stronger and more persistent patient, physician, and community advocacy to increase the numbers of patients screened, diagnosed, and treated.

Key Step Lacking in Preventing Perinatal Hep B Transmission

By Michael Smith, North American Correspondent, MedPage Today

Published: September 28, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of

Most babies born to mothers with hepatitis B (HBV) appear to get post-exposure prophylaxis as well as the full three-dose series of vaccine against the virus, the CDC is reporting.

But adherence to a key follow-up step – post-vaccination serologic testing – seems less complete, the agency reported in the Sept. 28 issue of Morbidity and Mortality Weekly Report.

About 25,000 infants are born every year in the U.S. to mothers who test positive for the hepatitis B surface antigen (HBsAg), the CDC report noted, and without intervention up to 90% of infants can become infected, increasing their risk for cirrhosis or early death.

For that reason, the CDC's Advisory Committee on Immunization Practices urges post-exposure prophylaxis with hepatitis B vaccine and hepatitis B immune globulin within 12 hours of birth. Exposed infants should also complete the three-dose HBV vaccine series.

To evaluate the effect of the treatment, the committee has recommended, babies should be tested – a month after the last dose of vaccine -- for the HBV surface antigen and for the antibodies against it.

To see how well those recommendations were being carried out, the agency studied outcomes at 24 months for babies whose HBV-positive mothers were enrolled during 2008–2009 in five Enhanced Perinatal Hepatitis B Case Management Projects.

All told, the five projects -- in Florida, Michigan, Minnesota, New York City, and Texas -- managed 5,075 infants, of whom 4,214 had been given at least three doses of HBV vaccine by the age of 24 months.

But post-vaccination serologic testing took place in only 3,244 children (77%) of those who got their three shots.

Of those, the CDC analysis found, the testing was incomplete in 412, including 41 tested only for antibodies and 371 tested only for the surface antigen.

The date of testing was not reported for 561 children.

Of the 2,683 children with both testing and dates reported, the agency found, 93.3% were protected, 3.2% remained susceptible but were not infected, and 1.2% were infected. The remaining 2.3% had indeterminate results.

The rates of post-vaccination serologic testing have been rising, the agency noted – in one study from about 25% in 1994 to 56% in 2008.

But "this analysis highlights areas in need of improvement," the CDC report said, adding that strategies are needed to increase overall testing rates, as well as complete testing for both antibodies and the surface antigen, which are needed to confirm outcomes.

The study, the agency report cautioned, is based on five HBV perinatal case management projects and might not be representative of all births to women with HBV infection.

The analysis was conducted by the CDC and state and local health departments. The authors are employees of those agencies.

Primary source: Morbidity and Mortality Weekly Report
Source reference:
Centers for Disease Control and Prevention "Postvaccination Serologic Testing Results for Infants Aged ≤24 Months Exposed to Hepatitis B Virus at Birth -- United States, 2008–2011" MMWR 2012; 61: 768-771.

Source

Improved Criteria for Identifying Transplant Candidates with Hepatocellular Carcinoma

A new model that includes alpha-fetoprotein level predicts 5-year recurrence of posttransplant HCC better than the standard Milan criteria.

Liver transplantation is the best treatment option for early stages of hepatocellular carcinoma (HCC). Currently, the Milan criteria are used to identify transplantation-eligible patients with a low risk (10%–15%) for posttransplantation tumor recurrence. However, recent evidence has raised concern that these criteria might be too restrictive.

Using data from a cohort of 537 patients in France who received a liver transplant for HCC, researchers developed a new predictive model that included alpha-fetoprotein (AFP) level. This AFP model was then validated in a separate cohort of 435 liver transplant recipients with HCC who were part of a national transplantation program in France and were followed prospectively.

Regression analysis showed that the number of tumors, tumor size, and AFP level were independent predictors of 5-year tumor recurrence (the primary endpoint). Three combinations of these variables defined patients as low risk:

• One to three nodules with maximum tumor diameter <3 cm and AFP 1000 ng/mL
• One to three nodules with maximum tumor diameter 3 to 6 cm and AFP 100 ng/mL
• More than four nodules with maximum tumor diameter <3 cm and AFP 100 ng/mL

In a simplified model, researchers transformed Beta coefficients of variables from the regression model into points, adding these to obtain a score. A score of 2 was the cutoff for low versus high risk. In the validation cohort, a score >2 (vs. 2) was associated with a higher 5-year recurrence rate (50.6% vs. 8.8%, P<0.001) and a lower 5-year survival rate (47.5% vs. 67.8%, P=0.002). The AFP model was superior to the Milan criteria in predictive performance based on a comparison of predicted and observed recurrence events with each. Some patients identified by the AFP model as low risk (e.g., patients with AFP 100 ng/mL) did not meet Milan criteria, and some identified as high risk (e.g., patients with AFP >1000 ng/mL) did meet the Milan criteria.

Comment: These new selection criteria identified not only transplantation candidates with low risk for HCC recurrence who would have been excluded using the standard Milan criteria, but also those at high risk for HCC recurrence who would have been eligible under those criteria. With the rise in the number of patients with HCC listed for transplantation, continual refinement of the selection criteria is critical. This AFP model could be the next iteration of those criteria.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology September 28, 2012

Citation(s):

Duvoux C et al. Liver transplantation for hepatocellular carcinoma: A model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012 Oct; 143:986.

Medline abstract (Free)

Source

Vertex Announces New Data on ALS-2200 in People With Hepatitis C, Supporting Advancement into Phase 2 All-Oral Studies in 2012; Ends Development of ALS-2158

September 25, 2012

- ALS-2158: Well-tolerated in a seven-day viral kinetic study; development discontinued due to lack of efficacy -

- ALS-2200: Data from additional cohort of seven-day viral kinetic study with ALS-2200 (200 mg, QD) in combination with ribavirin show median 4.18 log₁₀ reduction in HCV RNA with 5 of 8 people below the limit of quantification; treatment was well-tolerated -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and its collaborator Alios BioPharma, Inc. today announced results from a viral kinetic study of the adenosine nucleotide analogue pro-drug ALS-2158 for the treatment of hepatitis C. Data showed that seven days of dosing with up to 900 mg of ALS-2158 was well-tolerated in people with genotype 1 chronic hepatitis C, but that there was insufficient antiviral activity to warrant proceeding with further clinical development. The companies also announced new data from an additional cohort of an ongoing viral kinetic study of the uridine nucleotide analogue pro-drug ALS-2200 in combination with ribavirin. There was a median 4.18 log₁₀ reduction from baseline in HCV RNA after seven days of dosing with a once-daily 200 mg dose of ALS-2200 in combination with ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment (n=8). Five patients achieved HCV RNA levels below the limit of quantification ( < LOQ = < 25 IU/mL) and two of these five achieved HCV RNA levels below the limit of detection (Roche COBAS Taqman HCV test, Version 2) after seven days of treatment.

Similar to previously announced data from the monotherapy cohort, ALS-2200 was well-tolerated, no patients discontinued due to adverse events and there were no serious adverse events. Data from the ALS-2200 study will be presented in an oral presentation at The Liver Meeting^®, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, November 9 to 13, 2012.

"Our goal is to develop all-oral regimens that are well-tolerated and provide a high rate of viral cure in a broad population of people with chronic hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We're making good progress and expect to begin all-oral Phase 2 combination studies by the end of this year."

Pending discussions with regulatory agencies, Vertex is planning one Phase 2 study to evaluate ALS-2200 (VX-135) in combination with ribavirin, and one to evaluate ALS-2200 (VX-135) in combination with INCIVEK^® (telaprevir), the company's approved protease inhibitor for people with genotype 1 chronic hepatitis C. These studies will evaluate 12 total weeks of treatment with a primary endpoint of SVR12 (sustained viral response: undetectable hepatitis C virus 12 weeks after the end of treatment) in people with genotype 1 chronic hepatitis C.

About ALS-2200

ALS-2200 is a uridine nucleotide analogue pro-drug that appears to have a high barrier to drug resistance based on in vitro studies. It is designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. In vitro studies of the compound showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 through an exclusive licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

About INCIVEK

INCIVEK^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK^® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.² However, approximately 60 percent of people do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8

More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.^9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.¹⁰ The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.¹¹ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.^12,13 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.¹⁰

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 and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including HCV, RSV, Influenza and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the third paragraph of this press release and statements regarding (i) data supporting the advancement of ALS-2200 into Phase 2 all-oral studies this year and (ii) Vertex's plans regarding the design of these Phase 2 studies. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the initiation of Phase 2 studies of ALS-2200 may be delayed or prevented, outcomes from any future studies of ALS-2200 may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

References:

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed September 21, 2012.

² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

⁹ Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.

¹⁰ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed September 21, 2012.

¹¹ Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.

¹² Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

¹³ S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.

Vertex Pharmaceuticals Incorporated
Media:
Zach Barber
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617-444-6992
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Source: Vertex Pharmaceuticals Incorporated

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Treating Hepatitis C Infection in Prison is Good Public Policy, Study Says

September 27, 2012

Incarcerated patients with chronic hepatitis C virus (HCV) infection are just as likely to respond to treatment for the disease as patients in the community, according to findings published in the October issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases. The study from the University of Wisconsin School of Medicine and Public Health (SMPH) in Madison found that HCV patients in prison were just as likely to achieve a sustained viral response (SVR) as non-incarcerated patients.

Medical evidence reports that chronic HCV is the leading cause of end-stage liver disease (ESLD) and liver disease mortality in the U.S. Further studies have shown the risk of developing cirrhosis due to chronic HCV ranges between 5 and 25 percent over a 25 to 30 year period. Consequences caused by chronic HCV are major public health concerns within the U.S. prison system, with research conducted by the Centers for Disease Control and Prevention (CDC) estimating up to 31 percent of U.S. inmates have chronic HCV, compared to just two percent of the general population in this country.

"Given that a history of intravenous drug use is more frequent among inmates, there is a higher prevalence of HCV infection in the prison population," explains lead author Dr. Michael Lucey, Chief of the Division of Gastroenterology and Hepatology at the SMPH. "HCV treatment during incarceration provides an opportunity to make a significant improvement to public health."

Incarcerated and non-incarcerated patients with HCV who were seen at the University of Wisconsin Hepatology or Infectious Diseases Clinic between January 2002 and December 2007, were evaluated for antiviral therapy. Researchers identified 521 general-population patients and 388 from the prison population who were evaluated for HCV therapy.

Results show that 61 percent of non-incarcerated and 60 percent of incarcerated patients received treatment with pegylated interferon and ribavirin. Those from the prison population were more likely to be African-American males with a history of alcohol or intravenous drug use. The team reported that SVR was achieved in 43 percent of prisoners compared to 38 percent of patients in the general-population group.

"Our findings highlight the effectiveness of antiviral therapy in HCV-infected prisoners, and show that it is as successful as treatment for HCV patients in the general population," says Lucey. "With previous studies citing poor results of HCV treatment in high-risk groups on an outpatient basis, a correctional setting may be an optimal setting for treatment that will help curb the hepatitis C public health crisis."

This research was funded by the American Cancer Society Research Scholar Grant, the National Institutes of Health (NIH) Clinical and Translational Science Award, and by the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources at NIH.

Reference: Rice JP, et al. Comparison of Hepatitis C Virus Treatment Between Incarcerated and Community Patients. Hepatology; (DOI: 10.1002/hep.25770; Print Issue Date: October, 2012.

Source

Liver cells, insulin-producing cells, thymus can be grown in lymph nodes

September 27, 2012

(Phys.org)—Lymph nodes can provide a suitable home for a variety of cells and tissues from other organs, suggesting that a cell-based alternative to whole organ transplantation might one day be feasible, according to researchers at the University of Pittsburgh School of Medicine and its McGowan Institute for Regenerative Medicine. In a report recently published online in Nature Biotechnology, the research team showed for the first time that liver cells, thymus tissue and insulin-producing pancreatic islet cells, in an animal model, can thrive in lymph nodes despite being displaced from their natural sites.

Hepatitis virus infection, alcoholic cirrhosis and other diseases can cause so much damage that liver transplantation is the only way to save the patient, noted senior investigator Eric Lagasse, Pharm. D., Ph.D., associate professor, Department of Pathology, Pitt School of Medicine. Children with DiGeorge syndrome lack functional thymus glands to produce essential immune cells, and diabetes can be cured with a pancreas transplant.

"However, the scarcity of donor organs means many people will not survive the wait for transplantation," said Dr. Lagasse, whose lab is at the McGowan Institute. "Cell therapies are being explored, but introducing cells into tissue already ravaged by disease decreases the likelihood of successful engraftment and restoration of function."

In the study, his team tested the possibility of using lymph nodes, which are abundant throughout the body and have a rich blood supply, as a new home for cells from other organs in what is called an "ectopic" transplant.

They injected healthy liver cells from a genetically-identical donor animal into lymph nodes of mice at various locations. The result was an enlarged, liver-like node that functioned akin to the liver; in fact, a single hepatized lymph node rescued mice that were in danger of dying from a lethal metabolic liver disease. Likewise, thymus tissue transplanted into the lymph node of mice that lacked the organ generated functional immune systems, and pancreatic islet cell transplants restored normal blood sugar control in diabetic animals.

"Our goal is not necessarily to replace the entire liver, for example, but to provide sufficient cell mass to stabilize liver function and sustain the patient's life," Dr. Lagasse said. "That could buy time until a donor organ can be transplanted. Perhaps, in some cases, ectopic cell transplantation in the lymph node might allow the diseased organ to recover."

Journal reference: Nature Biotechnology

Provided by University of Pittsburgh Schools of the Health Sciences

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Also See: Growing Surrogate Organs in Lymph Nodes

Achillion Announces Positive Proof-of-Concept Data With ACH-3102

September 27, 2012

-Second-Generation Pan-Genotypic NS5A Inhibitor Achieves Potent Antiviral Activity
of Mean Maximum 3.74 Log₁₀ Reduction Following a Single Dose -

- Initiated Enrollment in a Phase 2 Clinical Trial Evaluating ACH-3102 Plus Ribavirin for the Treatment of HCV Genotype 1b-

- Hosting Analyst Day Today With Live Webcast Beginning at 1:00 p.m. ET -

NEW HAVEN, Conn., Sept. 27, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced positive proof-of-concept results with ACH-3102, a second-generation pan-genotypic NS5A inhibitor being developed for the treatment of chronic hepatitis C viral infections (HCV). Administration of a single-dose of ACH-3102 to genotype (GT) 1a HCV-infected subjects resulted in a mean maximum 3.74 log₁₀ reduction in HCV RNA (range 2.9 — 4.6 log₁₀). Significant reductions in HCV RNA were achieved in subjects with resistant variants at baseline, including L31M and Y93C variants.

Based on these data, combined with safety and tolerability results from the Phase 1a trial in healthy subjects evaluating up to 14 days of ACH-3102, Achillion has initiated a pilot Phase 2 clinical trial evaluating ACH-3102 in combination with ribavirin for the treatment of patients with chronic GT 1b HCV.

"We believe these proof-of-concept results demonstrate the differentiation of ACH-3102 from first-generation NS5A inhibitors. The potency of ACH-3102 was successfully shown against genotype 1a, historically the hardest to treat HCV subtype," commented Michael Kishbauch, President and Chief Executive Officer of Achillion. "Furthermore, we believe the enhanced resistance profile of ACH-3102 observed in vitro has been validated in the clinic with robust antiviral activity against baseline mutations such as L31M. These results support our belief that this second-generation pan-genotypic NS5A inhibitor has the potential to become a cornerstone compound."

ACH-3102: Phase 1 Program

In May 2012, Achillion initiated a Phase 1a clinical trial evaluating the safety and tolerability of single and multiple ascending doses of ACH-3102 in healthy volunteers. To date, 42 healthy volunteers have received a single dose of ACH-3102, ranging from 25 mg to 1,000 mg. An additional 32 healthy volunteers have received 14 days of ACH-3102 once-daily evaluating various dosing regimens. Preliminary data from the single and multiple ascending dose groups demonstrated that ACH-3102 was well tolerated at all doses evaluated. There were no serious adverse events and no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate and were transient in nature.

In August 2012, Achillion initiated a Phase 1b clinical trial enrolling a total of 14 patients infected with GT 1a chronic HCV, of which 2 received placebo and 12 received a single dose of 50 mg, 150 mg or 300 mg ACH-3102. No serious adverse events were reported and there were no patient discontinuations.

The mean maximum HCV RNA decline for each dose group is provided below:

An assessment of clinical virology was conducted on baseline samples from all 12 patients receiving a single-dose of ACH-3102. Sequencing revealed one patient had a baseline L31M mutation (300 mg dose group, maximum HCV RNA decline of 3.4 log₁₀) and another patient had a baseline Y93C mutation (300 dose group, maximum HCV RNA decline of 4.6 log₁₀). These mutations have been previously reported to convey a high level of resistance to first-generation NS5A inhibitors which was not observed following exposure to ACH-3102.

ACH-3102: All-oral, interferon-free pilot Phase 2 12-week trial of ACH-3102 and ribavirin for the treatment of HCV GT 1b

Achillion has initiated patient enrollment in an open-label Phase 2 pilot trial evaluating 12-weeks of once-daily ACH-3102 in combination with ribavirin for the treatment of HCV GT 1b. This study will initially enroll up to 16 treatment-naïve patients with GT 1b IL28B CC HCV. Patients will receive 225 mg of ACH-3102 on day 1 followed by 75 mg of ACH-3102 once daily on subsequent days in combination with twice daily ribavirin. The primary objective of the trial is to determine the safety and sustained virologic response 12 weeks after the completion of treatment (SVR12) with secondary endpoints assessing safety, pharmacokinetics, pharmacodynamics, and virologic endpoints including rapid virologic response (RVR) and extended RVR (eRVR). Achillion expects to report initial RVR results from this study during the fourth quarter of 2012.

Mr. Kishbauch further commented, "With the initiation of this all-oral 12-week study evaluating ACH-3102 and ribavirin for the treatment of HCV genotype 1b, we have rapidly advanced our portfolio and believe the attributes of ACH-3102, as well as sovaprevir, our Phase 2 protease inhibitor, have the potential to provide optimized compounds for the broad treatment of HCV."

Analyst Day Webcast

Achillion is hosting its inaugural Analyst Day and simultaneous webcast on Thursday, September 27, 2012 at 1:00 p.m. Eastern Time. To access a copy of the presentation and the live audio webcast of the event, please visit www.achillion.com. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary. A replay of the webcast will be available on www.achillion.com beginning approximately 2 hours after the conclusion of the event.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the favorable activity and potential benefits of ACH-3102 and sovaprevir, and expectations about milestone achievement including the potential to report RVR results during the fourth quarter of 2012. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things, Achillion's ability to: replicate in later clinical trials the positive results found in nonclinical studies and earlier stage clinical studies of sovaprevir, ACH-2684, and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

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Growing Surrogate Organs in Lymph Nodes

GENNewsHighlights

Sep 28, 2012

A patient’s lymph nodes may offer an ideal transplantation site for cell- or tissue-based therapies against a range of diseases that currently necessitate whole-organ transplantation, or the transfer and engraftment of cells into already damaged tissue, scientists claim. Studies in mice by University of Pittsburgh scientists have shown that healthy lymph nodes will support engraftment of diverse cell types such as hepatocytes, thymic tissue, and pancreatic islet cells, and that the transplanted cells generate functional surrogate organs in the lymph nodes that can reverse the pathology of diseases such as liver failure and diabetes.

The human body contains over 500 lymph nodes, and the concept that these sites can provide a foster home for a wide range of cell types is supported by the fact multiple cancer cell types will often metastasise first to lymph nodes, where they can continue to grow and proliferate. The latest work by Eric Lagasse, Ph.D., and colleagues now suggests that this hospitable environment could be harnessed for regenerative therapy.

The team tested to see whether the lymph node environment could also support the engraftment and function of different cell types for cell therapy application. For the first set of experiments, the researchers transferred syngeneic hepatocytes into a single jejuna lymph node of a mouse model of lethal metabolic liver failure. Twelve weeks later they found that the cells had engrafted in the lymph node and effectively generated a functional ectopic liver that rescued the recipient animals from lethal liver failure. In fact, in the Fah^-/- mouse model used, hepatocytes transplanted into just one jejunal lymph node developed into tissue representing about 70% of the mass of a mouse liver. Encouragingly, the technique was equally effective when other lymph nodes were used as the transplantation site.

Projecting the future use of this approach for treating liver disease in humans, the investigators say the overall aim wouldn’t necessarily be to replace the patient’s liver, rather the ectopic tissue would hopefully provide enough cell mass to stabilize liver function until an organ donor is found, or help the patient’s own liver regenerate.

For the second set of experiments the team transplanted thymuses taken from healthy newborn mice into jejuna lymph nodes of athymic (BALB/c) nude mice. A month later the recipient animals were producing CD4+ and CD8+ cells from their own bone marrow, and these immune cells were still being generated 10 months later. Notably, when the ectopic thymus tissue was analyzed, it was found that the transplanted cells had organized into thymic medullary and cortical epithelia, and that the T cell population induced a full complement of regulatory, naive, central memory, and effector T cells that could mount T cell-mediated immune responses to skin allografts and tumor xenografts.

In a third set of studies, the investigators harvested pancreatic islets from C57BL/6 mice and transplanted these into the jejuna lymph nodes of C57BL/6 wild type mice treated with streptozotocin, a compound that induces diabetes. Encouragingly, the transplanted islets expressed C-peptide and glucagon, which are indicators of pancreatic β-cell and α-cell function. Importantly, the transplanted islets functioned to restore glucose concentrations in the recipient animals to normal levels within six weeks, and, in one animal evaluated, normoglycemia was maintained for at least six months after lymph node transplantation.

Describing their work in Nature Biotechnology, the Pittsburgh investigators say that to their knowledge this is the first time that lymph node evaluation as a site for functional cellular transplantation has been reported. “By directly injecting the lymph node with hepatocytes, thymuses, or pancreatic islets, we demonstrate engraftment of the donor cells and subsequent organ function,” they state. “This new approach of using the lymph node as an in vivo bioreactor in which to regenerate functional organs may be beneficial to the field of regenerative medicine.”

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Poor HIV patients improve with care beyond drugs: study

AIDS activists take part in a rally across from the White House in Washington July 24, 2012. Credit: Reuters/Kevin Lamarque

By Susan Heavey

WASHINGTON | Fri Sep 28, 2012 2:56am EDT

(Reuters) - Patients stepping into Johns Hopkins University's HIV clinic in east Baltimore do not just see a doctor or get prescriptions for their antiretroviral drugs. Many also get help finding a place to live or bus fare to make it to their next appointment.

Such care that goes beyond the examination table and into patients' often challenging lives has been key to helping poorer HIV patients - particularly blacks and women - live long, healthier lives, according to a 15-year study published on Thursday in the journal Clinical Infectious Diseases.

Researchers at the university followed 6,366 patients in the mostly black, low-income part of a city marked by abandoned buildings and plagued by an illegal drug trade that drew national attention on the gritty television series "The Wire."

From 1995 to 2010, doctors at Hopkins joined with social workers and other experts to treat HIV, the human immunodeficiency virus that causes AIDs, and address other aspects of care that can often derail patients, such as being able to fill prescriptions or access health insurance programs for the needy.

They found that with additional assistance, patients at the clinic could expect to live to about age 73 despite their background. Researchers found no difference in patients' health over time despite their gender, race, risk group, or socioeconomic status - a finding they said showed comprehensive care could eliminate disparities that arise among at-risk groups.

"Just like over time we have developed medications that are easier to take, have fewer toxicities and are more effective, I think we've done exactly the same things in our ability to deliver quality care to this particular population," Dr. Richard Moore, the study's lead author, said in an interview.

Moore, a professor of infectious diseases and director of the university's clinic, said the program showed it was possible to counter the impact of economic disparities on healthcare.

Even though HIV medications have significantly improved since the virus emerged in the United States decades ago, accessing those medications, receiving consistent care and follow-up appointments for the chronic condition are key, he said.

HIV still hits certain populations harder than others, and rising infection rates among gay black men, for example, remain a major worry among public health experts.

IMPROVING OUTCOMES

"Our results emphasize that advances in HIV treatment have had a positive impact on all affected demographic and behavioral risk groups in an HIV clinical setting," Moore and his colleagues wrote.

Previous studies have shown that certain groups of HIV patients - the poor, minorities, women and drug users - tended to have worse outcomes and die earlier.

Moore found that more comprehensive care that addresses problems such as homelessness and a lack of reliable transportation could help an average 28-year-old with HIV live roughly 45 more years with no significantly higher risk of various infections or other complications, a result that "did not differ by demographic or behavioral risk group."

Moore also credited the roughly $2 billion Ryan White CARE Act, the largest federal program solely aimed at paying for care for low-income HIV patients who are uninsured or have inadequate coverage. The program, which President Barack Obama extended in 2009, is up for renewal next year.

About 92 percent of the clinic's patients are low-income, according to the study.

Michael Saag, head of the University of Alabama at Birmingham's Center for AIDS Research, said the new findings underscored the need to revamp the nation's healthcare system so that all people get quality care. HIV patients are lucky to have access to Ryan White funds, but others do not.

"This is likely a fundamental reason why the poor and disadvantaged in the United States have health disparities that cause disproportionately worse clinical outcomes than those with means," Saag said in an editorial accompanying the study.

To be sure, researchers only followed patients who continued with the clinic over time. Patients who dropped out for various reasons, even despite staff effort to contact them, were not included in the data.

Over the years, Moore said he and his colleagues had learned what tends to work, and what does not, when it comes to their patients.

Moore, who has worked at the Hopkins clinic for 24 years, said patients were immediately connected to a case worker who sometimes started counseling them even before their first appointment.

Other clinics have also started similar efforts in recent year, but this more comprehensive type of care is not yet available nationwide.

"Medical care, particularly for a lot of people who aren't necessarily well-insured or living in a stable situation, you have to just as much deal with all that aspect of assisting them with their lives," Moore said. "I wish that wasn't the case."

(Editing by Peter Cooney Steenhuysen)

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HIV Therapy Universally Effective

By Michael Smith, North American Correspondent, MedPage Today

Published: September 28, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

HIV therapy is equally effective regardless of race, ethnicity, sex, or economic class -- as long as patients can be engaged and retained in care.

The finding -- apparently at odds with reports of major disparities in HIV across the U.S. -- comes from a 15-year analysis of data from a long-standing and highly regarded Baltimore clinic.

Over that time, outcome differences along race, sex, or economic lines have steadily fallen, according to Richard Moore, MD, and colleagues at Johns Hopkins University.

By 2010, the proportion of patients getting triple-drug therapy, the average viral load, the rate of opportunistic infections, the average count of CD4-positive T cells, and the risk of dying were all similar across all demographic and HIV risk categories, Moore and colleagues found.

And a 28-year-old patient in care in 2009 in the Johns Hopkins HIV/AIDS Service could expect an additional 45 years of life, the researchers reported online and in the Nov. 1 issue of Clinical Infectious Diseases.

"What we have found is very optimistic," Moore told MedPage Today. "Our treatments really can work for everyone who's HIV-infected."

The catch is overcoming barriers that prevent patients from remaining in care, Moore said. Most disparities in outcomes arise from a failure to retain patients, and the current study only applies to the 6,366 patients who were engaged in care at Johns Hopkins from 1995 to 2010.

But in many cases, he said, "I think it would generalize" -- especially to other specialized centers that have been able to use federal money available under the Ryan White Care Act, to overcome patient barriers to care.

Using that resource, the Baltimore clinic is able to offer -- along with HIV care -- primary care, specialties such as substance abuse and mental health, and supportive services, including nutrition, treatment adherence, emergency services, and transportation.

In 2010, 92% of the clinic's patients were low-income and 75% were black -- two groups that are hardest-hit by HIV.

Indeed, the "remarkable outcomes" in Baltimore and similar centers are likely a result of Ryan White support, commented Michael Saag, MD, of the University of Alabama at Birmingham.

In an accompanying editorial comment, he noted that Ryan White support can be used to cover the cost of outpatient care and medications, including such things as psychology/psychiatry, substance use treatment, adherence counseling, and social services.

Most other disease-specific and primary care clinics don't have such extra support, Saag noted, "and this is likely a fundamental reason why the poor and disadvantaged in the U.S. have health disparities that cause disproportionately worse clinical outcomes than those with means."

Moore said other factors also play a role -- including improved treatments and better clinical understanding of HIV. But the absence of Ryan White support, he said, "would be a big blow to our program" assuming there were no compensating changes to healthcare.

The Ryan White act is due for reauthorization next year, Saag noted. The entire healthcare system needs an overhaul, he said, but until then "we will desperately need the support from (the act) to continue filling the holes in our primary care safety net for HIV patients."

Moore and colleagues reported that, as of 2010:

• 87% of their patients were receiving antiretroviral therapy.
• The median serum viral load was less than 200 copies of HIV RNA/mL.
• The median CD4 was 475 cells/mm² of blood.
• The rate of opportunistic illnesses was 2.4 per 100 patient-years.
• The mortality rate was 2.1 per 100 patient-years.

By and large, they reported, there were no differences by demographic or HIV risk group. The exception was that people infected through injection drug use had a lower CD4 count and a higher viral load than other risk groups.

The researchers cautioned that the study focused on a single center and may not apply more widely. In any case, they added, the results "certainly do not generalize to HIV-infected people in the U.S. who have not engaged in HIV care."

"Nevertheless," they concluded, "we believe that our results are an important demonstration of what can be achieved by contemporary HIV care in patients who are retained in care."

The study was supported by the National Institutes of Health. The journal said the authors reported no potential conflicts.

The journal said Saag reported no potential conflicts.

Primary source: Clinical Infectious Diseases
Source reference:
Moore RD, et al. "Improvement in the health of HIV-infected persons in care: Reducing Disparities" Clin Inf Dis 2012; DOI: 10.1093/cid/cis654.

Additional source: Clinical Infectious Diseases
Source reference:
Saag MS. "Viva no différence!" Clin Inf Dis 2012; DOI: 10.1093/cid/cis656.

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