March 8, 2012

CROI 2012: NATAP Updates and Slides

Merck's hepatitis C drug wins UK cost endorsement

LONDON, March 9 | Thu Mar 8, 2012 7:01pm EST

LONDON, March 9 (Reuters) - U.S. drugmaker Merck & Co's new hepatitis C drug Victrelis was recommended for use within Britain's state health service on Friday, despite its hefty price tag.

The National Institute for Health and Clinical Excellence, which often spurns expensive new medicines on cost grounds, said significant improvements seen with Victrelis made it a cost-effective option.

The drug, also known as boceprevir, is designed for use in combination with peginterferon alfa and ribavirin for patients with liver disease due to genotype 1 chronic hepatitis C, the most common form.

It costs 30,800 pounds ($48,400) for a 44-week course, with the other two drugs increasing the bill by around 11,000 pounds.

The draft guidance from NICE is now open for consultation before the agency finally issues it.

Source

Clinical Liver Disease

Volume 1, Issue 1, pages 20–23, February 2012

Andrew Aronsohn M.D., Donald Jensen M.D.‡,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.5

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

Watch the interview with the authors

Watch the video presentation of this article

Answer questions and earn CME

The direct-acting antivirals (DAAs) telaprevir and boceprevir have revolutionized hepatitis C virus (HCV) therapy by improving therapeutic outcomes for many patients. Although DAA-based therapy is a great leap forward, it is not a panacea, and many patients will not be appropriate candidates for this treatment. This review defines the patients who will remain untreated and explores emerging challenges in the era of triple therapy.

Patients with Contraindications to Pegylated Interferon (PEG) and Ribavirin (RBV)

PEG and RBV remain part of the current DAA-based therapy; therefore, patients with contraindications to the previous standard-of-care treatment are unlikely to be candidates for triple therapy (Table 1). This includes patients with previous adverse reactions to PEG or RBV and patients with uncontrolled autoimmune disease.1 In addition, interferon-induced bone marrow suppression, in combination with the hemolytic effects of RBV, can result in significant anemia and pancytopenia, and this makes patients with preexisting cytopenias, severe peripheral vascular disease, pulmonary disease, or coronary artery disease potentially unsuitable candidates for treatment.1 Finally, depression has been reported to occur in 23.2% of patients undergoing interferon therapy.2 Although patients tend to respond well to antidepressants during HCV therapy, severe uncontrolled depression remains a contraindication to treatment.1

Capture1

DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG, pegylated interferon; RBV, ribavirin; SVR, sustained virological response.

Patients with Contraindications or Limited Responses to DAA Therapy

Boceprevir and telaprevir have significant interactions with both cytochrome P450 3A and p-glycoprotein, and these result in significant drug-drug interactions (Table 2).3, 4 A thorough medication history should be taken before treatment, and it is possible in many cases to substitute or hold a contraindicated drug during HCV therapy. However, in rare instances, patients who are taking a contraindicated medication that cannot be modified may not be candidates for current DAA-based therapy.

Capture

Although triple therapy is highly effective in most patients, response rates among patients with cirrhosis (especially previous null responders) remain relatively low. In the Sprint (Serine Protease Inhibitor Therapy) 2 study, cirrhosis was a significantly negative predictor of sustained virological response (SVR) in patients treated with boceprevir [odds ratio = 2.5 (1.4–4.6), P = 0.003].5 Furthermore, in the REALIZE study, investigators performed a subgroup analysis of patients with cirrhosis who were treated with telaprevir-based therapy and were previous null responders, and they found an SVR rate of only 29%.6 Clearly, many patients with HCV-related cirrhosis (especially previous nonresponders) will have limited success with the current therapy and will require treatment beyond what is currently available.

Understudied Populations

HCV affects many patients who have unique characteristics that are beyond the scope of currently published phase 3 registration trials of DAAs. These patients may benefit from DAA therapy but will pose a significant challenge to clinicians because there are limited data (if any) for guiding their care (Table 3).

Capture

Patients Coinfected With Human Immunodeficiency Virus (HIV)

At least 17% of patients with HIV are coinfected with HCV.7 Progression to cirrhosis is more rapid in coinfected patients, and hepatic failure is an increasingly common cause of death in this patient population.8 The treatment of HCV in the setting of HIV is a longstanding clinical challenge because previous standard-of-care therapy with PEG/RBV has resulted in suboptimal SVR rates. In 2004, the AIDS Pegasys Ribavirin International Co-Infection Trial study group performed a multicenter, international study of HCV therapy in 868 patients coinfected with HIV. In genotype 1 patients, the SVR rate was 29%, which is lower than the published rates for PEG/RBV-based therapy in the non–HIV-infected population.9, 10 Currently, there are no available data describing DAA-based therapy in the HIV/HCV-coinfected population, and although improved treatment outcomes are anticipated, safety concerns (primarily involving drug-drug interactions) must first be addressed.

Liver Transplant Recipients

Patients with chronic HCV who undergo liver transplantation universally experience HCV recurrence in the transplanted liver. This leads to inferior posttransplant patient and graft survival in comparison with many other indications for liver transplantation.11 HCV therapy with PEG/RBV after liver transplantation has been largely unsuccessful because of poor SVR rates and significant adverse events, which include acute rejection.12, 13 Theoretically, direct-acting agents should be ideal in an immunocompromised host because there is less reliance on the host immune system for antiviral activity. Telaprevir and boceprevir are strong inhibitors of the enzyme cytochrome P450, which also plays a key role in the metabolism of the immunosuppressants commonly used in liver transplantation: cyclosporine and tacrolimus. Pharmacokinetic studies investigating the interaction between telaprevir and cyclosporine yielded extremely high drug concentrations of immunosuppressants when they were tested in healthy controls (a 70-fold increase in the tacrolimus concentration and a 4.6-fold increase in the cyclosporine concentration).14 Further prospective studies will be needed to determine safe and efficacious dosing strategies when these medications are used together.

Patients With Decompensated Cirrhosis

Successful HCV treatment in patients with cirrhosis has been shown to increase survival and decrease the development of ascites, esophageal varices, and hepatic encepaholpathy.15 Unfortunately, few decompensated patients with genotype 1 or 4 who undergo HCV treatment with PEG/RBV will achieve SVR (7%); therapy is often poorly tolerated, and frequent dose reductions and discontinuations are required.16 Current guidelines from the American Association for the Study of Liver Diseases recommend that for patients with decompensated cirrhosis, attempts at treatment should be “administered by experienced clinicians with vigilant monitoring for adverse events preferably in patients who have already been accepted as candidates for liver transplantation.”1 The risk of further decompensation along with the low SVR rates means that the previous standard-of-care treatment with PEG/RBV is rarely a viable option. With the use of more potent antiviral agents, SVR rates may increase; however, DAA metabolism appears to be different in patients with advanced cirrhosis versus patients with earlier stages of disease, and the tolerability and safety in this population remain largely unknown. Decisions to treat these patients with triple therapy rely solely on anecdotal accounts, and they should be made with extreme caution and should be based on physician experience and unique patient characteristics.

Pediatric and Elderly Populations

Recent National Health and Nutrition Examination Survey data suggest that approximately 0.2% to 0.4% of children up to 14 years old are infected with HCV.17 The majority of pediatric HCV infections occur as a result of maternal-fetal transmission. Because of the shorter period of chronic infection, pediatric patients usually have earlier stage disease at the time of diagnosis in comparison with adults; however, progression to cirrhosis and hepatocellular carcinoma has been reported.18, 19 In a pilot study of 62 patients between the ages of 2 and 17 years who were treated with PEG and RBV, 48% of the patients with genotype 1 achieved SVR.20 Although the results are based on limited data, the treatment outcomes appear to be similar to those of the adult population, and so are the adverse events during therapy, with the exception of spastic diplegia, which is a severe form of neurotoxicity seen in infants treated with interferon-α.17 The pediatric population would very likely tolerate and benefit from more potent agents; however, to date, there are no data on the use of telaprevir, boceprevir, or other new HCV therapies in this population. The current Food and Drug Administration treatment for patients who are 18 or less years old remains interferon plus RBV three times a week (3–18 years old) or PEG plus RBV once a week (5–18 years old).

In upcoming years, the highest prevalence of HCV infection will be seen in patients who are 65 years old or older.21 Older patients with HCV have a faster rate of progression to cirrhosis and have a higher incidence of hepatocellular carcinoma; this indicates a significant therapeutic need in this understudied population.22, 23 Patients more than 65 years old are more likely to be cirrhotic and have comorbidities that make treatment with PEG/RBV less effective. This was shown by Huang et al.24 in a study of 70 HCV patients older than 65 years who were treated with PEG/RBV. In comparison with younger cohorts, older patients had significantly inferior SVR rates and higher rates of dose reduction and therapy discontinuation. DAAs may improve response rates; however, there are significant concerns about the tolerability of triple therapy in this population and especially in patients who have been unable to tolerate PEG/RBV in the past. The consideration of alternate dosing schedules and treatment algorithms may be key to the use of DAA-based therapy in this population.

Patients With Previous DAA Exposure

Unlike dual-therapy treatment with PEG/RBV, treatment failure with DAAs is complicated by the emergence of resistant variants. Pawlotsky25 defined three major factors that influence the clinical ramifications of resistance: the genetic barrier to resistance, the fitness of the resistant variant, and the attainable drug exposure. First-generation protease inhibitors such as telaprevir and boceprevir have a low genetic barrier to resistance; however, after the discontinuation of therapy, the wild-type virus typically regains dominance, possibly to the point of the complete eradication of the resistant variants over time. Patients who develop resistant variants while they are being treated with one protease inhibitor will not likely be candidates for treatment with the other available protease inhibitor because boceprevir and telaprevir have been shown to share cross resistance in vitro. In addition, the emergence of resistance is also related to interferon insensitivity, which would hinder successful therapy with any DAA that requires interferon as part of the therapeutic regimen. As more DAAs become available, the treatment of patients who develop resistant variants may become similar to HIV treatment, in which combinations of agents are selected on the basis of viral resistance profiles.

Overcoming Current Challenges with DAA Therapy

This review describes many groups of patients who are underserved by currently available DAA therapy (Fig. 1). Fortunately, there are robust basic, translational, and clinical investigations aimed specifically at addressing these shortcomings. For those with limited responses or contraindications to telaprevir- or boceprevir-based treatment, ongoing clinical trials are evaluating the safety and efficacy of the next generation of protease inhibitors, polymerase inhibitors, and other novel agents such as cyclophilin inhibitors and short interfering RNA. In addition, many new agents are being investigated in interferon-free combinations that are targeted at patients who have deferred interferon-based treatment because of their own preference or medical contraindications. Finally, active research is taking place through both sponsored trials and investigator-initiated studies evaluating current DAA-based therapy in many of the understudied populations mentioned in this review.

nfig001

Figure 1. Treatment algorithm for difficult-to-treat patients.

Chronic HCV progresses slowly, and most patients do not develop advanced liver disease until at least 2 to 3 decades after the time of infection. Within understudied and difficult-to-treat populations, patients with early-stage disease will have the luxury of waiting for safer or more effective therapies; however, patients who already have advanced disease will have limited options and will remain a challenge, even in the era of DAA therapy.

References

Source

Clinical Liver Disease

Volume 1, Issue 1, pages 12–15, February 2012

Saurabh Agrawal M.D.1,*, Paul Y. Kwo M.D.2

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.7

Copyright © 2012 the American Association for the Study of Liver Diseases

Potential conflict of interest: Nothing to report

Abstract

Watch the interview with the authors

Answer questions and earn CME

The paradigm for hepatitis C virus (HCV) treatment relies on pegylated interferon and ribavirin (PR) as agents that enhance endogenous mechanisms for viral clearance and are dependent on host factors.1, 2 In May 2011, the US Food and Drug Administration (FDA) approved two new nonstructural 3 protease inhibitors, telaprevir (TVR) and response-guided therapy; SVR, sustained virological response; TID, three times a day; TVR, telaprevir

For genotype 1–infected individuals, the addition of TVR or BOC to PR markedly improves sustained virological response (SVR) rates. However, the newly approved protease inhibitors are associated with increases in the frequency and severity of side effects, which will require additional management strategies to allow patients the maximum opportunity for achieving SVR. The treatment of genotype 1–infected, therapy-naive patients with TVR is based on a recent international phase 3 trial (ADVANCE) that randomized subjects into three groups.3 Group 1 received PR and a placebo for 48 weeks. Groups 2 and 3 received TVR for either 8 or 12 weeks in addition to PR with response-guided therapy (RGT). Patients in whom HCV RNA was undetectable at weeks 4 and 12 [i.e., an extended rapid virological response (eRVR)] stopped taking PR in week 24, whereas those patients in whom HCV RNA was detectable at week 4 but undetectable at week 12 continued to complete 48 weeks of PR. Significantly higher SVR rates were seen in the patients on the 12-week regimens with TVR (75%) versus the control patients receiving 48 weeks of PR (44%), and this 12-week duration of TVR has been licensed in the United States in combination with PR as an RGT paradigm (Fig. 1). More than half of the individuals who received this treatment in trials were able to truncate their therapy at 24 weeks, and this was confirmed in a supplementary trial called ILLUMINATE (Illustrating the Effects of Combination Therapy With Telaprevir) in which 12 weeks of TVR in addition to 24 or 48 weeks of PR was shown to be equivalent if patients achieved an eRVR.4 Subsequent approval by the FDA recommended that patients with cirrhosis be considered for a full 48-week course of PR in addition to TVR for 12 weeks, regardless of the initial response to treatment.

nfig001

Figure 1. Treatment paradigm with futility rules for TVR and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. This figure is based on a TVR package insert (May 2011).

The approval of BOC was based on the Serine Protease Inhibitor Therapy 2 study, also called SPRINT 2, in which patients were randomized to 48 weeks of PR or to BOC plus PR in either an RGT arm or a fixed-duration arm. In all groups, a 4-week PR lead-in was used, and this was followed by the addition of BOC.5 In the RGT arm, patients in whom HCV RNA was undetectable during weeks 8 to 24 completed triple therapy at week 28, whereas patients in whom HCV RNA was detectable at week 8 but undetectable by week 24 discontinued BOC at week 28 and continued to complete another 20 weeks of PR for a total of 48 weeks of therapy. Patients in the fixed-duration arm received the lead-in treatment and then 44 weeks of BOC plus PR. The addition of BOC led to overall sustained response rates of 63% to 66% versus 38% in the PR-alone group.5 In this study, two cohorts were predefined as nonblack and black. The SVR rates in the nonblack cohort were 67% for the RGT arm and 68% for the 44-week (fixed-duration) BOC arm, and these rates were significantly higher than the rate for the PR control arm, for which an SVR rate of 40% was observed. In the black cohort, the SVR rate was 42% for the RGT arm, 53% for the 44-week BOC arm, and 23% for the PR control arm. The FDA subsequently approved an RGT paradigm for treatment with BOC. Specifically, if HCV RNA levels are undetected at weeks 8 and 24, individuals may be treated for 28 weeks. If HCV RNA is detected at week 8 and is undetected at week 24 (approximately half of treated patients), then patients should receive PR with BOC for 36 weeks and then a 12-week PR tail for a total of 48 weeks of therapy. Patients who have cirrhosis or respond poorly to PR (<1-log reduction after the PR lead-in treatment) should receive PR for 4 weeks and then 44 weeks of PR and BOC (Fig. 2). On the basis of these data, the American Association for the Study of Liver Diseases has revised its guidelines for the management of treatment-naive, HCV genotype 1–infected persons as follows6:

  1. The optimal therapy for chronic HCV genotype 1 infections is the use of BOC or TVR in combination with peginterferon-alfa and ribavirin (class 1, level A).
  2. BOC and TVR should not be used without peginterferon-alfa and weight-based ribavirin (class 1, level A).
  3. The recommended dose of BOC is 800 mg, and it should be administered with food three times a day (TID; every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 24 to 44 weeks. This should be preceded by 4 weeks of a lead-in treatment with peginterferon-alfa and ribavirin alone (class 1, level A).
  4. Patients without cirrhosis who are treated with BOC and PR (preceded by 4 weeks of a lead-in treatment with PR) and in whom HCV RNA is undetectable at weeks 8 and 24 may be considered for a shortened treatment duration of 28 weeks in all (4 weeks of a lead-in treatment with PR followed by 24 weeks of triple therapy; class 2a, level B).
  5. Treatment with all three drugs (BOC, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or HCV RNA is detectable at treatment week 24 (class 2a, level B).
  6. The recommended dose of TVR is 750 mg, and it should be administered with food (not low-fat food) TID (every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 12 weeks followed by an additional 12 to 36 weeks of peginterferon-alfa and ribavirin (class 1, level A).
  7. Patients without cirrhosis who are treated with TVR and PR and in whom HCV RNA is undetectable at weeks 4 and 12 should be considered for a shortened therapy duration of 24 weeks (class 2a, level A).
  8. Patients with cirrhosis who are treated with either BOC or TVR in combination with PR should receive therapy for a duration of 48 weeks (class 2b, level B).
  9. Treatment with all three drugs (TVR, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >1000 IU/mL at treatment week 4 or 12 and/or HCV RNA is detectable at treatment week 24 (class 2a, level B).

nfig002

Figure 2. Treatment paradigm with futility rules for BOC and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10 to 15 IU/mL. TW, treatment week.

Triple antiviral therapy presents the provider and patient with new issues to address. Additional side effects and potential drug-drug interactions are part of the price that we pay for enhanced viral responses. With TVR, rashes, anemia, and gastrointestinal side effects are all more common than they are with PR alone. Rarely, Steven-Johnson syndrome or drug rash with eosinophilia and systemic symptoms has been reported, and this requires the immediate discontinuation of all drugs. However, the vast majority of patients are able to continue treatment despite rashes, and with careful management, a high SVR rate can still be achieved. With BOC, the primary additional side effect is anemia. Finally, drug-drug interactions will be important. There is a list of contraindicated medicines for both of these drugs that must be addressed before the initiation of therapy (Table 1). These will be discussed in more detail in the second issue of Clinical Liver Disease.

Click table to enlarge

Capture1

In summary, the era of DAA agents has arrived. Approximately 70% of treatment-naive, genotype 1–infected individuals now may be treated successfully with PR plus DAA agents with RGT. High SVR rates have also been seen across difficult-to-treat groups, including patients with high viral levels, patients with advanced fibrosis, and black patients. Moreover, treatment may now be truncated at 6 months in approximately half of individuals. Finally, as we enter the era of DAA-based therapy for HCV, strict adherence to treatment futility rules should be maintained to prevent the emergence of resistance-associated variants that might hamper future therapy.

References

Source

Clinical Liver Disease

Volume 1, Issue 1, pages 16–19, February 2012

Naveen Gara M.D., Marc G. Ghany M.D., M.H.Sc.§,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.4

Copyright © 2012 the American Association for the Study of Liver Diseases

This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute (National Institutes of Health).

Potential conflict of interest: Nothing to report

Abstract

Watch the interview with the authors

Watch the video presentation of this article

Answer questions and earn CME

As the treatment for chronic hepatitis C virus (HCV) infection has improved over the last 2 decades, the number of patients for whom therapy fails has declined substantially. However, more than half of patients with HCV genotype 1 infections fail to achieve a sustained virological response (SVR) to pegylated interferon (PEG-IFN) and ribavirin (RBV).1–4 Subjects for whom combination therapy fails are a heterogeneous group and include individuals who experience virological breakthrough (detectable HCV RNA in serum during therapy after the achievement of an initial response) or virological relapse (the reappearance of HCV RNA in serum after the discontinuation of treatment and the achievement of an end of-treatment response) as well as individuals who fail to achieve an initial virological response [i.e., partial responders (≥2-log IU/mL decline in HCV RNA from the baseline to treatment week 12 but detectable HCV RNA at week 24) and null responders (≤2-log IU/mL reduction in HCV RNA from the baseline to treatment week 12; Fig. 1].

nfig001

Figure 1. Virological responses during and after therapy for chronic HCV. Relapse refers to the reappearance of HCV RNA in serum after treatment is discontinued and an end-of-treatment response is documented. A nonresponse may be partial (>2-log decline in HCV RNA by week 12 but still positive results at week 24) or null (<2-log decline in HCV RNA by week 12).

DAA, direct-acting antiviral; FDA, Food and Drug Administration; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin; RGT, response-guided triple-drug therapy; SOC, standard of care; SVR, sustained virological response.

The reasons for treatment failure are not well understood. Resistance to interferon is believed to be an important cause. Specific polymorphisms of the interleukin-28b gene probably explain 50% or more of the resistance to PEG-IFN, but other host and viral factors are likely involved.5–7 Poor compliance with the prescribed regimen and adverse events requiring a dose reduction or discontinuation of therapy also contribute to treatment failure.8, 9 The latter two causes may be amenable to interventions, and successful retreatment with PEG-IFN and RBV may be permitted.

Until recently, retreatment options were limited for persons for whom a PEG-IFN/RBV regimen failed. Studies evaluating retreatment with PEG-IFN and RBV yielded SVR rates of only 6% to 9% in partial and null responders and 33% in prior relapsers with an HCV genotype 1 infection.10, 11 In comparison with standard therapy, a higher dose of PEG-IFN as induction therapy had no effect on either the end-of-treatment response rate or the SVR rate.10 However, extending therapy to 72 weeks resulted in a marginal increase in the SVR rate from 9% to 16%, primarily because of the prevention of virological relapse.10 Similarly, a different preparation of interferon, consensus interferon, was minimally effective.12 Three studies have evaluated the role of maintenance, low-dose PEG-IFN in prior nonresponders with advanced liver disease.3–5 All three studies showed no differences in clinical outcomes between treated and control subjects and suggested no benefit of maintenance, low-dose PEG-IFN in this group of patients. However, the Colchicine Versus PegIntron Long-Term study and the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis 3 study hinted at a lower rate of complications (particularly variceal bleeding) in patients with portal hypertension who were receiving colchicine or a placebo, respectively, instead of PEG-IFN.14, 15

In May 2011, two new direct-acting antiviral (DAA) agents belonging to a class of drugs known as protease inhibitors, boceprevir and telaprevir, were approved for use in combination with PEG-IFN and RBV for both previously untreated and treatment-experienced subjects.6–9 In comparison with PEG-IFN and RBV, these drugs led to 2- to 3-fold increases in SVR rates for patients with previous treatment failures17, 19 (Figs. 2 and 3). Consequently, boceprevir or telaprevir in combination with PEG-IFN and RBV now represent the new standard of care (SOC) for the retreatment of relapsers, prior partial responders, and null responders.17, 19

nfig002

Figure 2. Boceprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. Overall, the SVR rates were significantly higher for patients receiving a boceprevir-containing regimen versus patients receiving PEG-IFN and RBV (59% and 66% versus 21%). The response was dependent on the prior response, with prior relapsers responding better than prior partial responders. Adapted with permission from New England Journal of Medicine.17 RGT means response guided therapy. PR48 means pegylated interferon and ribavirin taken for 48 weeks.

nfig003

Figure 3. Telaprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. The SVR rates were significantly higher for patients receiving telaprevir with or without a lead-in phase. The SVR rates were not improved with a lead-in phase. There was a gradient in the response, with the highest SVR rates achieved by relapsers and partial responders and the lowest rates achieved by null responders. T12PR48: telaprevir × 12 weeks, pegylated interferon and ribavirin × 48 weeks; LI means ‘lead-in’ phase using pegylated interferon and ribavirin; SOC is ‘standard of care’ i.e., pegylated interferon and ribavirin.

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2 study, also known as RESPOND-2, (a phase 3 boceprevir trial) enrolled relapsers and partial responders; previous null responders were excluded.17 The study design began with a 4-week lead-in phase of PEG-IFN and RBV for all subjects, after which the subjects were stratified to one of three study arms:

  • Response-guided triple-drug therapy (RGT). The duration of PEG-IFN and RBV was tailored to the HCV RNA response after 4 and 8 weeks of triple therapy; all subjects in this arm received 32 weeks of boceprevir plus PEG-IFN and RBV and completed therapy at week 36 if HCV RNA was undetectable at weeks 8 and 12. Slow responders, that is, those for whom HCV RNA was detectable at week 8 but undetectable at week 12, received another 12 weeks of PEG-IFN and RBV alone after week 36 for a total duration of 48 weeks.
  • Fixed-duration triple therapy for 44 weeks.
  • SOC therapy. This comprised PEG-IFN and RBV plus a placebo for 48 weeks.

The study × demonstrated that SVR rates were significantly higher among subjects receiving a boceprevir-containing regimen versus patients receiving SOC therapy: 59% in the RGT arm and 66% in the fixed-duration arm versus 21% in the SOC arm (Fig. 2). Successful treatment was more common in prior relapsers (69%-75%) than prior partial responders (40%-52%); the response was lower in patients with cirrhosis, particularly in the RGT arm. Anemia, dry skin, dysgeusia, and rashes were reported more commonly by subjects who received boceprevir versus subjects who received SOC. On the basis of this phase 3 trial, the Food and Drug Administration (FDA) approved the regimen shown in Fig. 4. Because of low response rates in patients with cirrhosis receiving RGT,17 the FDA has recommended that this group of patients receive lead-in therapy and then triple therapy for a fixed duration of 44 weeks.20

nfig004

Figure 4. Boceprevir plus PEG-IFN/RBV for previous partial responders and relapsers: the FDA-approved regimen. Subjects should start treatment with PEG-IFN and RBV for 4 weeks; after this, boceprevir (800 mg three times a day with food) is given. The duration of boceprevir use depends on the response to treatment at weeks 8 and 24. If HCV RNA is undetectable at weeks 8 and 24, patients should receive 32 weeks of triple therapy. If a patient is slow to respond and has detectable HCV RNA at week 8 but HCV RNA is undetectable at week 24, then triple therapy should be given for 32 weeks and should be followed by another 12 weeks of PEG-IFN and RBV. TW, treatment week.

The REALIZE study, a phase 3 trial of telaprevir with PEG-IFN and RBV in treatment-experienced patients, compared 12 weeks of triple therapy with or without a 4-week lead-in phase of PEG-IFN and RBV plus 36 or 32 weeks of PEG-IFN and RBV, respectively, for a total treatment period of 48 weeks to SOC therapy for 48 weeks. A response-guided approach was not investigated. The study included previous relapsers, partial responders, and null responders. SVR rates were significantly higher for patients receiving telaprevir with or without the lead-in phase (64% and 66%) versus patients receiving SOC therapy (17%). The SVR rates were similar for the arms with and without a lead-in strategy, and this demonstrated no advantage from a lead-in phase. There was a gradient in the response based on prior response, with the highest SVR rates found in relapsers (followed by partial responders) and the lowest rates noted in null responders. These results serve to emphasize the importance of knowing the previous response to treatment when retreatment is being considered. Among previous relapsers, SVR rates with telaprevir plus PEG-IFN and RBV were independent of the liver fibrosis stage. However, among partial and null responders, SVR rates declined with worsening fibrosis.19 Thus, the lowest response rate was observed for null responders with cirrhosis. Adverse events were more common in subjects receiving triple therapy containing telaprevir versus those receiving SOC, and they included fatigue, pruritus, rashes, nausea, anemia, anorectal symptoms, and diarrhea. On the basis of these results, the FDA approved the regimen shown in Fig. 5.20

nfig005

Figure 5. Telaprevir for partial and null responders: the FDA-approved regimen. Partial and null responders should receive 12 weeks of triple therapy and then another 36 weeks of PEG-IFN and RBV. Relapsers should be treated in the same way as treatment-naive subjects and are eligible for response-guided therapy. This regimen resulted in SVR rates of 83%, 59%, and 29% for relapsers, partial responders, and null responders, respectively.

A majority of patients who fail to achieve an SVR in response to triple therapy (including boceprevir or telaprevir) develop antiviral resistance.17, 19 Some of these viral variants may persist over the long term, but the clinical significance of resistance mutations is unclear at this time.

Whether a subject should be retreated now or wait for potentially better therapy in the future depends on many factors, including the individual's desire to be retreated, the reasons underlying the failure (e.g., inadequate drug dosing or side-effect management), the severity of the underlying liver disease, the prior response to therapy, and the risk of disease progression over the next 3 to 5 years. More effective therapies that do not include interferon are likely to be available in the future. Indeed, a recent pilot trial compared a four-drug regimen (PEG-IFN, RBV, a protease inhibitor, and a nonstructural 5A inhibitor) to a combination of DAA agents without PEG-IFN or RBV in previous null responders. This pilot trial reported an impressive 100% response rate with the four-drug regimen, and 36% of nonresponders achieved an SVR after only 24 weeks of a combination of DAAs alone.21

There are currently no data on the management of individuals for whom a protease inhibitor–containing regimen has failed. Until such data become available, the implementation of futility rules and strict adherence to the drug regimen will be important to prevent the development of resistance and to optimize the chances for SVR while more effective and safer treatment is awaited.

In response to these registration studies, the guidelines committee of the American Association for the Study of Liver Diseases has approved the following guidelines for the use of antiviral therapy in treatment-experienced patients with HCV genotype 1:22

  • Retreatment with boceprevir or telaprevir, together with PEG-IFNβ and weight-based RBV, can be recommended for patients who experienced virological relapse or were partial responders after a previous course of treatment with standard interferon-β or PEG-IFNβ and/or RBV (class 1, level A).
  • Retreatment with telaprevir, together with PEG-IFNβ and weight-based RBV, may be considered for patients who were previously null responders to a course of standard interferon-β or PEG-IFNβ and/or weight-based RBV (class 2b, level B.)
  • In the case of treatment-experienced patients, response-guided therapy with a boceprevir- or telaprevir-based regimen can be considered for relapsers (class 2a, level B for boceprevir; class 2b, level C for telaprevir), may be considered for partial responders (class 2b, level B for boceprevir; class 3, level C for telaprevir), but cannot be recommended for null responders (class 3, level C).
  • Patients retreated with boceprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).
  • Patients retreated with telaprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 1000 IU at week 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).
References

Source

CROI 2012: UNC researchers make key HIV discovery

Published Thu, Mar 08, 2012 03:36 PM
Modified Thu, Mar 08, 2012 03:36 PM

By Jay Price - jprice@newsobserver.com

CHAPEL HILL -- Researchers at UNC-Chapel Hill have discovered what could be a vital step toward a cure for HIV.

By giving patients a drug normally used for treating some kinds of lymphoma, scientists have managed to make dormant, hidden HIV viruses reveal their presence.

That’s crucial if scientists want to find a way to target and completely eliminate the virus from the body, said Dr. David Margolis, a professor of medicine, microbiology and immunology, and epidemiology, who led the study.

Margolis spoke by telephone this afternoon from Seattle, just before presenting the findings at the 19th Conference on Retroviruses and Opportunistic Infections.

HIV is the virus that causes AIDS. In recent years, patients have been able to hold it at bay with elaborate cocktails of antiretroviral drugs.

Even though these regiments halt the progress of the disease, the virus remains, hiding in certain cells, and can turn active again if the drug regimen ends.

Researchers thought that a crucial step toward purging the body of HIV was finding a trigger to luring the virus from its hiding place. That’s what the UNC team did, for the first time.

The next steps in the research include a fuller exploration of the lymphoma drug’s effects on the virus, Margolis said.

The findings from that research will determine the next directions for research.

Source


AIDS Cure Quest Advances as Merck Cancer Drug Attacks Hidden HIV

By Simeon Bennett - Mar 8, 2012 3:00 PM ET

The 30-year quest for an AIDS cure advanced as scientists succeeded for the first time in attacking HIV in its hardest-to-reach hideouts with a cancer drug made by Merck & Co.

In a trial among six men with HIV, researchers led by David Margolis at the University of North Carolina at Chapel Hill used a dose of Merck’s Zolinza to rouse the virus from inside certain immune-system cells, where it evades regular AIDS drugs. That’s a crucial step toward eliminating the virus from the body. The findings were presented at a conference in Seattle today.

While no patients were cured, the trial shows that Zolinza, or similar drugs, may have the potential to purge the virus, Margolis said. He said he expects to hear from the U.S. Food and Drug Administration within “a couple of weeks” on approval for an additional test using more doses of Zolinza.

“What people want to know is when can someone go to a doctor and be handed a pill and be cured,” Margolis said by phone. “That’s decades away. Think of it more in terms of curing cancer. I think in 10 years someone with HIV infection could go to a specialist and get a complicated treatment and have some likelihood of a prolonged remission of their HIV.”

Mysterious Virus

HIV was first observed in the U.S. as a mysterious, deadly illness among gay men in 1981. Since then it’s killed more than 30 million people globally, making it the world’s deadliest infectious disease.

The hunt for a cure has gathered pace because of improvements in the drugs used to control HIV, such as Gilead Sciences Inc. (GILD)’s once-daily pill Atripla, the world’s top-selling AIDS treatment.

While those drugs reduce HIV to undetectable levels in the body, they don’t completely clear it. The virus hides in certain cells, where it switches off the normal process of replication. That enables HIV to avoid detection by the medicines, which are designed to block steps in its reproduction.

Studies have shown that when patients who have the virus under control stop treatment, latent HIV reactivates and comes roaring back, forcing victims to resume daily pill therapy.

“It’s sort of like the virus is a rabbit at the bottom of a hole, but it needs a boost to get it out of the hole,”Margolis said. “It doesn’t fall in the hole very much, but when it does, it’s stuck there.”

Fine Line

Margolis and colleagues have been looking for ways to reactivate the virus without switching on the so-called resting CD4 T-cells in which it’s hiding. Arousing those cells may trigger a dangerous over-stimulation of the immune system that can cause lasting damage.

In the trial, the researchers recruited volunteers who were taking AIDS drugs to subdue the virus, then added Zolinza to see if they could reactivate latent HIV. It worked, with no serious side effects. The scientists saw an average 4.8-fold increase in HIV’s genetic fingerprints, showing the virus was awake and active inside the cells.

In theory, that means the drug has kick-started HIV’s normal process of replication. That could spur an immune-system attack that kills the host cells, or result in the virus exiting and killing the cells in search of new ones to infect. AIDS drugs patrolling the body would prevent it from doing so, and with nowhere left to go, the virus would die.

If that were to happen on a large enough scale, most latent HIV could be eradicated, enabling patients to stop their regular treatment without the virus rebounding -- a cure.

Next Trial

The study wasn’t designed to see whether Zolinza depleted the number of CD4 cells harboring HIV because the doses of the drug were too low, Margolis said. That’s the objective of the next trial now being considered by the FDA.

“We need to make some progress, we need some signal that we can potentially alter or disturb latently infected cells, and this study suggests that might be possible,” said Sharon Lewin, a professor at The Alfred Hospital in Melbourne. She’s also running a trial using multiple doses of Zolinza to target latent HIV and expects to have results from 10 patients later this year, she said.

Zolinza, also known as vorinostat and SAHA, was approved in 2006 for use against a rare type of blood cancer. The drug earned Merck $15 million in 2008, the last year the Whitehouse Station, New Jersey-based company disclosed sales of the medicine. Laboratory tests had shown it could purge HIV from cells in dishes, but the real challenge was to achieve the same result in humans.

“The study gives us hope because it provides an idea that’s worth exploring further,” said Daria Hazuda, Merck’s head of infectious diseases research, and one of the main developers of Isentress, an AIDS drug that generated $1.36 billion for Merck last year. “It’s a very important first step, but we’re still a long way away,” Hazuda said by telephone today.

Forcing Replication

The drug targets an enzyme called histone deacetylase, or HDAC, that helps HIV go to sleep in cells by interfering with its ability to replicate. By blocking HDAC, Zolinza would reactivate the virus, forcing replication.

This is Margolis’s second attempt at flushing out latent HIV. In 2005 he published a paper in The Lancet journal showing that Depakote, an approved treatment for bipolar disorder made by Abbott Laboratories, reduced the number of infected resting cells by as much as 84 percent when combined with Roche Holding AG’s AIDS drug Fuzeon, in a study involving four patients. Subsequent research by Margolis and others contradicted those findings.

Today’s results, the first to show that a mechanism known to keep HIV dormant could be successfully targeted in humans, were presented at the Conference on Retroviruses and Opportunistic Infections in Seattle.

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

Source

A Dose Of Caution : Petition Filed To Block HIV Prevention Pill

Mar 8, 2012 | 12:41PM

(RTTNews.com) - There has been much debate regarding Truvada ever since Gilead Sciences Inc. (GILD) sought regulatory approval to market its HIV treatment medication Truvada as a HIV prevention pill. Some public health advocates are concerned about Gilead's move as they fear that the expanded use of the drug would lead to individuals engaging in unprotected sex, and would, in fact, increase the incidence of HIV and other infections.

Truvada, a combination of Gilead's two drugs - Viread and Emtriva, received an accelerated approval from the FDA in August 2004, followed by traditional approval in March 2006, for the treatment of HIV in combination with other antiretroviral drugs.

Last December, Gilead filed a supplemental New Drug Application with the FDA seeking approval of its once-daily Truvada for HIV prevention. This prevention approach is known as pre-exposure prophylaxis or PrEP. The idea behind PrEP is that people who do not have HIV may protect themselves against HIV infection by taking Truvada, which is already approved as a daily treatment for people infected with HIV or living with AIDS.

The sNDA application was based on two large phase III trials known as Pre-Exposure Prophylaxis Initiative, or iPrEx, and Partners PrEP.

In the iPrEx study, which involved 2,499 high-risk HIV-negative homosexuals in the US and other countries, the once daily use of Truvada reduced the risk of acquiring HIV by 44 percent compared with placebo and by up to 73 percent in men who took the drug consistently. In men with enough detectable drug presence, the risk was reduced by more than 90 percent.

In the other trial, Partners PrEP, which involved 4,758 heterosexual couples in Kenya and Uganda in which only one partner was infected with HIV, once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73 percent compared with placebo.

Despite the impressive results, experts remain wary about expanding the use of antiretrovirals to include HIV prevention.

An article that appeared in The Lancet, a British medical journal, last year, cautions that "pre-exposure prophylaxis is unlikely to be 100%, and making drugs available as prophylaxis could encourage high-risk sexual behaviour among those who believe themselves to be protected".

On March 1st, two UK organizations, the British HIV Association and the British Association for Sexual Health and HIV issued a statement stating that the existing data on the efficacy of pre-exposure prophylaxis is not compelling enough for it to be offered to patients on demand, and therefore needs more study.

In light of experts voicing concern over the new pharmaceutical prevention approach to HIV, AIDS Healthcare Foundation, the largest global AIDS organization, is gearing up to block the regulatory approval of Gilead's AIDS treatment, Truvada, for expanded use as a method of preventing HIV infection in non-infected people.

The AIDS Healthcare Foundation, or AHF, filed a citizen's petition on March 7 asking the FDA not to approve the pending sNDA submitted by Gilead, which seeks permission to market once-daily Truvada for pre-exposure prophylaxis to reduce the risk of HIV transmission in uninfected adults.

Under law, the FDA has 180 days to respond to AHF's complaint. However, the FDA can approve Gilead's supplemental New Drug Application for expanded use of Truvada during that same time window.

The supplemental New Drug Application for Truvada, which has been granted a six-month Priority Review, has a decision date set for June 15, 2012. The application of Truvada for PrEP is also expected to be discussed at the FDA Antiviral Drugs Advisory Committee meeting scheduled in May.

According to the AHF, the prevention approach to HIV, will not work on a large-scale basis because, "consistent with poor medication adherence rates for most diseases, people will not be able to take Truvada as directed. Because of this, there will be little or no preventative effect, and drug resistance and drug resistant strains of HIV will develop. In addition, people who falsely believe they are fully protected against HIV very likely may engage in riskier behavior, thereby increasing their risk of HIV infection".

A new analysis by UCSF (University of California at San Francisco) researchers, published last month in the journal AIDS, reveals that Tenofovir - the active ingredient in Viread, ( one of the two drugs that make up Truvada) is associated with an increased risk for kidney disease and damage that increases over time and doesn't appear to be reversible.

According to Michael Weinstein, AHF's president, it is sheer corporate greed that is behind the idea of giving healthy people a toxic drug that will damage their kidneys in order to possibly prevent HIV - when a simple condom use is 95% effective.

Truvada, Gilead's second-best selling product, generated sales of $2.88 billion in 2011 compared to $2.65 billion in 2010. If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV.

The first mention of the HIV virus was made in a report by the Centers for Disease Control and Prevention, or CDC, on June 5, 1981, which marked the official beginning of the HIV/AIDS epidemic. It is estimated that over 33 million people are living with HIV worldwide and 28 million have died from an AIDS-related illness since 1981, mostly in Africa.

There has been a tremendous progress in the treatment of HIV/AIDS since the introduction of antiretroviral therapy in 1996. Advancing to HIV prevention from HIV treatment may mark the beginning of the end of AIDS.

For comments and feedback: contact editorial@rttnews.com

Source

The REAL Drug to Beat in Treating Hepatitis C: Ribavirin

March 7, 2012 12:31 pm

The REAL Drug to Beat in Treating Hepatitis C: Ribavirin , by Chris Barnes

By now, most of us are aware – some of us painfully so – that the Hepatitis C drug development market is red hot. Investors and developers alike need a scorecard to keep track of who is buying who and for what potential blockbuster drug in the race to make it big in treating Hepatitis C. All of this hullabaloo is for good reason – the CDC estimates there are over 170 million people infected with Hepatitis C worldwide[1], a vast majority of them don’t know that they have it. That is paradoxically both an enormous and lucrative problem. This means there are a lot of potential patients for pharmaceutical companies to treat with blockbuster anti-HCV drugs.

The names of the compounds in development are like alphabet soup – GS-7977, VX-222, BMS-790052, BI-201335, TMC 435, BL-8020… protease inhibitors, polymerase inhibitors, cyclophilin inhibitors… the list goes on and on. This is a good thing for both drug makers and patients. Drugs to treat Hepatitis C are becoming more potent and more tolerable. And the race for the next blockbuster drug means there is no shortage of drugs and drug classes to choose from. Drug developers may even realize the holy grail of Hepatitis C treatment – an all oral, interferon-free regimen consisting of 2-4 pills a day. That’s right, no shots, no interferon. This would potentially make treatment for Hepatitis C infinitely more tolerable for patients.

So the HCV drug development biz is booming… but the hottest drug to beat in Hepatitis C? Ribavirin. A cheap, generic anti-viral. It turns out that even with all the advances drug makers are realizing in interferon-free drug combinations, ribavirin is critical to the success in curing patients of Hepatitis C. The trouble is that no one is really sure how ribavirin works. All we know is that treatment response rates are infinitely higher when it is part of a Hepatitis C antiviral regimen.[2][3][4]

Researchers are busy trying to find out just what makes ribavirin tick, but let’s look at a few of the current theories on how the drug works:

  • Ribavirin may cause something called ‘error catastrophe’ in the lifecycle of the HCV virus.[5]Ribavirin is a nucleoside analog – this means that ribavirin can fool the virus into thinking that it’s one of the building blocks needed for the virus to replicate. So when the virus tries to replicate itself, it picks ribavirin as a building block instead of the real thing. This mucks up the replication process leading to ‘error catastrophe’ – in other words, the virus is no longer able to make copies of itself.
  • Inosine monophosphate dehydrogenase (IMPDH). That’s a tongue-twister to be sure, but it’s also a cellular enzyme the human body makes and the HCV virus needs. Ribavirin may inhibit this enzyme, which consequently shuts down the energy supply the Hepatitis C virus requires to survive and replicate.[1]
  • The Hepatitis C virus is sneaky. It has a peculiar knack for evading the body’s immune system[2], so anything that might disrupt that ability would be very valuable to an anti-HCV regimen. It turns out that ribavirin may have this unique ability by helping the body mount a specific anti-viral response to the Hepatitis C virus, which is essential in fully clearing the virus. [3]

While ribavirin’s exact mechanism of action remains a mystery, there is one thing we do know for certain – we need ribavirin to fight Hepatitis C. Paring ribavirin with the above new antiviral compounds currently in development – called Direct Acting Antivirals or DAAs - that target and disrupt numerous points in the lifecycle of the virus, lead to significantly better cure rates then just using the DAAs alone. While interferon may go the way of the buffalo, it appears that the lowly, unsexy ribavirin is here to stay. This makes ribavirin the REAL drug to beat in the Hepatitis C drug development marketplace.

References

[1] Perz JF, et al. The contribution of hepatits B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-38

[2] Vertex Pharmaceuticals, Inc. (2010) Vertex adds ribavirin in additional treatment arm in ongoing phase II VX-222 & Telaprevir combo trial. [Press Release] Retrieved from http://viralmatters.blogspot.com/2010/11/vertex-adds-ribavirin-in-additional.html

[3] Hezode, Christopher, et al. (2009) Telaprevir and Peginterferon with or without Ribavirin for chronic HCV Infection. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa0807650

[4] Smith, M. (2012). New Combo KOs HCV Without Interferon, Ribavirin [Online article] Retrieved from: http://www.medpagetoday.com/InfectiousDisease/Hepatitis/30739

[5] Maag D, et al. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sck. 2001; 98: 6895-900

About the Author

Chris-Barnes-photo--150x150

Chris Barnes is a 18 year veteran of medical affairs and commercial functions of the biopharma and pharmaceutical industry, with expertise in Hepatitis and HIV. He actively follows Hepatitis C drug development through his blog and LinkedIn discussion group, Viral Matters. He can be contacted at christopherjbarnes10@gmail.com

Source

medxpress-logo

March 7, 2012

A multi-institutional team of researchers, led by The Wistar Institute, has announced the results of a clinical trial that shows how the immune system can engage in fighting HIV infection if given the right boost. In their study, HIV-infected volunteers suspended their daily antiretroviral therapy to receive weekly doses of interferon-alpha, an antiviral chemical produced by the human immune system. The study provides the first clinical evidence for a means of reducing the persistent amount of HIV in patients and the ability to control HIV without continued antiretroviral therapy.

Wistar's Luis J. Montaner, D.V.M., D.Phil., today presents their findings of the first clinical strategy able to harness host control and decrease HIV reservoir measures, at the 2012 Conference on Retroviruses and Opportunistic Infections in Seattle, Washington. HIV reservoirs are populations of cells that harbor HIV-1, enabling the virus to persist as a chronic infection.

"Our data shows that our human immune response can be made to control HIV in persons who have otherwise lost that ability and, if sustained by natural interferon production, it establishes proof-of-concept that a functional cure is theoretically possible," said Montaner, a professor at Wistar and director of the Institute's HIV-1 Immunopathogenesis Laboratory. "And while we still have much to pursue with this early clinical finding, I firmly believe this gives us hope that one day we can control—and eventually eradicate—HIV in absence of antiretroviral therapy."

The trial showed that interferon-alpha when used as a drug (Peg-IFN-α2A) sustained control of HIV in 9 of 20 patients while also decreasing measures of HIV reservoirs in patients otherwise dependent on antiretroviral therapy (ART). No other clinical strategy to date has shown an impact on decreasing integrated HIV DNA levels in HIV-infected humans.

Click here to see video clip …

Luis Montaner, D.V.M., D.Phil., discusses how the immune system can engage in fighting HIV infection if given the right boost. In a recent study, HIV-infected volunteers suspended their daily antiretroviral therapy to receive weekly doses of interferon‑alpha, an antiviral chemical our bodies produce naturally. The study provides the first clinical evidence for a means of reducing the persistent amount of HIV in patients and the ability to control HIV without continued antiretroviral therapy. Montaner presents his results March 7 at the 2012 Conference on Retroviruses and Opportunistic Infections. Credit: The Wistar Institute

"While our data may not immediately change clinical practice, it identifies the first strategy that shows a clinical response where both viral replication and HIV reservoir indicators are observed to be reduced in absence of current chemotherapy," Montaner said. "This is the type of response HIV cure research aims to achieve."

The study analyzed 20 patients over a period of 24 weeks. Remarkably, 45 percent of these patients were able to sustain viral control under 400 copies per mililiter and a similar frequency showed more than 50 percent reduction in circulating HIV reservoirs, as measured by the laboratory of Una O'Doherty, M.D., at the University of Pennsylvania. According to the researchers, these results show that our immune system, which is targeted by the HIV-1 virus, can mount a defense to HIV infection, if given the right stimulation.

"In previous studies, we have seen that when people suspend ART, their viral loads begin to creep upward while their white blood cell count gradually drops," Montaner said. "We expected to see the same thing during this trial, but we were, frankly, surprised to see patients maintain the gains made through ART using only interferon that modulates our body's response rather than acting directly against HIV as all current HIV drugs do."

"When someone is first infected with HIV-1, the immune system is overwhelmed, and the natural release of interferon into the bloodstream is ineffective as cells that produce it are quickly impaired," Montaner said. "But in our study, conducted at a later stage of chronic infection in an individual, we saw that adding interferon to a recovered immune system can have a dramatic effect in directing responses against HIV-1 to both control and reduce its detection within places we know it can hide."

Patients were recruited in partnership with local HIV/AIDS clinical treatment programs, including the University of Pennsylvania, Drexel University, and the Philadelphia Field-initiating Group for HIV Trials Philadelphia (FIGHT). The trial followed the progress of 20 men and women of various ethnicities as they started on either of two different doses of interferon on ART, discontinued ART, and maintained interferon treatment for up to 24 weeks. The trial lasted either 24 weeks or until either their HIV-1 levels rose or CD4 T cell counts dropped to a pre-determined level, at which point they would resume ART. Surprisingly, at midpoint (12 weeks), 45 percent (9 out of 20) of the patients still controled viral replication, and those that dropped out still compared favorably to the controls. Eight patients remained in the trial during the entire 24 weeks. Both dosage arms achieved similar results.

"It is exciting to show control against HIV-1 can be regained by way of stimulating natural mechanisms," Montaner said. "Our findings also open the way to determine if we can move this clinical research strategy towards a cure based on the decrease in HIV reservoirs we observed."

Interferon-alpha is a chemical naturally manufactured by the human immune system to "interfere" with the ability of viruses to replicate within cells. Since human interferon does not persist long enough in the body to serve as a useful antiviral drug, pharmaceutical researchers modified it by adding polyethelyne glycol (PEG) to the interferon molecule, making it last longer in the bloodstream with less toxicity. This "pegylated" form of interferon was approved in 2008 to treat hepatitis B and C infections.

Provided by The Wistar Institute

Source

Also See: CROI 2012: Penn, Wistar researchers thwart HIV without antiviral drugs

20120308_inq_he1hiv08-a

Wistar's Luis Montaner led the immune- therapy study.

Posted: Thu, Mar. 8, 2012, 3:01 AM

By Marie McCullough

Inquirer Staff Writer

For the first time, researchers have shown that they can suppress the AIDS virus by bolstering patients' immune systems, while taking them off standard antiviral drugs.

The small, six-month-long study, led by scientists at the Wistar Institute and the University of Pennsylvania, put patients on interferon, an old drug with nasty side effects. Interferon by itself had not worked against HIV, the virus that causes AIDS, in previous studies. The researchers can only speculate about why their protocol - which initially gave antivirals and interferon together - was effective.

Still, the study offers tantalizing evidence that an immune system damaged by HIV can nonetheless be prompted to control the virus on its own - without the powerful antiviral drugs that keep the microbe from reproducing.

While antivirals have transformed HIV infection from a death sentence into a manageable disease, they are costly, must be taken for life, and can spur the virus to develop drug resistance.

The new study was "designed to answer the question: Is it possible to control the virus with immune therapy? The answer is yes," said Wistar immunologist Luis Montaner, who presented the results Wednesday at an international AIDS conference in San Francisco. "There have been a lot of false hypotheses, so people are very jaded. But I firmly believe this gives us hope that one day we can control HIV in the absence of" antiviral therapy.

Virologist Satish Pillai, an AIDS researcher at the University of California San Francisco who was not involved in the study, called the findings "really amazing." The implication, he said, is that the body has natural defenses against the virus that are just waiting to be tapped by the right therapy.

At the National Institutes of Health, which funded the study, AIDS expert Carl W. Dieffenbach had a more reserved reaction.

"It's an important first step, so I don't want to damn it with faint praise," said Dieffenbach, director of the division of AIDS. "But I don't want to oversell it, either. While I suspect that the response to interferon was far more than we would have expected, we can't be sure."

Interferon, a drug based on a protein naturally produced in the body, is used to treat hepatitis C and some cancers. Side effects include flulike symptoms, hair loss, and depression.

In the new study, 20 patients took antiviral drugs plus interferon for five weeks, then interferon alone for up to 24 weeks. Any patient whose "viral load" - the amount of virus in the blood - surged above a low threshold was immediately put back on antivirals.

Based on previous studies in which patients tried taking breaks from antiviral treatment, the researchers predicted HIV would surge within about a month in all but a few of the patients.

Instead, nine patients - 45 percent - suppressed the virus on interferon alone. Three patients kept HIV in check for 12 weeks, while six patients were still suppressed at the end of the 24-week study.

Even more encouraging, sophisticated DNA tests showed that seven patients had a significant decrease in the amount of HIV hiding in their T cells, the immune cells that the virus invades and hijacks to reproduce. Normally, this reservoir of "integrated" HIV would start churning out more virus copies as soon as antivirals were stopped.

"Generally, we've assumed the integrated HIV is silent and invisible" to the immune system, said Una O'Doherty, a transfusion medicine specialist in the University of Pennsylvania's pathology department who conducted the DNA tests. "Maybe it's not invisible."

Interferon was shelved for HIV long ago, when antivirals revolutionized therapy. So why did it suppress the virus in the new study?

Montaner speculated that the key was the five weeks of overlapping treatment. Perhaps the antivirals gave interferon a chance to prime the immune system for defensive action, much like a vaccine primes the system to prevent infection.

UCSF's Pillai, who had studied interferon in patients co-infected with HIV and hepatitis C, believes the drug boosts "restriction factors" - immune-system chemicals that help neutralize or divert viruses.

In any case, the quest for therapies that work on the immune system - as opposed to the virus - is growing. At least seven companies and many academic labs are pursuing vaccines, gene therapies, or other immune boosters that would suppress HIV without necessarily eradicating it, a so-called functional cure.

Cure is a heady term, but it is theoretically possible, as a patient living in Berlin has shown. He has been free of the virus since 2008, following a bone-marrow transplant to treat leukemia, because the marrow came from one of the rare Northern Europeans who has a natural genetic resistance to HIV infection.

For Montaner's team - 14 scientists from seven institutions, including Philadelphia Fight, which helped enroll research subjects - the next step is finding funding for a larger trial.

"When the study was started, it was expected by most people to fail," he said. "Now, everyone is intrigued and hopeful."


Contact Marie McCullough

at 215-854-2720 or mmccullough@phillynews.com.

Source

Also See: Small US trial looks at body's ability to fight HIV

logo

Achillion Reports 2011 Fourth Quarter and Year-End Financial Results

March 8, 2012

Conference Call and Webcast to be Held Today, March 8th, at 8:30am ET

NEW HAVEN, Conn., March 8, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN), a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today reported financial results for the three and twelve months ended December 31, 2011.

For the three months ended December 31, 2011, the Company reported a net loss of $12.4 million, compared to a net loss of $6.2 million in the three months ended December 31, 2010. For the full year ended December 31, 2011, the Company's net loss was $44.2 million, compared to a net loss of $25.5 million for the year ended December 31, 2010. Cash and cash equivalents and marketable securities at December 31, 2011 were $79.9 million.

Recent HCV Pipeline Accomplishments

"Throughout 2011 and into 2012, we consistently achieved the milestones that will enable us to initiate a combination study evaluating a proprietary all-oral, interferon-free trial with our lead protease inhibitor, ACH-1625, in combination with our second generation NS5A inhibitor, ACH-3102, later this year," commented Michael Kishbauch, President and Chief Executive Officer of Achillion.

  • Reported 100% complete early virology response (cEVR) following interim analysis of 35 patients enrolled in a Phase 2a 12-week study evaluating ACH-1625 in combination with pegylated interferon plus ribavirin (P/R) for the treatment of chronic hepatitis C (HCV) genotype 1 treatment-naive patients. Enrollment in this trial has been completed;
  • Completed three and six-month preclinical toxicity studies with ACH-1625, with nine-month studies to be completed in the first quarter;
  • Reported clinical proof-of-concept with ACH-1625 against HCV genotype 3;
  • Received Fast Track designation for ACH-1625 for the treatment of HCV;
  • Achieved Phase 1 proof-of-concept with ACH-2684, a pan-genotypic protease inhibitor;
  • Achieved Phase 1 proof-of-concept with ACH-2928, a first generation NS5A inhibitor; and
  • Completed IND-enabling studies to support the filing of an IND for a second generation NS5A inhibitor, ACH-3102.

Mr. Kishbauch continued, "The clinical profile of ACH-1625 continues to excel, featuring not only 100% cEVR against genotype 1 HCV, but apparent pan-genotypic activity as demonstrated in a pilot study against HCV genotype 3, and lack of viral breakthrough with its continued suppression of known resistant variants of HCV. This extremely robust drug profile for ACH-1625 has led us to complete all the additional activities necessary to enter registrational clinical trials in 2013, including completion of a commercially feasible formulation and a full non-clinical toxicology package."

Upcoming Clinical Milestones for 2012

ACH-1625: Phase 2 pan-genotypic protease inhibitor

  • Present Phase 2a cEVR results for fully enrolled trial of ACH-1625 in combination with P/R, accepted for presentation at The International Liver Congress (EASL 2012), April 18-22, in Barcelona, Spain;
  • Initiate multiple drug-drug interaction studies during the second and third quarters evaluating ACH-1625 in combination with methadone, atorvastatin, and oral contraceptives;
  • Complete a relative bioavailability study of ACH-1625 tablet formulation during the second quarter; and
  • Initiate an all-oral therapeutic trial evaluating ACH-1625 in combination with ACH-3102 in HCV genotype 1 patients during the fourth quarter of 2012.

ACH-3102: Second generation NS5A inhibitor

  • Initiate a Phase 1 clinical trial in healthy subjects and HCV infected patients during the second quarter of 2012;
  • Report Phase 1 proof-of-concept results in HCV infected patients during the third quarter of 2012; and
  • Initiate a drug-drug interaction trial with ACH-1625 in the third quarter to support a fourth quarter therapeutic combination trial.

Fourth Quarter Financial Results

The Company reported a net loss of $12.4 million for the three months ended December 31, 2011, compared to a net loss of $6.2 million for the three months ended December 31, 2010. Research and development expenses were $9.9 million in the fourth quarter of 2011, compared to $6.1 million for the same period of 2010. Research and development expenses increased in 2011 and were primarily related to costs incurred from clinical testing of the Company's HCV protease inhibitors, ACH-1625 and ACH-2684, clinical testing of the Company's first generation HCV NS5A inhibitor, ACH-2928, and preclinical testing of the Company's second-generation NS5A inhibitor, ACH-3102.

Revenue for the three months ended December 31, 2011 totaled $62,000, compared to $2 million in the three months ended December 31, 2010. During the fourth quarter of 2010, the Company recognized grant revenue of $2 million related to the Qualifying Therapeutic Discovery Project, or QTDP, program. In comparison, revenue in the fourth quarter 2011 consisted of payments related to the NS4A collaboration with Gilead, and no grant-related revenue was recognized.

For the three months ended December 31, 2011, general and administrative expenses totaled $2.6 million, compared to $2.2 million in the same period in 2010.

Year-end 2011 Financial Results

For the year ended December 31, 2011, the Company reported a net loss of $44.2 million, compared to a net loss of $25.5 million in 2010. For the year ended December 31, 2011, research and development expenses totaled $35.4 million, compared to $20.5 million in 2010. The increase in research and development expenses was primarily a result of increased clinical trial costs associated with ACH-1625, ACH-2684 and ACH-2928, as well as IND-enabling preclinical testing costs associated with ACH-2928, ACH-2684 and ACH-3102.

Total revenues were $247,000 for the year ended December 31, 2011, compared to $2.4 million for the year ended December 31, 2010. During 2011, no grant revenue was recognized. In comparison, during 2010, grant revenue under a SBIR grant and the Qualifying Therapeutic Discovery Project, or QTDP, program totaled approximately $2.3 million.

General and administrative expenses were $9.2 million for the year ended December 31, 2011, compared to $7.2 million for the year ended December 31, 2010, the increase primarily resulting from higher business development and professional services fees.

2012 Financial Guidance

At December 31, 2011, Achillion had cash and cash equivalents and marketable securities of approximately $79.9 million. The Company expects that research and development expenses during 2012 will be approximately $40 million and that net cash used in operating activities in 2012 will approximate $45 million based on current operating plans, anticipated timelines and the estimated cost of clinical trials and product development programs. The net loss per share is anticipated to range from $0.65 to $0.70 per share.

Conference Call

The Company will host a conference call and simultaneous webcast on Thursday, March 8, 2012 at 8:30 a.m. Eastern time. To participate in the conference call, please dial (877) 266-0482 in the U.S. or (631) 291-4567 for international callers. A live audio webcast of the call will be accessible at www.achillion.com, under the News Center section of the website. 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. Alternatively, a replay of the conference call will be available starting at 12:30 p.m. Eastern time on March 8, 2012, through 11:59 p.m. Eastern time on March 15, 2012 by dialing (800) 585-8367 or (404) 537-3406. The replay passcode is 58851443.

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 potency, safety, tolerability, effectiveness and other characteristics of Achillion's protease inhibitors and NS5A inhibitors; Achillion's expectations regarding timing for the commencement, completion and reporting of results of clinical trials of drug candidates in its protease inhibitor and NS5A inhibitor programs; Achillion's ability to advance a potentially best-in-class all-oral, interferon-free combination protease and NS5A inhibitor; and Achillion's estimates for research and development expenses, net cash used in operations and net loss per share for the year ended December 31, 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 positive results found in earlier stage clinical trials of ACH-1625, ACH-2684 and its other product candidates; 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.

-- Financial Tables Attached --

Continue Reading for financial tables …