Tracy Swan
Dedicated to Dr. Roy Arad
Although curable, hepatitis C virus (HCV) has been described by the World Health Organization (WHO) as a “viral time bomb” due to both its prevalence (3% of the world’s population, or 170 million people, have been infected) and potential for causing serious, life-threatening complications (WHO 2010). Up to 130 million people have chronic hepatitis C, and
20 to 30% of them—between 13 and 19.5 million people—will develop cirrhosis if untreated or unsuccessfully treated. People with cirrhosis are at risk for liver cancer (hepatocellular carcinoma; HCC) and liver failure. In fact, more than 365,000 people die each year from these HCV complications (Perz 2006).
Worldwide, an estimated 4–5 million people are coinfected with HIV and hepatitis C (Alter 2006). They need more effective and tolerable HCV treatment. In places where people have access to antiretroviral therapy, end-stage liver disease from HCV coinfection has become a leading cause of death among HIV-positive people (Weber 2006). This is because HIV accelerates HCV progression and increases the likelihood of complications: HIV doubles the risk of cirrhosis, and immunodeficiency increases the risk of HCC (Clifford 2008; Graham 2001). Unfortunately, HCV treatment with the current standard of care (SOC) is less effective for coinfected people than their HCV monoinfected counterparts (Carrat 2004; Chung 2004; Torriani 2004).
Introduction
Approximately half of the people who undergo hepatitis C treatment are cured. In the near future more people with hepatitis C will be cured, some in half the time required now. Scientific advances and keen pharmaceutical interest have led to a flurry of HCV drug development; more than thirty drugs have entered clinical trials. Sales of HCV drugs, which have been plummeting in the U.S., are expected to increase from $2.3 billion to $4.5 billion by 2017 as new drugs enter the marketplace. The U.S. ($1.9 billion), and the E.U. ($1.7 billion) will be major consumers (Datamonitor 2009).
Oral drugs (known as direct-acting antivirals, or DAAs) that specifically target certain steps in the hepatitis C virus life cycle are in late-stage development. In 2011, the U.S. Food and Drug Administration (FDA) approval of two HCV protease inhibitors, boceprevir and telaprevir, is expected. But pegylated interferon (also known as peginterferon) and ribavirin—the current standard of care for hepatitis C—will remain as the therapeutic backbone for the first few generations of HCV drugs.
Peginterferon and ribavirin work by killing infected cells (immunologic effect) and protecting new cells from hepatitis C by preventing HCV replication (antiviral effect). Nobody knows whether a combination of DAAs will cure HCV by preventing the virus from reproducing (an approach that has been successful for treating, but not eradicating, HIV). Peginterferon (or another therapy that stimulates the immune response to HCV) may still be required to cure HCV.
Everyone would like to be rid of interferon. It is a huge barrier to HCV treatment access, uptake, and completion because of its cost (~$25,000 per year), medical contraindications, and many side effects. Even when HCV treatment is readily available at no cost, tolerability is a problem: only one out of 56 people who received HCV treatment through the Veteran’s Administration completed their regimen (Butt 2009).
Hopefully, DAA combinations will become the standard of care. By 2013, results from a trio of groundbreaking trials will be available. These studies combine two DAAs, with or without peginterferon and ribavirin. Study populations and drugs differ (in treatment-naive people, a protease inhibitor/non-nucleoside polymerase inhibitor combination; in prior null responders, a protease inhibitor plus an NS5a inhibitor), but if successful, these trials will provide initial proof-of-concept for peginterferon-free regimens.
In the meantime, results from the first phase III study of a DAA (telaprevir, an HCV protease inhibitor) plus SOC were reported in May 2010, and others are nearing completion. Several ongoing triple therapy trials—adding a single DAA to SOC—are exploring treatment strategies and duration, and evaluating early predictors of successful treatment. Quad trials—two DAAs plus SOC—will soon be underway as well.
The biggest limitation to DAAs is the emergence or development of drug resistance. Drug resistance means that an organism—such as HCV—is able to grow or reproduce despite presence of levels of a drug that would normally stop it from doing so. HCV makes billions of copies of itself each day. They are not identical; some individual virus particles (virions) have structural changes (mutations). Some mutations may allow the virus to escape from drug pressure, leading to drug resistance. In fact, resistance to one or more DAA classes has already been detected in people who have never used these drugs (Kuntzen 2008; Legrand-Abravanel 2009).
HCV treatment strategies must continue to evolve in order to forestall drug resistance and meet the needs of different populations. Some people cannot use peginterferon and ribavirin, and it is ineffective for ~50%, leaving many unsuccessfully treated people (see box: Terms for HCV Treatment Response by Population and Time Point). But adding a single DAA to SOC will not work for all treatment-experienced people.
So far, it is clear that adding a DAA to SOC therapy is most likely to work for people who relapsed or experienced viral breakthrough. Adding a single drug is less likely to work for people who have HCV that is not responsive to peginterferon, as is the case with treatment nonresponders and null responders. Using two or more DAAs may be effective and lower the risk of drug resistance for non- and null responders, but more research is needed to determine retreatment strategies for these groups.
Terms for HCV treatment response by population and time point
Population
Relapse means that HCV became—and remained—undetectable during treatment, but reappeared within weeks to months after finishing it.
Viral breakthrough means that HCV reemerged after becoming undetectable during treatment.
Non-response means that the hepatitis C viral load drops by two logs (99%) but does not ever become undetectable during treatment.
Null response means that hepatitis C viral load drops by less than one log (10%) after four weeks of treatment, and drops by less than two logs (99%) drop after 12 weeks of treatment.
Time point
Very rapid virological response (vRVR) is a new term, used to indicate that HCV RNA has become undetectable after 14 days of treatment.
Rapid virological response (RVR) means that HCV cannot be detected in the blood after four weeks of treatment. RVR is a significant milestone in response-guided therapy because it predicts sustained virological response (see below) in ~90% of cases—regardless of HIV status, but a person can still be cured in the absence of RVR.
Sustained virological response (SVR) means that no HCV is detectable in a person’s bloodstream six months after completion of treatment. SVR is durable, and linked to reductions in liver-related morbidity and mortailty; HCV is cured.
Extended rapid virlogic response (eRVR) is a newly coined term indicating that HCV RNA has becomes undetectable after 4 weeks of treatment and remains undetectable at week 12.
Partial early virological response (pEVR) means that HCV RNA has dropped by at least two logs (99%).
Complete early virological response (cEVR) means that HCV RNA is undetectable after 12 weeks of treatment. SVR is more likely for people who have a cEVR than people who have a pEVR. Although an early virological response cannot predict who will be cured, it does indicate who will not be cured if they remain on treatment. Since SVR is extremely unlikely in people who don’t have a pEVR or cEVR, HCV treatment is usually discontinued at this point. Sometimes this is called an early stopping rule.
End-of-treatment response (EOT) means that HCV viral load is undetectable at the end of HCV treatment.
SVR-12 means that HCV remains undetectable 12 weeks after completion of treatment. Although it has not been prospectively validated (meaning that researchers have found this to be true by looking back at trial results rather than planning in advance to see if it is true), SVR-12 is a good predictor of SVR because relapse usually occurs within a few weeks after treatment completion.
HCV treatment: population-specific issues
Hopefully, DAAs will be safe and effective for HIV/HCV coinfected people, since SOC is less effective for HIV/HCV coinfected people than for people with HCV monoinfection (see Table 1: HCV Treatment Outcomes, by Population). Coinfected people usually have higher HCV viral loads (HCV RNA) than people with HCV alone. A less effective backbone and a high hepatitis C viral load increase the risk for drug resistance, so coinfected people may require treatment with more than one DAA. But DAAs may interact with some antiretroviral agents, complicating treatment of both viruses. Coinfected people and their medical providers are awaiting results from a pair of ongoing DAA studies in HIV/HCV coinfected people.
The safety and efficacy of DAAs have yet to be explored—or have not been adequately explored—in other key populations. No studies have been initiated in transplant candidates and recipients, despite the urgent need for such studies. Only a small proportion of people with cirrhosis have been enrolled in DAA trials to date. Enrollment of African Americans, Latinos, and Latinas has been inadequate. Although they constitute the highest-prevalence population, people who use drugs are usually excluded from clinical trials, even when they are ready and willing to participate.
Table 1. HCV Treatment Outcomes, by Population
Treatment with peginterferon plus ribavirin (weight-based or flat dosing) for 24–72 weeks; HCV genotype 1 unless indicated
| International Registration Trials: HCV Monoinfection (reference) |
| Study and Date | Source | Population | SVR |
| Fried, 2002; Manns 2001 | Clinical trial | HCV genotype 1 | 42–44% |
| International Trials: HIV/HCV Coinfection |
| Study and Date | Source | Population | SVR |
Carrat 2004 (Europe) Chung, 2004 (U.S.)
Laguno, 2004 (Europe)
Torriani 2004 (international) | Clinical trial | HIV/HCV genotype 1 | Carrat: 21% Chung: 14%
Laguno: 38%
Torriani: 29% |
| Clinical Practice: U.S. and Non-U.S. |
| Study and Date | Source | Population | SVR |
| Borroni 2008 | Non-U.S. clinical practice (Italy) | HCV genotype 1 | 46% |
| Feuerstadt 2009 | U.S.-based faculty practice (FP) and clinic (C) | HCV genotype 1 56% Hispanic, 27% African American, 9% Caucasian, 8% other | Overall: 14% FP: 27%
C: 15% |
| Gheorghe 2007 | Non-U.S. clinical practice (Romania) | HCV genotype 1 | 55.9% |
| Jacobson 2007 | U.S. clinical trial (community and academic setting) | Genotype 1; fixed-dose ribavirin (FDR) vs. weight-based ribavirin (WBR) | FDR: 28.9% (overall) vs. 10.1% (African American) WBR: 34% (overall) vs. 20.7% (African American) |
| Lee 2006 | Non-U.S. clinical practice (Canada) | Cirrhosis vs. noncirrhotic, HCV genotype 1 | 34% (cirrhotic) vs. 41% (noncirrhotic) |
| African Americans: Clinical Trials and Clinical Practice |
| Study and Date | Source | Population | SVR |
| Conjeevaram 2006 | Clinical trial | African American, HCV genotype 1 | 28% (vs. 52% among Caucasians) |
| Jeffers 2004 | Clinical trial | African American, HCV genotype 1 | 26% (vs. 39% among Caucasians) |
| Muir 2004 | Clinical trial | African American, HCV genotype 1 | 19% (vs. 52% among Caucasians) |
| Satapathy 2010 | Clinical practice, retrospective review | African American, HCV genotype 1 | 16.1% |
| Srivastava 2005 | Clinical practice | African American, HCV genotype 1 | 19% (vs. 24% among Caucasians) |
| Latino Populations: Clinical Trials and Clinical Practice |
| Study and Date | Source | Population | SVR |
| Rodriguez-Torres 2009 | Clinical trial | Latino, HCV genotype 1 | 34% (vs. 49% among Caucasians) |
| Satapathy 2010 | Clinical practice, retrospective review | Latino, HCV genotype 1 | 13.7% |
| Yu 2009 | Clinical practice, retrospective review | Latino and Caucasian, HCV genotypes 2 and 3 | 65.9% (vs. 87.3% among Caucasians) |
| Asian Population: Clinical Trial |
| Study and Date | Source | Population | SVR |
| Liu 2008 | Clinical trial | Asian, HCV genotype 1 | 76% (after 48 weeks of treatment) |
| Prior Relapse/Nonresponse to Standard or Peginterferon plus RBV |
| Study and Date | Source | Population | SVR |
| Berg 2006 | Clinical trial | Relapse after 24 weeks of peginterferon/RBV | 51% (retreated for 48 weeks) |
| Sagir 2007 | Clinical practice | Nonresponders to standard interferon/ribavirin | 4% |
| Scotto 2008 | Clinical trial | Nonresponders to standard interferon/ribavirin | ~19% |
| Yoshida 2009 | Clinical practice | HCV genotype 1, prior relapse/nonresponse to peginterferon plus RBV | 65% (prior relapse) 17% (prior nonresponse) |
| People with Cirrhosis |
| Study and Date | Source | Population | SVR |
| Lee 2006 | Clinical practice | People with bridging fibrosis and cirrhosis (stages F3 and F4) | 34% |
| Di Marco 2007 | Clinical trial | People with cirrhosis and portal hypertension (low-dose peginterferon and low-dose ribavirin) | 11.3% |
| Iacobellis 2007 | Open-label, single-arm study | People with decompensated cirrhosis; 24 weeks of treatment (low-dose peginterferon; standard-dose ribavirin) | 7% |
| Iacobellis 2009 | Open-label, single-arm study | People with decompensated cirrhosis; 48 weeks of treatment (standard-dose peginterferon and ribavirin) | 16% |
| Transplant Recipients |
| Study and Date | Source | Population | SVR |
| Hanouneh 2008 | Clinical practice | Transplant recipients; full-dose peginterferon and ribavirin | 23% |
| Lodato 2008 | Clinical trial; response-guided, open-label study | Transplant recipients; 48 weeks of low-dose peginterferon and standard-dose ribavirin | 26% |
| Zimmermann 2007 | Open-label study | Transplant recipients, genotype not specified | 19% |
| Injection Drug Users (IDUs) |
| Study and Date | Source | Population | SVR |
| Bruggmann 2008 | Clinical Practice | Active IDU; HCV genotype not specified | 69.3% (versus 59.8% among control group of non-users) |
| Hellard 2009 | Meta-analysis | Active IDUs; genotype not specified | Median 54% Range 18.1 to 94.1% |
HCV treatment access
Patent protection of peginterferon extends until 2016 (Peg-Intron®) or 2017 (Pegasys®) in the United States. The high cost of peginterferon drastically limits access to HCV treatment; it is unavailable to most of the world’s 130 million chronically infected people. According to Viral Hepatitis: Global Policy, a 2010 report from the World Hepatitis Alliance, over 80% of low income countries want assistance to improve access to HCV (and hepatitis B) treatment.
Lack of access to HCV treatment is unacceptable. Pharmaceutical companies can remedy this situation. They have an opportunity to save millions of lives while generating unanticipated revenue and goodwill. Global access to peginterferon and DAAs can—and ought to be—facilitated by these and other measures:
- adopting a high-volume, low-profit strategy for low and middle income countries
- registering HCV treatments in all countries
- granting licenses to generic manufacturers supplying low- and middle-income countries.
Moving forward: HCV drug development
Making sense of the flood of data from HCV trials is difficult. New acronyms appear after each scientific meeting (see box: Terms for HCV Treatment Response by Population and Time Point); HCV treatment duration and strategy vary according to the characteristics of each drug and the populations it is studied in; and trial designs are becoming more complex. Interim reporting (at 4 and 12 weeks) and incomplete data (from press releases, posters, and brief presentations at conferences) add to the confusion. For example, in May 2010, Vertex issued a press release with results from ADVANCE, an international phase III trial of triple combination therapy (telaprevir plus SOC) in treatment-naive people with HCV genotype 1. They reported an overall SVR of 75% (after 12 weeks of a telaprevir-based regimen plus SOC) without specifying treatment duration. A closer look at the data revealed that SVR for short-course treatment (24 versus 48 weeks) dropped to ~52%, still a significant improvement over SOC.
Ongoing studies are exploring DAA combination studies, shorter-course treatment, and response-guided therapy. Boehringer-Ingelheim, Bristol-Myers Squibb (BMS), Gilead, and Vertex have launched multidrug studies; these are proceeding in parallel with trials adding a single DAA to standard of care. Abbott, Anadys, Idenix, Merck, and Pharmasset have drugs from different classes in clinical development, but have yet to announce combination studies.
A tantalizing glimpse of an interferon-free future comes from Roche/Genentech’s pioneering INFORM-1, a two-week proof-of-concept study combining danoprevir, an HCV protease inhibitor, with RG7128, an HCV polymerase inhibitor. The two drug combination worked well in treatment-naive and treatment-experienced study participants with HCV genotype 1. INFORM-3, a longer combination study, has been delayed by a serious safety issue—elevated liver enzyme levels in some people who got the highest dose (900 mg) of danoprevir (in a different trial); this was resolved when the drug was stopped. Results from a study of ritonavir-boosted danoprevir (meaning that another drug, ritonavir, is used to keep danoprevir in the bloodstream longer to make it more effective, with a lower pill burden and frequency of dosing) will determine the optimal dose for future studies.
Meanwhile, four studies combining DAAs (with or without peginterferon and ribavirin) have begun.
- Boehringer Ingelheim has opened a two-part, peginterferon-sparing study exploring different dosing, and duration of BI 201335 (an HCV protease inhibitor) with different durations of BI 207127 (a non-nucleoside polymerase inhibitor), with or without ribavirin in treatment naïve people with HCV genotype 1.
- BMS has launched a study combining an HCV protease inhibitor (BMS-650032) with a first-in-class NS5a inhibitor (BMS-790052) with or without SOC, in prior null responders with HCV genotype 1.
- Gilead has opened a 28-day, two-arm study of GS-9256 (an HCV protease inhibitor plus GS-9190 (a non-nucleoside polymerase inhibitor), with and without ribavirin, followed by SOC in treatment-naive people with HCV genotype 1.
- Vertex is combining telaprevir (an HCV protease inhibitor) with VX-222 (an HCV polymerase inhibitor) in treatment-naive people with HCV genotype 1. Depending on randomization and early treatment response, participants will receive dual DAAs (followed by SOC if indicated) or quad therapy (DAAs plus SOC).
Characteristics of the class: HCV protease inhibitors
HCV-specific protease inhibitors will be the first DAA class available. This family of drugs has been used for more than a decade to treat HIV (in combination with other antiretroviral drugs). Protease inhibitors block cleaving of viral proteins (which would otherwise be reassembled into new virus particles) in the same way that inserting something between the blades of a scissor prevents them from cutting.
The first generation, Merck/Schering Plough’s boceprevir and Vertex/Tibotec’s telaprevir, are in phase III; barring unforeseen circumstances, approval is expected in early 2011. Although treatment strategies and durations differ (see Table 2: Dueling HCV Protease Inhibitors), adding one of these drugs to SOC has significantly boosted SVR among people with HCV genotype 1.
Table 2. Dueling HCV Protease Inhibitors
| Drug | Dosing/Pill Burden | SVR in Treatment-naive People* | Duration of Treatment | Strategy | Drawbacks |
| Boceprevir | 3 times daily, 12 pills/day | 54-56% (triple therapy and lead-in, respectively) 67-75% (triple therapy and lead-in, respectively)
63-66% (lead-in, response-guided therapy or set duration therapy ) | 24–48 weeks 44–48 weeks
28–48 weeks | Triple therapy, or after a 4-week lead-in with SOC4-week lead-in followed by triple therapy, either response-guided or set duration | Anemia; epoetin alfa used by ~50% in phase II; long treatment duration **lack of data in treatment experienced people due to protocol amendments in phase II; phase III data in treatment experienced people limited to top-line results from a press release |
| Telaprevir | Q8hrs (every eight hours); or possibly Q12hrs (every 12 hours) 6 pills/day (Q8H regimen) | 52–61% after 24 weeks 72% (response-guided therapy; this SVR is among people with undetectable HCV RNA at W 4 and W 12)
*A 24-week regimen was also effective for treatment-experienced people: overall: 51%
prior non-responders (31%); prior viral breakthrough (57%); prior relapse (69%) | 8–12 weeks of triple therapy followed by 12–16 weeks of SOC alone (24 weeks total) 24-48 weeks | Triple therapy followed by SOC Triple therapy followed by SOC | Rash (which can be severe), anemia, itchy skin, nausea, vomiting, diarrhea |
Sources:
Kwo P, Lawitz E McCone C, et al. (abstract 4) HCV SPRINT-1 final results: SVR 24 from a phase 2 study of boceprevir plus PegIFN alpha-2b/ribavirin in treatment naïve subjects with genotype-1 chronic HCV. 44th Annual Meeting of the European Association for the Study of the Liver. 22-26 April, 2009. Copenhagen, Denmark.
McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; April 30; 360:1827–1838.
Merck. Press Release. August 4, 2010.
Vertex Pharmaceuticals. Press releases. May 25 and August 10, 2010.
.
Adherence to these drugs will be crucial, since resistance to an HCV protease inhibitor—or to the entire class (cross-resistance)—can develop or emerge within days. Adherence to the first generation of HCV protease inhibitors is likely to be challenging: ribavirin is taken twice daily; boceprevir and telaprevir need to be taken three times a day—although a study comparing twice-daily to thrice-daily dosing of telaprevir reported that efficacy was equivalent (Marcellin 2009). Pill count ranges from 6 (telaprevir) to 12 (boceprevir) per day, not including ribavirin.
Known side effects of HCV protease inhibitors include anemia, rash, anal itching and hemorrhoids, fatigue, nausea, vomiting, diarrhea, dysgeusia (bad taste in the mouth or changes in taste), headaches, dizziness, jaundice, and elevated alanine aminotransferase (ALT) and bilirubin.
Table 3. HCV Protease Inhibitors in Development
| Agent/Sponsor | Status | Comments |
ABT-450
Abbott | Phase I/II; HCV genotype 1, treatment-naive | Currently being studied with low-dose ritonavir |
ACH-1625
Achillon | Phase Ib; HCV genotype 1, treatment-naive and treatment-experienced | Once-daily dosing will be explored in future trials |
BI 201355
Boehringer Ingleheim | Phase II; HCV genotype 1, treatment-naive and treatment-experienced | May be a once-daily drug |
BMS-650032
Bristol-Myers Squibb | Phase II; HCV genotypes 1 and 4, treatment-naive | Genotype 4 and people with cirrhosis added in phase IIb |
Boceprevir
Merck/Schering-Plough | Phase III; HCV genotype 1, treatment-naive and treatment-experienced | Used 3 times daily; large pill burden (12/day); anemia is common side effect; likely to be approved by 2011 |
CTS 1027
Conatus | Phase II; HCV genotype 1, null responders | 24-week study with SOC |
Danoprevir
ITMN-191/RG 7227
Intermune/Genentech/Roche | Phase II; HCV genotype 1 | Has been studied with RG 7128, a nucleoside polymerase inhibitor; dose-limiting liver toxicity was resolved with ritonavir boosting |
GS 9256
Gilead Sciences | Phase II | Being studied in combination with GS 9190, a non-nucleoside HCV polymerase inhibitor |
GS 9451
Gilead Sciences | Phase I | No other information available. |
MK 5172
Merck | Phase I; HCV genotypes 1 and 3, males only | Demonstrated activity against resis-tant virus in lab studies and chimps |
IDX 320
Idenix | Phase I; healthy volunteers | No other information available. |
TMC 435350
Tibotec | Phase IIa; HCV genotype 1, treatment-naive and treatment-experienced | Favorable dosing (possibly once daily); preliminary data suggests efficacy in treatment experienced |
Telaprevir
Vertex/Tibotec | Phase III; HCV genotypes 1, 2, 3, and 4, treatment-naive and treatment-experienced | Approval expected by 2011 |
Vaniprevir (MK 7009)
Merck | Phase II; HCV genotype 1, treatment-experienced | A phase II trial in treatment-naive people with HCV genotype 1 is slated to open in August 2010 |
VX 985
Vertex | Phase I |
|
Characteristics of the class: HCV polymerase inhibitors
Nucleoside, nucleotide, and non-nucleoside polymerase inhibitors have been part of combination HIV treatment for years. Now, analogues of those drugs, made specifically for HCV, are in development. Nucleoside and nucleotide polymerase inhibitors are imperfect copies of nucleotides that insert themselves into hepatitis C RNA. Since they are faulty, other nucleotides cannot attach themselves; in other words, nucleoside and nucleotide polymerase inhibitors cause viral dead ends. Non-nucleoside polymerase inhibitors interfere with HCV replication by binding to the hepatitis C polymerase and preventing viral replication—it’s as if the virus is a car trying to park in a space that just got too small for it.
Some nucleoside/nucleotide polymerase inhibitors have already been discontinued for toxicity, but other candidates in this promising class are moving forward. If these are safe, effective, and tolerable, nucleoside/nucleotide polymerase inhibitors are likely to become the backbone of HCV treatment, since they are active across genotypes and have a high genetic barrier to resistance (meaning that resistance to this family of drugs is less likely to develop than resistance to protease inhibitors and non-nucleoside polymerase inhibitors).
So far, the hepatitis C non-nucleoside polymerase inhibitors in development are active only against HCV genotype 1, and resistance develops quickly. In fact, mutations that confer resistance to non-nucleoside polymerase inhibitors have already been detected in people who have never taken these drugs (Dryer 2009).
It may be possible to combine non-nucleoside polymerase inhibitors, since the HCV polymerase has at least four binding sites.
Side effects reported in trials of nucleoside/tide and non-nucleoside polymerase inhibitors include nausea, vomiting, diarrhea, fever, weakness, flatulence, chills, headache, fatigue, and rash.
Table 4. HCV Polymerase Inhibitors in Development
| Non-nucleoside Polymerase Inhibitors |
| Agent/Sponsor | Status | Comments |
ABT-333
Abbott | Phases I /II; HCV genotype 1, healthy volunteers and treatment-naive |
|
ABT-072
Abbott | Phases I /II; HCV genotype 1, healthy volunteers and treatment-naive |
|
ANA 598
Anadys | Phase II; HCV genotype 1, treatment-naive | Twice-daily dosing |
BI-207127
Boehringer Ingelheim | Phase I; HCV genotype 1, treatment-naive and treatment experienced | Dosing is q.8 h |
BMS 791325
Bristol-Myers Squibb | Phase I/II |
|
GS 9190
Gilead Sciences | Phase II; HCV genotype 1, treatment-naive | Being studied with SOC and in a combination trial with GS 9256, an HCV protease inhibitor |
IDX 375
Idenix | Phase I; healthy volunteers | Possibly once- or twice-daily dosing |
PF-00868554/Filibuvir
Pfizer | Phase II; HCV genotype 1, treatment-naive |
|
VX-222
Vertex | Phase II; HCV genotype 1, treatment-naive | VX-222 is being studied in combination with telaprevir, an HCV protease inhibitor |
VX-759
Vertex | Phase II; HCV genotype 1, treatment-naive |
|
| Nucleoside/Nucleotide Polymerase Inhibitors |
| Agent/Sponsor | Status | Comments |
IDX 184 (nucleotide)
Idenix | Phase IIa; HCV genotype 1, treatment-naive | Once-daily dosing |
| PSI 7977 (nucleotide) Pharmasset | Phase IIa; HCV genotype 1, treatment-naive | Once-daily dosing |
| RG 7128 (nucleoside) Roche/Genentech/Pharmasset | Phase II; HCV genotypes 1 and 4, treatment-naive; also studied in 20 prior nonresponders with HCV genotypes 2 and 3 | Twice-daily dosing |
Characteristics of the class: NS5a inhibitors
NS5a inhibitors may have cross-genotype activity, can be used in combination with DAAs from other classes, and are likely to be effective in people who have developed resistance to other DAA classes.
BMS’s first-in-class NS5a inhibitor demonstrated impressive potency after a single 100mg dose.
Longer-term data on this drug, although promising, are limited to 12 weeks.
Side effect profile is unclear so far, aside from reports of headache.
Table 5. NS5a Inhibitors in Development
| Non-nucleoside Polymerase Inhibitors |
| Agent/Sponsor | Status | Comments |
A-831
Arrows Therapeutics | Phase I |
|
BMS 790052
Bristol-Myers Squibb | Phase II; HCV genotype 1, treatment-naive and treatment-experienced | Studied in treatment-naive people (including people with cirrhosis) with SOC; also being studied in combination with BMS 650032 (protease inhibitor), plus or minus SOC, in null responders |
| BMS 824393 | Phase II (slated to open in July 2010); HCV genotype 1, treatment-naive | Study not open as of 4 August 2010 |
CF-102
CAN-FITE | Phase I/II; HCV genotype 1 | Also studied as a treatment for liver cancer |
PPI-461
Presidio | Phase I; healthy volunteers |
|
HCV antivirals
Several antiviral agents, including cyclophilin inhibitors, silymarin, an NS4b inhibitor, an HCV entry inhibitor, a serine C-palmitoyltransferase inhibitor, are in development; more detail is available in TAG’s upcoming Hepatitis C Pipeline Report.
Nitazoxanide
Nitazoxanide (Alinia®), was approved in 2002, to treat diarrhea from two intestinal parasites (Cryptosporidium parvum and Giardia lambia). Since then, it has been studied as a treatment for HCV genotypes 1 and 4 with SOC. Initially, nitazoxanide generated significant excitement, but SVR rates have been unimpressive so far, with the exception of a small Egyptian study in people with HCV genotype 4 (See Table 6: Nitazoxanide and SVR).
Nitazoxanide (NTZ) monotherapy is being studied to prevent post-transplant HCV recurrence, and in combination with SOC in HIV/HCV coinfected people who have genotype 1 and have never been treated for hepatitis C.
Table 6. Nitozoxanide and SVR
| Study | Population | SVR | Comments |
STEALTH C-1;
12 weeks of NTZ, followed by 36 weeks of SOC or 12 weeks of NTZ, followed by 36 weeks of peginterferon vs. SOC | HCV genotype 4 | 61% NTZ + PEG
79% NTZ + SOC
50% SOC | In genotype 4, SVR ranges from 43 to 70% with SOC |
STEALTH C-2;
4 weeks of NTZ or placebo, followed by 48 weeks of triple therapy (SOC+ NTZ or placebo) | HCV genotype 1, 80%
null responders and nonresponders | 7% (NTZ+ SOC) vs. 0%
(SOC + placebo) | Missing data on response to prior treatment in 20% |
STEALTH C-3
4 weeks of NTZ or placebo, followed by 48 weeks of triple therapy (SOC+ NTZ or placebo) | HCV genotype 1,
treatment -naive | 44% (NTZ + SOC) 32%
(placebo + SOC) |
|
Sources: Antaki 2009; Bacon 2010; Rossignol 2009; Shiffman 2010.
Novel interferons
Although the future of interferon is unclear, some sponsors have gambled on development of novel formulations. These novel formulations offer more convenient dosing, and—perhaps—fewer side effects. Development of delivery devices, such as external pumps or implants, is also underway.
Table 7. Novel Interferon Formulations in Development
| Agent/Sponsor | Status | Comments |
Albuferon/Zalbin/Joulferon
Human Genome Sciences/
Novartis | Phase III; HCV genotypes 1, 2, and 3, treatment-naive and treatment-experienced | Dosed every two weeks; efficacy equivalent to peginterferon. The future of albuferon is unclear; European regulatory authorities have delayed its approval, although FDA filing is expected in 2010 |
Locteron interferon
Biolex Therapeutics | Phase IIb; HCV genotype 1, treatment-naive | Dosed every two weeks; may have more favorable side effect profile than peginterferon |
PEG Interferon Lambda
(PEG-rIL-29)
Bristol-Myers Squibb/
ZymoGenetics | | Phase II; HCV genotypes 1, 2, 3, and 4, treatment-naive, with the exception of DAA monotherapy for 2 weeks | So far, side effect profile has been favorable; possibly because PEG-IFN Lambda binds to a unique receptor with less distribution throughout the body than the interferon alfa receptor |
Other strategies to stimulate and enhance HCV-specific immune responses are being explored, including therapeutic vaccines, monoclonal antibodies, toll-like receptor agonists and interleukin-7. More detail will be available in TAG’s upcoming Hepatitis C Pipeline Report.
TAG research recommendations
Study drugs in clinically relevant populations prior to approval, such as African Americans and Latinos/-as, people with cirrhosis, current and former injection drug users, people with a history of psychiatric disorders, and HIV/HCV coinfected persons.
Often, response rates from HCV clinical trials do not apply to “real-life” populations. HCV treatment safety, efficacy, and tolerability must be characterized in high-prevalence populations, particularly those less responsive to SOC; those at risk for rapid progression of liver disease; and those usually excluded from clinical trials. So far, enrollment of African Americans and Latinos/-as in HCV treatment trials has been disappointing, hovering at approximately 10% (Kwo 2009; McHutchison 2009).
TAG continues to track and document enrollment of African Americans and Latinos/-as in clinical trials, and pushes for sufficient enrollment of members of these populations in HCV clinical trials (Chou 2009).
Numerous studies have reported that drug users can be safely and effectively treated with SOC (Bruggmann 2008; Dore 2010; Harris 2010; Hellard 2009). Once they are given access to ongoing mental health care (including medication, if indicated), people with psychiatric disorders can be safely treated (Martin-Santos 2008; Schaefer 2003). Since depression, mood swings, hypomania, and mania are known side effects of interferon, it is sensible for clinical trials to offer a baseline psychiatric assessment, regular screening for neuropsychiatric side effects, and mental health care during clinical trials to avert treatment discontinuation.
TAG works with other activists, regulatory authorities, researchers, the pharmaceutical industry, harm reduction organisations, and clinicians to advocate for trials in representative populations.
HIV accelerates HCV progression, and SOC is less effective for coinfected people than those with HCV monoinfection (see Table 1:HCV Treatment Outcomes, by Population – printed online and in full PDF report). Hepatitis C–associated end-stage liver disease has become a leading cause of death among HIV-positive people in the United States and Western Europe, where HIV treatment is widely available (Weber 2006). Drug interactions between DAAs and HIV drugs may limit use of specific drugs in coinfected people; this must be fully characterised early in development to facilitate HCV treatment trials—and ultimately-safe and effective use of DAAs in coinfected people.
TAG has co-organised three multi-stakeholder meetings on HCV drug development for HIV/HCV coinfected people with the European AIDS Community Advisory Board (ECAB). These meetings paved the way for preapproval HCV treatment trials in HIV/HCV coinfected people by asking that “Trials of novel HCV therapies in HIV/HCV coinfected people should begin before approval is granted for their use in HCV monoinfection, once results from Phase 2B studies are known, and there are indications from earlier toxicology, pharmacokinetic and drug-drug interaction studies that the specific agent, or agents under investigation will not have the potential for significant dru-drug interactions, or other toxicities relevant to HIV.” (Sitges Declaration 2007).
TAG has co-organized three multi-stakeholder meetings on HCV drug development for HIV/HCV coinfected people with the European AIDS Community Advisory Board (ECAB). These meetings paved the way for preapproval HCV treatment trials in HIV/HCV coinfected people by asking that “Trials of novel HCV therapies in HIV/HCV coinfected people should begin before approval is granted for their use in HCV monoinfection, once results from Phase 2B studies are known, and there are indications from earlier toxicology, pharmacokinetic and drug-drug interaction studies that the specific agent, or agents under investigation will not have the potential for significant drug-drug interactions, or other toxicities relevant to HIV.” (Sitges Declaration, 2007). The consensus built at these meetings and continuing pressure from activists has paid off: HCV treatment trials in HIV/HCV coinfected people are now being launched in parallel with phase III. Trials of boceprevir and telaprevir in HIV/HCV coinfected people are underway.
Develop mechanisms to provide early access to DAA combination therapy for people who are ineligible for clinical trials, and cannot wait for their approval.
It is unacceptable that people with the most urgent need lack access to potentially life-saving therapies. Although preapproval access to single or multiple DAAs poses medical, administrative, and regulatory challenges, it has been accomplished in HIV and is certainly feasible for HCV. Regulators, industry, physicians, and community members need to address and surmount barriers to early access.
In Spring 2010, TAG asked regulators and sponsors attending an FDA meeting on preapproval access to DAAs to develop a framework so that sponsors could provide potentially life-saving drugs to high-risk populations without endangering drug development programs.
Study drugs in liver transplant candidates and recipients as soon as it is safe to do so.
Hepatitis C is the leading indication for liver transplantation, accounting for more than 35% of all liver transplants in the United States (Thuluvath 2010). Survival after transplantation is significantly worsened by recurrent HCV, which is difficult to treat; SOC is often ineffective in or intolerable for transplant candidates and recipients (see Table 1: HCV Treatment Outcomes, by Population).
Despite their desperate need for better HCV treatment, clinical trials of new HCV drugs in transplant candidates and recipients are generally last on the list, lagging until drugs have already been approved. HCV clinical trials in transplant candidates and recipients should be launched prior to approval, and should allow use of other experimental agents—an approach used successfully in HIV research.
Clear regulatory guidance is needed to prod sponsors into launching studies in transplant candidates and recipients, as well as in other high-risk populations. For example, panelists at a 2006 FDA meeting on development of novel agents for HCV treatment recommended that “approval of an effective agent in compensated subjects should not be adversely affected by poor outcomes observed in separate studies of decompensated liver disease” (Sherman 2007).
TAG continues to work with patients, activist groups, academic, and community-based researchers, regulatory agencies, and the pharmaceutical industry to ensure that new HCV drugs and treatment strategies are studied in people with the greatest need, as soon as it is safe to do so.
In addition, TAG advocates for:
- Prioritizing access to single or multiple DAAs for trial participants in the control arm of clinical trials, and those who did not achieve SVR. Crossover or rollover study designs provide access to an experimental drug for people in the control arm. This approach should be broadened to include study participants unsuccessfully treated with single or multiple DAAs, providing that virtual monotherapy (a multidrug regimen containing only one active agent) can be avoided. A cross-company registry of treatment-experienced trial participants should be established, and these participants should be prioritized for enrollment into trials of DAAs from novel classes.
- Continued characterization of resistance to all classes of DAAs. Further characterization of resistance mutations is needed to optimize HCV treatment with DAAs, although the clinical utility of resistance testing is not clear at present. Further assessment of clinical implications of HCV drug resistance is needed. One way to assess the impact of drug resistance would be to retreat people who acquired drug resistance in monotherapy trials with the same drug, plus SOC.
- Development of second- and third-line drugs effective against commonly occurring resistance mutations. Adding a single DAA increases the likelihood of SVR for treatment-experienced people, but is not 100% effective. In fact, ~60% of prior nonresponders did not achieve SVR after retreatment with telaprevir plus SOC in Vertex’s PROVE-3 trial (McHutchison 2010). Thus, an increasing population of people resistant to at least one drug, or one class of drugs, is likely. Cross-resistance to HCV protease inhibitors has already been reported. Sponsors should prioritize drugs with a unique resistance profile and a high genetic barrier over “me-too” drugs.
- Development of drugs with activity against all HCV genotypes. There are at least six HCV genotypes. Most new HCV drugs were designed to be effective against HCV genotype 1, because it is difficult to cure with peginterferon and ribavirin, and it is predominant in the United States, Western Europe, and Japan (major pharmaceutical markets). But some people, such as current and former injection drug users and recipients of blood and blood products in the early to mid-1980s, are infected with more than one HCV genotype, and may require drugs with cross-genotype coverage (Preston.1995; Silva 2010).
As more people with genotype 1 are cured, and immigration patterns shift, global distribution of HCV genotypes will change. It will not be possible to eradicate HCV without safe and effective drugs for all genotypes.
- Full characterization of predictors and indicators of response and nonresponse to HCV treatment across populations. Stopping rules may change as HCV treatment evolves. Reliable predictors of response will motivate people to continue their HCV treatment, and facilitate reimbursement for response-guided therapy. In turn, accurate indicators of nonresponse will lower the risk of resistance, spare people from side effects, and save money.
- Establishment of a system for HCV treatment strategy trials, to facilitate cross-company collaboration. It is time to scale up HCV research. The opportunity to address key clinical questions in the next five to seven years must not be squandered. Sponsors prioritize getting their drugs to market, and the current landscape is highly competitive. But HCV treatment is complex, and a dedicated research network could advance crucial areas—exploration of multi-experimental agent trials, population-specific questions, and development of treatment strategies—that are likely to languish without a public/private research network. This has been a fruitful approach in HIV disease, where policy makers have allocated funds and sponsors have contributed drugs and diagnostics.
In the meantime, regulators, researchers, sponsors, and community members need to continue the dialogue on launching cross-company collaborations.
- Studying DAAs for HCV Prophylaxis. There is no postexposure prophylactic strategy for hepatitis C, regardless of exposure type. HCV transmission from occupational exposures ranges from 0.2% to 10% (Corey 2009). Clearly, research on efficacy of DAAs for postexposure prophylaxis for occupational and nonoccupational exposures is warranted.
TAG works with activist partners domestically and internationally to advocate for access to HCV treatment for all who need it.
Additional resources
Information about clinical trials is available at:
http://www.clinicaltrials.gov (accessed 4 June 2010).
HCV Advocate offers conference reporting, news, fact sheets, an up-to-date HCV pipeline chart, and other resources at
http://www.hcvadvocate.org (accessed on 6th June 2010).
HIVandHepatitis.com provides news and conference reports at
http://www.hivandhepatitis.com (accessed 6 June 2010).
The National AIDS Treatment Advocacy Project provides comprehensive coverage of HCV, HIV, and HBV research, access, treatment, and policy issues at
http://www.natap.org (accessed 6 June 2010).
References
Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(1 Suppl):S6-9.
Antaki N, Craxi A, Kamal S, et al. The neglected hepatitis C virus genotypes 4, 5 and 6: An international consensus report. Liver Int. 2010 Mar;30(3):342-55.
Bacon BR, Shiffman ML, Lim JK, et al. (Abstract 711b.) Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in naive patients with chronic hepatitis C genotype 1 infection: Final report. Paper presented at the conference Digestive Disease Week, New Orleans, 1–5 May 2010.
Berg C, Goncales FL Jr, Bernstein DE, et al. Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin. J Viral Hepat. 2006 Jul;13(7):435-40.
Berg T, Mc Hutchison JG, Adda N, et al. (Abstract.) SVR with telaprevir, peginterferon-alfa2a and ribavirin in HCV patients with well-characterized prior null response, partial response, viral breakthrough or relapse after PR: Rollover study 107. Paper presented at 45th Annual Meeting of the European Association for the Study of the Liver, Vienna, 14–18 April 2010 .
Borroni G, Andreoletti M, Casiraghi MA, et al. Effectiveness of pegylated interferon/ribavirin combination in ‘real world’ patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2008 May;27(9):790-7.
Bruggmann P, Falcato L, Dober S, et al., Swiss Hepatitis C Cohort Study. Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients. J Viral Hepat. 2008;15(10):747–52.
Butt AA, McGinnis KA, Skanderson M, Justice AC. Hepatitis C treatment completion rates in routine clinical care. Liver Int. 2010 Feb;30(2):240-5.
Carrat F, Bani-Sadr F, Pol S, et al., ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA 2004; 292(23):2839–48.
Chung RT, Andersen J, Volberding P, et al, AIDS Clinical Trials Group A5071 Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004; 351(5):451–59.
Clifford GM, Rickenbach M, Polesel J, et al, Swiss HIV Cohort. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS 2008;22(16):2135–41.
Chou L, Swan T. (abstract 51) Do the right thing: Eliminating racial disparities in viral hepatitis drug development. Global Antiviral Journal. Volume 5, S1. December 2009.
Conjeevaram HS, Fried MW, Jeffers LJ, et al; Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006 Aug;131(2):470-7.
Corey KE, Servoss JC, Casson DR, et al. Pilot study of postexposure prophylaxis for hepatitis C virus in healthcare workers. Infect Control Hosp Epidemiol. 2009;30(10):1000–1005.
Datamonitor. Hepatitis C Market Forecast. January 2009.
Di Marco V, Almasio PL, Ferraro D, et al. Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol. 2007 Oct;47(4):484-91.
Dore GJ, Hellard M, Matthews GV, et al., Australian Trial in Acute Hepatitis C Study Group. Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. Gastroenterology 2010;138(1):123–35.e1–2.
Dryer PD, Limketkai BN, Martin CM, et al. Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women. J Antimicrob Chemother. 2009 Nov;64(5):94
Evon DM, Ramcharran D, Belle SH, Terrault NA, Fontana RJ, Fried MW, Virahep-C Study Group. Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: Results of the Virahep-C study. Am J Gastroenterol. 2009;104(12):2949–58.
Feuerstadt P, Bunim AL, Garcia H, et al. Effectiveness of hepatitis C treatment with pegylated interferon and ribavirin in urban minority patients. Hepatology. 2010 Apr;51(4):1137-43.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347(13):975-82.
Gheorghe L, Iacob S, Sporea I, et al. Efficacy, tolerability and predictive factors for early and sustained virologic response in patients treated with weight-based dosing regimen of PegIFN alpha-2b ribavirin in real-life healthcare setting. Gastrointestin Liver Dis. 2007 Mar;16(1):23-9.
Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: A meta-analysis. Clin Infect Dis. 2001;33(4):562–69.
Hanouneh IA, Miller C, Aucejo F, Lopez R, Quinn MK, Zein NN. Recurrent hepatitis C after liver transplantation: on-treatment prediction of response to peginterferon/ribavirin therapy. Liver Transpl. 2008 Jan;14(1):53-8.
Harris KA, Arnsten JH, Litwin AH. Successful integration of hepatitis C evaluation and treatment services with methadone maintenance. J Addict Med. 2010;4(1):20–26.
Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: A review of the available evidence. Clin Infect Dis. 2009;49(4):561–73.
Iacobellis A, Siciliano M, Perri F, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study. J Hepatol. 2007 Feb;46(2):206-12.
Iacobellis A, Siciliano M, Annicchiarico BE, et al. Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients. Aliment Pharmacol Ther. 2009 Jul 1;30(2):146-53.
Jacobson IM, Brown RS Jr, McCone J, et al; WIN-R Study Group. Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1. Hepatology. 2007 Oct;46(4):982-90.
Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004 Jun;39(6):1702-8.
Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology 2008;48(6):1769–78.
Kwo P, Lawitz E McCone C, et al. (Abstract 4.) HCV SPRINT-1 final results: SVR 24 from a phase 2 study of boceprevir plus PegIFN alpha-2b/ribavirin in treatment-naive subjects with genotype-1 chronic HCV. 44th Annual Meeting of the European Association for the Study of the Liver, Copenhagen, 22–26 April 2009.
Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004 Sep 3;18(13):F27-36.
Lee SS, Bain VG, Peltekian K, et al; CANADIAN PEGASYS STUDY GROUP. Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice. Aliment Pharmacol Ther. 2006 Feb 1;23(3):397-408.
Legrand-Abravanel F, Henquell C, Le Guillou-Guillemette H, et al. Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1–5. Antivir Ther. 2009;14(5):723–30.
Liu CH, Liu CJ, Lin CL, et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis. 2008 Nov 15;47(10):1260-9.
Lodato F, Berardi S, Gramenzi A, et al Bologna Liver Transplantation Group (BLTG). Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation. Aliment Pharmacol Ther. 2008 Aug 15;28(4):450-7.
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 Sep 22;358(9286):958-65.
Marcellin P, Forns X, Goeser T, et al. (abstract 194) Virological analysis of patients receiving telaprevir administered q8h or q12h with peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis C: study C208. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. 30 October-1 November, 2009.
Martín-Santos R, Díez-Quevedo C, Castellví P, et al. De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C. Aliment Pharmacol Ther. 2008;27(3):257–65.
McHutchison J, Manns MP, Muir AJ, et al., PROVE 3 Study Team. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292–303.
McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.
Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004 May 27;350(22):2265-7.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38.
Preston FE, Jarvis LM, Makris M, et al. Heterogeneity of hepatitis C virus genotypes in hemophilia: Relationship with chronic liver disease. Blood 1995;85(5):1259–62.
Rodriguez-Torres M, Jeffers LJ, Sheikh MY, et al; Latino Study Group. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med. 2009 Jan 15;360(3):257-67.
Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009;136(3):856–62.
Sagir A, Heintges T, Akyazi Z, Oette M, Erhardt A, Häussinger D. Relapse to prior therapy is the most important factor for the retreatment response in patients with chronic hepatitis C virus infection. Liver Int. 2007 Sep;27(7):954-9.
Satapathy SK, Lingisetty CS, Proper S, Chaudhari S, Williams S. Equally poor outcomes to pegylated interferon-based therapy in African Americans and Hispanics with chronic hepatitis C infection. J Clin Gastroenterol. 2010 Feb;44(2):140-5.
Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003;37(2):443–51.
Scotto G, Fazio V, Fornabaio C, et al. Early and sustained virological response in non-responders with chronic hepatitis C: a randomized open-label study of pegylated interferon-alpha-2a versus pegylated interferon-alpha-2b. Drugs. 2008;68(6):791-801.
Sherman KE, Fleischer R, Laessig K, Murray J, Tauber W, Birnkrant D, FDA Antiviral Products Advisory Committee. Development of novel agents for the treatment of chronic hepatitis C infection: Summary of the FDA Antiviral Products Advisory Committee recommendations. Hepatology 2007;46(6):2014–20.
Shiffman ML, Ahmed A, Jacobson IM, Pruitt RE, Keeffe EB. (Abstract 296 LB.) Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide with peginterferon alfa-2a and ribavirin in nonresponders (NR) with chronic hepatitis C genotype 1: Final report. Paper presented at the 45th Annual Meeting of the European Association for the Study of the Liver, Vienna, 14–18 April 2010.
Silva MB, Andrade TM, Silva LK, et al. Prevalence and genotypes of hepatitis C virus among injecting drug users from Salvador-BA, Brazil. Mem Inst Oswaldo Cruz. 2010;105(3):299–303.
Sitges Statement. 2007. http://www.eatg.org/eatg/ECAB/Conferences/Brussels-I-Sitges-III-Nov-20-Brussels. Accessed 16 June 2010.
Srivastava S, Bertagnolli M, Lewis JH. Sustained virological response rate to pegylated interferon plus ribavirin for chronic hepatitis C in African Americans: results in treatment-naïve patients in a university liver clinic. J Natl Med Assoc. 2005 Dec;97(12):1703-7.
Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, 1999–2008. Am J Transplant. 2010;10(4, pt 2):1003–19.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al., APRICOT Study Group. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351(5):438–50.
Vertex Pharmaceuticals. Press release. 25 May 2010.
Weber R, Sabin CA, Friis-Møller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: The D:A:D Study. Arch Intern Med. 2006;166(15):1632–41.
World Health Organization, Initiative for Vaccine Research. Viral Cancers, Hepatitis C. 2009. http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html. Accessed 5 June 2010.
World Hepatitis Alliance. Viral Hepatitis Global Policy. 2010. http://www.worldhepatitisalliance.org/en/Policy/2010PolicyReport.aspx. Accessed 6 June 2010.
Yoshida EM, Sherman M, Bain VG, et al; Pegasys Study Group. Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy. Can J Gastroenterol. 2009 Mar;23(3):180-4.
Yu S, Douglass JM, Qualls C, Arora S, Dunkelberg JC.Response to therapy with pegylated interferon and ribavirin for chronic hepatitis C in hispanics compared to non-Hispanic whites. Am J Gastroenterol. 2009 Jul;104(7):1686-92.
Zimmermann T, Böcher WO, Biesterfeld S, et al. Efficacy of an escalating dose regimen of pegylated interferon alpha-2a plus ribavirin in the early phase of HCV reinfection after liver transplantation. Transpl Int. 2007 Jul;20(7):583-90.
