HCV protease inhibitors share metabolic pathways with medications that are commonly used by people with hepatitis C. Drug-drug interactions can lead to drug resistance and HCV treatment failure when levels of an HCV protease inhibitor are too low, or worsen side effects when they are too high. In turn, HCV protease inhibitors may decrease levels of other drugs to sub-therapeutic levels, or increase them to toxic levels.
Interactions between antiretroviral agents and DAAs complicate HIV treatment; a single drug or entire regimen may need to be switched before initiating hepatitis C treatment. This is tricky, because HIV/HCV coinfected people have limited options for treating their HIV while on HCV treatment; in the ongoing telaprevir coinfection trial, participants could either use an efavirenz-based regimen (with a higher dose of telaprevir) or a boosted atazanavir-based regimen (other HIV protease inhibitors cannot be used with telaprevir, due to significant drug-drug interactions).6 Unfortunately, data on boceprevir drug-drug interactions are limited to efavirenz (which lowers boceprevir levels) and tenofovir.7
Since hepatitis C is highly prevalent among current and former injection drug users, drug-drug interaction studies with DAAs and opioid substitution therapy (OST) must be a priority. If DAAs are used in people on OST without this information, a range of consequences may occur, including HCV drug resistance and treatment failure, drug overdose, or withdrawal symptoms. So far, it has been established that telaprevir reduces methadone levels; although dose adjustment may not be needed, clinical monitoring is recommended. A drug-drug interaction study of telaprevir and buprenorphine is underway. Unfortunately, there are no drug-drug interaction data on methadone and buprenorphine for boceprevir, save the warning in the label, which reads "Plasma concentrations of methadone or buprenorphine may increase or decrease when coadministered with VICTRELIS [boceprevir's brand name]. However, the combination has not been studied. Clinical monitoring is recommended as the dose of methadone or burenorphine may need to be altered during concomitant treatment with VICTRELIS."
|Are You Experienced?|
The FDA has categorized treatment-experienced people into three groups:
Responder-Relapser: HCV RNA undetectable at end of treatment with peginterferon and ribavirin, but HCV RNA detectable within 24 weeks of treatment follow-up.
Partial Responder: greater than or equal to 2 log10 (99%) reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment with peg-interferon and ribavirin.
Null Responder: less than 2 log10 (99%) reduction in HCV RNA at week 12 of treatment with peginterferon and ribavirin.
People who could not tolerate treatment or do not know their prior response are not included; nor are people who experienced viral breakthrough during treatment.
There are dozens of HCV clinical trials underway, but most are for treatment-naive participants. Of the nine phase II/III HCV protease inhibitor trials, six are open to treatment-experienced participants (some may be limited to responder-relapsers and partial responders). Current phase II polymerase and NS5a inhibitor trials offer few options: treatment-experienced participants are eligible for only one of three NS5a inhibitor trials, one of two nucleoside/nucleotide polymerase inhibitor trials, and one of seven non-nucleoside polymerase inhibitor trials.
At present, an estimated 750,000 people in the United States (and thousands more in Western Europe) have been unsuccessfully treated for hepatitis C. Treatmentexperienced patients are likely to be first in line for treatment with new HCV drugs; financial experts project that by 2013 they will comprise at least two-thirds of the market share for DAAs. The population of treatment-experienced people is large, and will continue to grow once the first generation of hepatitis C protease inhibitors have been widely used. More trials exploring DAA combinations and treatment strategies are needed for treatment-experienced people.
Multi-DAA/quad therapy trials will help to clarify the best approach based on HCV subtype, treatment history and other factors. Abbott, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Genentech, Gilead, Merck, Pharmasset, and Vertex have opened in-house combination trials.
A single company may not have all of the most exciting drugs, so cross-company clinical collaborations are needed to optimize HCV treatment. BMS and Pharmasset, who have very exciting DAA candidates, launched the first cross company clinical collaboration; in May of 2011, they announced a peginterferon-sparing trial combining BMS's NS5a inhibitors with one of Pharmasset's nucleotide polymerase inhibitors (PSI-7977), with or without ribavirin.
In July 2011, Pharmasset announced another clinical collaboration with Tibotec/Medivir, pairing PSI-7977 (its nucleotide analog) with TMC435 (a protease inhibitor), with and without ribavirin in a phase II trial of prior null responders with HCV genotype 1. The trial will be launched in the third or fourth quarter of 2011. These joint ventures are crucial for identifying best-in-class regimens and optimizing HCV treatment.
Improvements in HCV treatment (such as response-guided therapy and drug- and patient specific treatment algorithms) bring a new level of complexity to clinical care, making it unappealing to inexperienced providers. During FDA approval hearings for boceprevir and telaprevir, an antiviral advisory committee member remarked that the amount of knowledge required to treat HCV approaches the complexity-if not the wisdom-of a Talmudic scholar. Complexity brings consequences, such as greater potential for errors in prescribing and administering treatment, higher dropout rates from poorly managed side effects, and increased risk for drug resistance and treatment failure.
Clinicians and their patients will have a choice between boceprevir and telaprevirbased treatment. Although they are in the same class, these drugs are used differently. Boceprevir requires a four-week "lead-in" with peginterferon and ribavirin to lower ontreatment failure and relapse rates; telaprevir is initiated along with peginterferon and ribavirin. With each drug, there may be a peginterferon and ribavirin "tail" after triple therapy, lasting 12 to 36 weeks.
Telaprevir offers treatment-naive patients a less complex treatment algorithm, higher cure rates, and a better chance to shorten treatment than boceprevir, but tolerability may be an issue. More than half of the participants in all phase III trials were afflicted with rash (versus 32% for PEG/RBV alone). Although most cases were mild-to-moderate, 1% suffered severe rash, and a subset of these cases (<1%) experienced Stevens Johnson Syndrome (SJS, a rare, life-threatening reaction to a medication or infection) or Drug-Related Eruption with Systemic Symptoms (DRESS, another severe drug reaction).
Boceprevir worsens the hemotologic side effects of peginterferon and ribavirin, especially anemia. During phase III trials, more than 40% of participants in the boceprevir arms were treated with epoetin alfa, a red blood growth cell factor.3,8 Red blood cell growth factors carry a warning about increased mortality, serious cardiovascular and thromboembolic events, stroke and risk of tumor progression or recurrence in cancer patients. They are also expensive, adding at least $500 per week to the cost of HCV treatment. Anemia can also be managed by reducing the dose of ribavirin, but this strategy may reduce treatment efficacy; an ongoing trial of boceprevir-based treatment is comparing ribavirin dose reduction to epoetin alfa use.
|Table 2. Translating Trial Results Into Clinical Practice: Boceprevir and Telaprevir in Treatment-Naive Persons
||Characteristic||Boceprevir||Telaprevir||Lead-in||Yes; 4 weeks of PEG/RBV||No||Dosing||750 mg, every 7-9 hours, with food (meal or light snack); 12 pills/day||800 mg, every 7-9 hours with food (not-low fat); 6 pills/day.||Treatment duration||28-48 weeks||24-48 weeks||Eligible for 24-28 weeks of treatment||44%||58-60%||Adverse events||Anemia, neutropenia, thrombocytopenia, dysgeusia, dry mouth, vomiting and diarrhea||Mild to severe rash, itching, anemia, ano-rectal itching and burning, hemorrhoids, elevated bilirubin and uric acid, gout, thrombocytopenia and gastrointestinal events||Discontinuation for adverse events||14%||10-19%||SVR, overall||63-66%||72-79%||Relapse rate||9%||9%||SVR, African Americans||42-53% (~14% of participants)||65% (range: 50-94%) (~10% of participants)||SVR, Latinos/Latinas||Data not provided||79% (range: 70-94%) (~10% of participants)||SVR, bridging fibrosis or cirrhosis||41-52% (~11% of participants)||53-88% (~8% of study participants)||SVR, people on methadone maintenance||No data||33% (only 11 patients in phase III trials)||SVR, HIV/HCV coinfected people||Ongoing pilot studies; data are not yet available. Drug-drug interactions with HIV protease inhibitors and non-nucleosides; coadministration not recommended (except efavirenz)||Ongoing pilot study; data are not yet available. Cannot be used with boosted darunavir, fosamprenavir, and lopinavir; tenofovir levels are increased; monitoring recommended.||Use in hepatic and renal impairment||No dose adjustment required for mild, moderate and severe hepatic impairment; no data in decompensated cirrhosis; no dose adjustment required for renal impairment||Should not be used in people with moderate to serious hepatic impairment, since drug exposure is reduced; exposure increased in renal impairment; analysis of single-dose study underway to see if dose adjustment or multiple dose study is required||Drug-drug interactions||An extensive list is available in the prescribing information (accessed May 14, 2011)||An extensive list is available in the prescribing information (accessed May 25, 2011)||Early access trials||None||None|
Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir in combination with peginterferon alfa-2a and ribavirin in genotype 1 HCV treatment naive patients: final results of phase III ADVANCE study. [abstract LB-2] 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. October 29-November 2, 2010. Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1195-206.
Sherman KE, Flamm SL, Afdhal NH, et al; ILLUMINATE Study Team. Telaprevir in combination with peginterferon alfa-2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response; final results of phase III ILLUMINATE study. (Abstract LB-1) 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. October 29 - November 2, 2010.
Source: Prescribing information for boceprevir. (Accessed May 25, 2011.)
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