Telaprevir Monotherapy Induces Rapid Resistance
BOSTON, Nov. 1 -- Apparently telaprevir (VX-950) needed a little help to be effective against hepatitis C virus.
Drug-resistant viral strains developed rapidly when exposed to telaprevir, the investigational protease inhibitor against HCV, but both wild-type virus and mutants were controlled by follow-on therapy with interferon and Rebetol, researchers reported here.
In a phase Ib trial of telaprevir, also known as VX-950, drug resistant viral strains cropped up in six of eights patients within two weeks of starting on monotherapy with the protease inhibitor.
But both these new strains and wild-type virus were significantly suppressed when the patients received follow-on combination of Pegasys (pegylated interferon α-2a) and Rebetol (ribavirin), reported Tara Kieffer, Ph.D., of Vertex Pharmaceuticals. and colleagues, at the American Association for the Study of Liver Diseases meeting here.
The findings suggest that as with protease inhibitors for HIV infection, protease inhibitors against HCV are likely to be used as just one element in a cocktail of therapies aimed at knocking down virus while preventing the development of drug-resistant virus.
"In all patients, we have observed that telaprevir has demonstrated a rapid and profound reduction in HCV RNA," said Dr. Keefer. "In a subset of patients dosed with telaprevir alone we did see a clinical breakthrough associated with resistant variants. However, these variants were suppressed in all patients after they began interferon and ribavirin follow-on therapy."
No clinical breakthroughs were seen in patients who were initiated on telaprevir and interferon, including those in whom resistant variants were detected using a sensitive detection method, she noted.
The investigators used a highly sensitive sequencing assay to detect minor populations of viral variants (≥ 5%) in 14 patients. They isolated plasma HCV RNA was isolated at days four, eight, 12, and 14 during dosing, and at days seven and 10 after the end of the dosing phase. The NS3 protease domain cDNA targeted by telaprevir was amplified by nested polymerase chain reaction, cloned and sequenced with a lower limit of detection of 100 IU/mL. Sequence changes were analyzed from about 75 clones per patient per time point.
They found that in patients initially dosed with telaprevir/Pegasys, wild-type virus was detected at day four. On day eight, either wild-type or resistant virus was seen on in four of eight patients with HCV RNA levels above the lower limit of detection. All eight of these patients began standard therapy with Pegasys/Rebetol and their HCV RNA levels were undetectable three months after the 14-day study period, the authors reported.
All eight patients had undetectable HCV RNA at 24 weeks of follow-on treatment. Six of these patients stopped therapy at 24 weeks, and five of the six had undetectable HCV RNA at 12 weeks post-treatment. Two of the six eventually resumed follow-on therapy out to 48 weeks.
Only one of four patients initially treated with Pegasys alone had undetectable RNA at 12 weeks, while three of four had no discernible RNA at 24 weeks.
In a separate study presented in a poster session, Maribel Rodriguez-Torres, M.D., of the Fundacion de Investigacion de Diego in Puerto Rico reported on the status of 12 patients who were originally enrolled in a 28-day trial of telaprevir, Pegasys, and Rebetol.
At the end of 24 weeks of follow-on with Pegasys/Rebetol, eight patients who were continuing on the follow-on treatment had undetectable HCV RNA. These patients continue to receive the drugs out to 36 weeks of follow-on therapy.
One patient stopped treatment at week 18 and had no detectable HCV RNA six weeks after stopping therapy.
Two other patients had detectable HCV RNA and stopped treatment at week 24 of follow-on therapy. In these patients, viral sequencing analyses at week 24 showed predominantly wild-type virus, with a minority population of R155K variants also detected.
The remaining patient had undetectable HCV RNA at week 12, but had been lost to follow-up by week 18 of follow-on therapy, Dr. Rodriguez-Torres reported.
Dr. Kieffer is an employee of Vertex and owns company stock. Dr. Rodriguez-Torres receives grant support from the company.
Drug-resistant viral strains developed rapidly when exposed to telaprevir, the investigational protease inhibitor against HCV, but both wild-type virus and mutants were controlled by follow-on therapy with interferon and Rebetol, researchers reported here.
Action Points
* Explain to patients who ask about telaprevir/VX-950 monotherapy that as with therapy for HIV/AIDS, antiviral drugs used alone often promote the rapid development of drug-resistant viral strains. This study shows that for patients treated with an investigational protease inhibitor against hepatitis C, follow-on with interferon and Rebetol (ribavirin) helped to suppress both wild-type and drug-resistant viral clones.
* These studies were published as abstracts and presented orally and as a poster at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
In a phase Ib trial of telaprevir, also known as VX-950, drug resistant viral strains cropped up in six of eights patients within two weeks of starting on monotherapy with the protease inhibitor.
But both these new strains and wild-type virus were significantly suppressed when the patients received follow-on combination of Pegasys (pegylated interferon α-2a) and Rebetol (ribavirin), reported Tara Kieffer, Ph.D., of Vertex Pharmaceuticals. and colleagues, at the American Association for the Study of Liver Diseases meeting here.
The findings suggest that as with protease inhibitors for HIV infection, protease inhibitors against HCV are likely to be used as just one element in a cocktail of therapies aimed at knocking down virus while preventing the development of drug-resistant virus.
"In all patients, we have observed that telaprevir has demonstrated a rapid and profound reduction in HCV RNA," said Dr. Keefer. "In a subset of patients dosed with telaprevir alone we did see a clinical breakthrough associated with resistant variants. However, these variants were suppressed in all patients after they began interferon and ribavirin follow-on therapy."
No clinical breakthroughs were seen in patients who were initiated on telaprevir and interferon, including those in whom resistant variants were detected using a sensitive detection method, she noted.
The investigators used a highly sensitive sequencing assay to detect minor populations of viral variants (≥ 5%) in 14 patients. They isolated plasma HCV RNA was isolated at days four, eight, 12, and 14 during dosing, and at days seven and 10 after the end of the dosing phase. The NS3 protease domain cDNA targeted by telaprevir was amplified by nested polymerase chain reaction, cloned and sequenced with a lower limit of detection of 100 IU/mL. Sequence changes were analyzed from about 75 clones per patient per time point.
They found that in patients initially dosed with telaprevir/Pegasys, wild-type virus was detected at day four. On day eight, either wild-type or resistant virus was seen on in four of eight patients with HCV RNA levels above the lower limit of detection. All eight of these patients began standard therapy with Pegasys/Rebetol and their HCV RNA levels were undetectable three months after the 14-day study period, the authors reported.
All eight patients had undetectable HCV RNA at 24 weeks of follow-on treatment. Six of these patients stopped therapy at 24 weeks, and five of the six had undetectable HCV RNA at 12 weeks post-treatment. Two of the six eventually resumed follow-on therapy out to 48 weeks.
Only one of four patients initially treated with Pegasys alone had undetectable RNA at 12 weeks, while three of four had no discernible RNA at 24 weeks.
In a separate study presented in a poster session, Maribel Rodriguez-Torres, M.D., of the Fundacion de Investigacion de Diego in Puerto Rico reported on the status of 12 patients who were originally enrolled in a 28-day trial of telaprevir, Pegasys, and Rebetol.
At the end of 24 weeks of follow-on with Pegasys/Rebetol, eight patients who were continuing on the follow-on treatment had undetectable HCV RNA. These patients continue to receive the drugs out to 36 weeks of follow-on therapy.
One patient stopped treatment at week 18 and had no detectable HCV RNA six weeks after stopping therapy.
Two other patients had detectable HCV RNA and stopped treatment at week 24 of follow-on therapy. In these patients, viral sequencing analyses at week 24 showed predominantly wild-type virus, with a minority population of R155K variants also detected.
The remaining patient had undetectable HCV RNA at week 12, but had been lost to follow-up by week 18 of follow-on therapy, Dr. Rodriguez-Torres reported.
Dr. Kieffer is an employee of Vertex and owns company stock. Dr. Rodriguez-Torres receives grant support from the company.