Telaprevir Improves Treatment Outcomes for HIV/HCV Coinfected People

	SUMMARY: The experimental hepatitis C virus (HCV) protease inhibitor telaprevir, combined with pegyalted interferon plus ribavirin, reduced HCV viral load to undetectable levels in about 70% of HIV positive patients at weeks 4 and 12 in the first study of the drug in HIV/HCV coinfected people. Based on these eagerly awaited Phase 2 results, presented this week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston, Vertex Pharmaceuticals plans to start a Phase 3 coinfection study later this year.

By Liz Highleyman

David Thomas, Stefan Zeuzem, and Mark Sulkowski (Photo: Liz Highleyman)

HIV positive people coinfected with HCV tend to experience more rapid liver disease progression than individuals with hepatitis C alone. Furthermore, some studies -- though not all -- suggest that HIV/HCV coinfected patients do not respond as well to standard therapy consisting of pegylated interferon plus ribavirin.

Mark Sulkowski from Johns Hopkins University and colleagues reported interim results from Study 110, a Phase 2 clinical trial comparing telaprevir vs placebo combined with standard therapy in HIV/HCV coinfected participants not previously treated for chronic hepatitis C.

The study was divided into 2 parts. Part A included 13 coinfected patients with CD4 T-cell counts >500 cells/mm3 who were not yet taking antiretroviral therapy (ART) but had HIV viral loads <100,000 copies/mL. Part B included 46 coinfected patients with CD4 counts >300 cells/mm3 and undetectable HIV RNA (< 50 copies/mL) on 1 of 2 ART regimens:

	Efavirenz plus tenofovir plus emtricitabine (the drugs in the Atripla pill)
	Atazanavir (Reyataz) plus tenofovir plus either emtricitabine (Emtriva) or lamivudine (Epivir).

As described in another CROI presentation, pharmacokinetic studies of healthy HIV and HCV negative volunteers showed that telaprevir has modest drug-drug interactions with several antiretroviral agents including lopinavir/ritonavir (Kaletra), darunavir (Prezista), and fosamprenavir (Lexiva). Based on these findings, efavirenz (Sustiva) and atazanavir were judged to be the most suitable HIV drugs for use with telaprevir. Efavirenz lowers telaprevir blood levels, but raising the telaprevir dose can compensate for this effect. No dose adjustment was considered necessary with atazanavir.

In both parts of the study participants who were randomly assigned to the active drug arm received telaprevir 3 times daily plus 180 mcg/week pegyalted interferon alpha 2a (Pegasys) plus either 800 mg/day or weight-based ribavirin for 12 weeks, followed by pegyalted interferon/ribavirin alone through week 48. Patients taking atazanavir received the usual 750 mg telaprevir dose, while those on efavirenz received a higher 1125 mg dose. People assigned to the control arm received standard-of-care therapy using pegyalted interferon/ribavirin for 48 weeks, with a placebo substituting for telaprevir during the first 12 weeks.

Most study participants were men, with an average age of 46 years. More than half of patients in Part A were black (a population that does not respond as well to interferon-based therapy), but this fell to less than one-third in Part B. Most patients had high HCV viral load and about 10% had bridging fibrosis or cirrhosis, 2 other predictors of poor treatment response.

Results

	In an overall intention-to-treat analysis at 4 weeks, 70% of participants taking telaprevir achieved rapid virological response (RVR), or undetectable HCV viral load, compared with only 5% in the placebo group.
	Telaprevir was also significantly more effective than standard therapy when broken down by type of HIV treatment:
	Not on ART: 71% in telaprevir arm, 0 in placebo arm; Efavirenz-based ART: 75% vs 12%, respectively; Atazanavir-based ART: 64% vs 0, respectively.
	A similar pattern was observed when looking at complete early virological response (cEVR), or continued undetectable HCV RNA, among participants followed through week 12:
	Overall: 68% in telaprevir arm vs 14% in placebo arm; Not on ART: 71% vs 17%, respectively; Efavirenz-based ART: 75% vs 12%, respectively; Atazanavir-based ART: 57% vs 12%, respectively.
	2 patients taking telaprevir in Part B experienced HCV breakthrough:
	1 using atazanavir at week 4; 1 using efavirenz at week 8.
	1 telaprevir recipient and 3 people in the placebo arm discontinued treatment due to pre-defined stopping rules for non-response.
	Telaprevir was generally safe and well-tolerated, though most patients experienced at least 1 adverse event:
	Serious adverse events (AEs): 3 in telaprevir arms vs 0 in placebo arms; Discontinuation due to AEs: 2 in telaprevir arms (1 jaundice and 1 anemia, both in atazanavir recipients) vs 0 in placebo arms.
	The most common AEs among telaprevir recipients were fatigue, nausea, pruritis (itching), and headache, all reported by more than 25%.
	AEs that occurred significantly more often in the telaprevir arm compared with the placebo arm were:
	Nausea: 35% vs 14%, respectively; Pruritis: 35% vs 5%, respectively; Dizziness: 22% vs 5%, respectively; Fever: 26% vs 9%, respectively; Anorexia (loss of appetite): 19% vs 9%, respectively; Vomiting: 19% vs 9%, respectively.
	Mild skin rash occurred with similar frequency in the telaprevir and placebo arms (16% vs 14%, respectively), but moderate rash was more common among telaprevir recipients (11% vs < 1%, respectively).
	In both arms, however, there were no cases of severe rash, as occasional reported in HCV monoinfection studies.
	Median telaprevir trough, or lowest, blood concentrations were similar with and without ART.
	Antiretroviral drug trough concentrations decreased by less than 20% when telaprevir was added.
	There were no cases of HIV breakthrough.
	Average HIV RNA levels in people not on ART decreased by about 1 log in both telaprevir and placebo arms (a known effect of interferon).
	CD4 cell counts did not change significantly.

"In this interim analysis, substantially more patients receiving a telaprevir-based regimen achieved undetectable HCV RNA at weeks 4 and 12," the investigators concluded. "The safety and tolerability of [telaprevir plus pegylated interferon/ribavirin] was consistent with that previously observed in HCV monoinfected patients; no novel adverse events were detected."

Follow-up will continue through 24 weeks after the end of treatment to determine sustained virological response (SVR) rates. In telaprevir studies of HCV monoinfected patients, RVR and cEVR were strong predictors of SVR.

In response to a question about the somewhat lower response rates at weeks 4 and 12 among atazanavir recipients compared with efavirenz recipients, Sulkowski said it was not possible to make conclusions about how ART choice might affect telaprevir efficacy based on the small numbers in this study.

After Sulkowski summarized these finings at a press conference following his presentation, fellow speaker Joseph Eron form the University of North Carolina said that given the data so far, he would only feel comfortable giving telaprevir in combination with atazanavir or efavirenz. Sulkowski concurred, adding that more studies of telaprevir/antiretroviral drug interactions are needed.

At the same press conference, Stefan Zeuzem from University Hospital in Frankfurt gave a brief recap of his Wednesday morning plenary talk on new antiviral therapies for management of HCV.

The impending approval of the first 2 direct-acting HCV agents -- telaprevir and boceprevir -- is a boon not only for the fields of infectious disease and hepatology, but for medicine as a whole, Zeuzem said. "30% more cure in a difficult-to-treat disease is a major achievement," he noted.

Zeuzem added that he expects 1-2 new anti-HCV drugs to be approved per year until 2015. "By the end of the decade we may well see an all oral regimen," he said. "That's what I want to achieve before retirement."

He cautioned, however, that a major education effort will be needed to help gastroenterologists and hepatologists use these new medications correctly, as they are less familiar with the lessons learned in the HIV field about drug combination, resistance, and adherence.

Investigator affiliations:

Abstract 146LB: Johns Hopkins Univ School of Medicine, Baltimore, MD; Mt. Sinai School of Medicine, New York, NY; Univ of Cincinnati College of Medicine, Cincinnati, OH; Univ of Bonn, Germany; Vertex Pharmaceuticals Inc, Cambridge, MA; Hosp Carlos III, Madrid, Spain.

Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA.

3/4/11

References

M Sulkowski, D Dieterich, K Sherman M, and others. Interim Analysis of a Phase 2a Double-blind Study of TVR in Combination with pegIFN-a2a and RBV in HIV/HCV Co-infected Patients. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 146LB.

R van Heeswijk, A Vandevoorde, G Boogaerts, and others. Pharmacokinetic Interactions between ARV Agents and the Investigational HCV Protease Inhibitor TVR in Healthy Volunteers. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 119.

S Zeuzem. New Antiviral Therapies in the Management of HCV (plenary). 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011.

Other Source
Vertex Pharmaceuticals. Positive Phase 2 Interim Data from First Study of Telaprevir in People Co-Infected with Hepatitis C and HIV Presented at CROI Conference. Press release. March 2, 2011.