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New Hepatitis C Treatments Highly Effective for HIV/HCV Coinfected People

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A pair of interferon-free combinations -- AbbVie's 3-drug Viekira Pak regimen and Gilead Science's sofosbuvir/ledipasvir (Harvoni) -- demonstrated good safety and cured more than 90% of genotype 1 HIV/HCV coinfected people, according to studies published in the February 23 advance edition of the Journal of the American Medical Association.

About one-third of people with HIV are coinfected with hepatitis C virus (HCV). Coinfected people experience more rapid liver disease progression and do not respond as well to interferon-based therapy, so traditionally were considered hard-to-treat. But with the advent of direct-acting antivirals (DAAs) that can be combined into interferon-free regimens, coinfected people have cure rates and side effects similar to those of HIV negative people.

Viekira Pak Regimen

As described in the first article, Mark Sulkowski and fellow investigators with the TURQUOISE-I trial evaluated AbbVie's Viekira Pak or "3D" regimen, consisting of the HCV NS3/4A protease inhibitor paritaprevir, NS5A inhibitor ombitasvir, and a ritonavir booster in a once-daily coformulation, taken with the twice-daily non-nucleoside HCV NS5B polymerase inhibitor dasabuvir.

This open-label trial included 63 coinfected patients in the U.S. and Puerto Rico with HCV genotype 1. Most were men, three-quarters were white, and the average age was 51 years. Two-thirds were treatment-naive while one-third had previously undergone interferon-based therapy (6% prior relapsers, 11% partial responders, and 16% null responders). More than 90% had harder-to-treat HCV subtype 1a, with a minority having 1b. More than half had absent to mild liver fibrosis, but nearly one-fifth had cirrhosis.

Participants had CD4 T-cell counts of at least 200 cells/mm3 (mean of approximately 600 cells/mm3). They were taking stable suppressive antiretroviral therapy (ART) containing tenofovir/emtricitabine (the drugs in Truvada) plus either atazanavir (Reyataz) or raltegravir (Isentress), which were found to have no clinically relevant interactions with the AbbVie HCV drugs.

Participants were randomly assigned to receive the AbbVie regimen plus weight-based ribavirin for either 12 or 24 weeks.

Results  

  • At 12 weeks post-treatment, 29 of 31 of participants (94%) in the 12-week arm achieved sustained virological response (SVR12), or continued undetectable HCV viral load.
  • 29 of 32 people (91%) in the 24-week arm achieved SVR12.
  • Of the 5 patients who did not achieve SVR12, 1 withdrew consent, 2 had confirmed viral relapse or breakthrough, and 2 had a clinical history and genetic evidence suggesting HCV reinfection.
  • The AbbVie regimen plus ribavirin was generally safe and well-tolerated.
  • There were no serious adverse events or treatment discontinuations due to adverse events.
  • The most common treatment-emergent adverse events were fatigue (48%), insomnia (19%), nausea (18%), and headache (16%).

"In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients coinfected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks," the study authors concluded.

Sofosbuvir/Ledipasvir

As reported in the second article, Anu Osinusi, Shyam Kottilil, and colleagues with the ERADICATEtrial evaluated a coformulation of the HCV polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir for HIV/HCV coinfected patients previously untreated for hepatitis C. This investigator-initiated Phase 2b study conducted by the National Institute of Allergy and Infectious Diseases was designed to test a simple once-daily regimen for an urban population in Washington, DC.

The study included 50 HIV/HCV coinfected participants with HCV genotype 1, about 80% of whom had subtype 1a. A majority were men, more than 80% were African-American, and the median age was 58 years. About one-quarter had advanced liver fibrosis (stage F3), but people with cirrhosis were excluded.

About one-quarter were not yet be taking ART and had a CD4 cell count greater than 500 cells/mm3, while the rest were on ART with HIV viral load below 50 copies/mL and CD4 count greater than 100 cells/mm3. Everyone on ART was taking tenofovir/emtricitabine, mostly with efavirenz (Sustiva; 41%), raltegravir (Isentress; 27%), or rilpivirine (Edurant; 21%).

All participants were prescribed thefixed-dose combination of 400 mg sofosbuvir plus 90 mg ledipasvir once-daily for 12 weeks.

Results  

  • 49 of 50 participants (98%) achieved SVR12.
  • 1 patient experienced HCV viral relapse at week 4 after the end of treatment.
  • In this patient deep sequencing revealed a NS5A inhibitor resistance-associated mutation.
  • Here too, treatment was generally safe and well-tolerated.
  • The most common adverse events were nasal congestion (16%) and muscle pain (14%).
  • There were no serious adverse events or discontinuations attributable to study drugs.

"In this open-label, uncontrolled, pilot study enrolling patients coinfected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion," the researchers concluded. "Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients coinfected with HCV and HIV."

Transformative Treatment

"These 2 studies leave many questions unanswered, but details in each reinforce the transformative nature of new treatment regimens of all-oral DAAs," Camilla Graham from Beth Israel Deaconess Medical Center wrote in an accompanying editorial.

"One key observation is that DAA-containing regimens result in equivalent SVR rates in patients coinfected with HIV/HCV compared with HCV-monoinfected patients," she continued. "Because the data generated from trials involving HCV monoinfection and HIV/HCV coinfection are being treated as interchangeable from a clinical and regulatory standpoint, it is time to integrate patients with HIV/HCV coinfection into trials with patients with HCV monoinfection once appropriate antiretroviral drug interaction studies are complete."

She also noted that these studies closed the gap in sustained response rates between black and white hepatitis C patients that as previously seen in the interferon era. "Because only 3 patients across both studies experienced virologic failure, the present results help extend the opportunity for high cure rates with non-interferon-containing regimens to black patients with hepatitis C infection," she wrote.

"The high SVR rates in these 2 studies suggest that future barriers to prevention of unnecessary deaths due to HCV may be related to failures of the health care system," Graham concluded. "With the current concern about the high price of these regimens, it is critical that the patients who are living with hepatitis C and the value of treating this disease remain front and center."

2/24/15

References

MS Sulkowski, JJ Eron, D Wyles, et al. Ombitasvir, Paritaprevir Co-dosed With Ritonavir, Dasabuvir, and Ribavirin for Hepatitis C in Patients Co-infected With HIV-1A Randomized Trial. Journal of the American Medical Association. February 23, 2015 (Epub ahead of print).

A Osinusi, K Townsend, A Kohli, S Kottilil, et al. Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection. Journal of the American Medical Association. February 23, 2015 (Epub ahead of print).

CS Graham. Hepatitis C and HIV Co-infection: Closing the Gaps. Journal of the American Medical Association. February 23, 2015(Epub ahead of print).

Other Source

JAMA Network. Two Studies Show Promising Results in Treating Hepatitis C in Patients Co-Infected with HIV. Press release. February 23, 2015.