September 26, 2014
The administration of the oral 3D regimen plus ribavirin achieved very high rates of sustained virologic response at four and 12 weeks post-treatment (SVR4 and SVR12) in patients coinfected with both HIV and hepatitis C virus (HCV) genotype 1 (GT1), according to findings from the TURQUOISE-1 study, presented this week in Washington, D.C., at ICAAC 2014. The study found that the interferon-free combination of ritonavir-boosted ABT-450, ombitasvir and dasabuvir plus ribavirin was well tolerated with no treatment-emergent serious adverse events, even in patients with cirrhosis.
"An SVR12 rate of 93.5% was achieved with 12 weeks of 3D plus ribavirin, with only two patients not meeting that benchmark, and an SVR4 rate of 96.9% was achieved with 24 weeks of 3D + RBV, with only one patient not meeting that benchmark," said Joe Eron, M.D., of the University of North Carolina Medical School, who presented the study findings.
In addition, the regimen didn't cause any patient discontinuations due to side effects even though treatment was co-administered with atazanavir or raltegravir-based ART.
About 20% to 40% of HIV-infected patients are coinfected with HCV -- though this varies depending on the proportion of people with a history of injecting drugs in the clinic or cohort. Data suggests liver progression to cirrhosis is more rapid in HCV patients who are coinfected with HIV. Conversely, in the era of antiretroviral therapy (ART), liver-related diseases have become a major cause of morbidity and mortality in people living with HIV.
Treatment of HCV in people living with HIV used to be challenging, complicated by the treatment-limiting toxicities associated with interferon. However, the development of new oral agents that act directly upon HCV-related targets has dramatically improved treatment responses in HCV monoinfected patients even when given without pegylated interferon.
The 3D regimen consists of three directly acting antiviral drugs: ABT-450, an HCV NS3/4A protease inhibitor; ombitasvir (ABT-267), which targets the NS5A protein; and dasabuvir (ABT-333), an HCV NS5B RNA polymerase inhibitor. ABT-450 has been coformulated with a small dose of ritonavir to boost its pharmacokinetics and with ombitasvir in a once-daily fixed dose combination, while dasabuvir must be dosed at 250 mg orally twice a day.
But can the 3D regimen plus ribavirin be given safely and effectively to those coinfected, particularly those on concurrent ART? Drug interaction studies in healthy volunteers have at least shown no clinically meaningful alterations in HCV or HIV drug exposures when the 3D regimen is given together with at least some antiretrovirals, including tenofovir (Viread), emtricitabine (FTC, Emtriva), atazanavir (Reyataz) or raltegravir (Isentress) -- though anyone taking ritonavir-boosted atazanavir would need to drop ritonavir, since the 3D regimen already includes it.
The TURQUOISE-1 trial, a two-part, multicenter study, was performed to assess the safety and efficacy of either 12 or 24 weeks of the 3D-plus-ribavirin regimen in HCV/HIV coinfected individuals. Participants had to be on a stable atazanavir or raltegravir-based regimen with CD4 counts above 200 (CD4 greater than or equal to 14%) and HIV viral loads below 40 copies/mL (the safety analyses included an assessment of whether participants maintained suppression of HIV while on concurrent HCV treatment).
The study enrolled 63 HIV-infected adults (aged 18-70) with chronic HCV-GT1 infection (plasma HCV RNA >10,000 IU/mL).
More than 90% of the participants were male in both arms, and just under 25% were African American. The mean age was 51 and 19% in each arm had cirrhosis. About two-thirds were treatment naive.
By week four of treatment, all participants had a rapid virologic response (an undetectable HCV viral load); at the end of treatment, only one patient in each arm did not meet the criteria for response -- one in the 12-week arm withdrew consent (but had an undetectable HCV viral load at the last visit) and one patient in the 24-week arm relapsed. An additional patient in the 12-week arm relapsed, after treatment, but as noted earlier, the available SVR4 and SVR12 rates were very high -- similar to the rates seen in the HCV-monoinfected patients. The SVR12 data for the 24-week arm are not yet available.
Notably, the two patients who had virologic failure were both treatment-experienced, had no response to prior interferon-ribavirin treatment and had cirrhosis -- in other words, of the most difficult patients to treat. In addition, when they rebounded, genotypic analysis showed that they both had some level of resistance.
None of the participants discontinued due to adverse events. The majority of adverse events were mild or moderate in severity; the most common event was fatigue. There were only five severe adverse events -- insomnia, hypophosphatemia, disseminated herpes zoster, tooth abscess and vertigo -- and most of those severe adverse events were not attributable to therapy. There were no treatment-emergent serious adverse events reported.
Five patients had a confirmed increase in their HIV viral load above 40 but not above 200, and all of those patients suppressed to below 40 again while maintaining the same ART regimen without interrupting their HCV treatment.
In the next phase of the study, a cohort of patients on a stable darunavir-inclusive ART regimen will be enrolled. TURQUOISE- 2 will be a larger globally conducted trial that will be initiated later this year.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience.
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