Phase 3 DAA trials do not reflect wider HIV/HCV population

Many recent phase 3 clinical trials supporting direct-acting antiviral therapy for HIV/hepatitis C virus coinfection mandated strict eligibility criteria for their participants and may not be an accurate representation of the general population affected by these comorbidities, according to new data.

“The development of direct-acting antivirals (DAAs) for HCV has been rightfully described as revolutionary,” the researchers wrote. “Trials evaluating these new agents have so far included relatively small numbers of participants and have applied very strict eligibility criteria, likely excluding a substantial segment of the coinfected population. Substance abuse, comorbid medical and psychiatric conditions, advanced liver disease, drug-drug interactions with antiretrovirals are common and are among some of the primary factors that may influence access to treatment and outcomes in the real world.”

To investigate the generalizability of these studies, the researchers reviewed a collection of all published phase 3 trials evaluating second-generation DAAs among coinfected patient samples. Five trials with available protocols were identified: NCT01479868 (Olysio, Janssen Therapeutics; simeprevir), the PHOTON-1 trial (Sovaldi, Gilead Sciences; sofosbuvir), the TURQUOISE-1 trial (Viekira Pak, AbbVie; ombitasvir/paritaprevir/ritonavir and dasabuvir), the ION-4 trial (Harvoni, Gilead Sciences; sofosbuvir/ledipasvir) and the ALLY-2 trial (Daklinza, Bristol-Myers Squibb/sofosbuvir, Gilead Sciences; daclatasvir/sofosbuvir). Researchers compared the inclusion criteria for each study against data from the Canadian Coinfection Cohort (CCC), which is estimated to include approximately 23% of Canada’s HIV/HCV coinfected population.

After excluding those who died, withdrew from the study or were otherwise lost to follow-up, 874 CCC participants remained and were considered reflective of the general HIV/HCV population. Among these, 70% had evidence of chronic HCV infection, 410 were infected with genotype 1, and 80% had a history of injection drug use. In addition, 87% of included CCC participants reported receipt of combination ART, and 15% had evidence of advanced fibrosis.

When applying each trial’s inclusion criteria to the CCC participants, the researchers found an overall low rate of eligibility. Eligibility ranged from 5.9% in the simeprevir trial to 43% in the ALLY-2 trial; however, ALLY-2 was the only trial included in the analysis to exceed 10%. The most frequent reasons for exclusion in these other trials were the restriction to specific ART (63%-79% excluded) and active non-marijuana drug use (53%-55% excluded). Among all trials, detectable HIV RNA and low CD4 counts had an impact on exclusion, while safety concerns related to anemia and liver function had a minimal impact.

These low levels of eligibility suggest that many of these trials were conducted among patient cohorts that may not reflect the characteristics of the general HIV/HCV population, the researchers wrote. As such, further trials may be necessary to confirm that the beneficial effects of DAAs are not diminished by various ART regimens or active drug use.

“This work illustrates the need to evaluate the external validity of all marketed pharmaceuticals in order to determine whether trial populations represent target populations,” the researchers wrote. “If generalizability is found to be limited, then targeted phase 4 studies need to be considered.”