All but one participant treated for hepatitis C virus (HCV) with a co-formulation of sofosbuvir and ledipasvir (Harvoni) achieved sustained virological response at 12 weeks post-treatment, in a study involving people with traditionally hard-to-treat HIV and HCV co-infection, researchers reported on Sunday at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting in Boston, USA.
Sofosbuvir/ledipasvir – a combination nucleotide HCV polymerase inhibitor and NS5A inhibitor produced by Gilead Sciences – has performed very well in phase 3 clinical trials, leading to its recent approval by the US Food and Drug Administration (FDA). But such studies, usually sponsored by drug-makers, may not reflect the range of difficult-to-treat patients seen in real-world clinical practice.
The ERADICATE trial, an investigator-initiated study conducted by the US National Institute of Allergy and Infectious Diseases (NIAID, part of the National Institutes of Health), was designed to test a simple once-daily regimen for an urban population in Washington, DC.
This analysis included 50 participants with HIV and HCV co-infection, with HCV genotype 1, about 80% of whom had harder-to-treat subtype 1a. All participants were being treated for hepatitis C for the first time. A majority were men, more than 80% were African-American and the median age was 58 years. Most had high HCV viral load. About one-quarter had advanced liver fibrosis (stage F3), but people with cirrhosis (stage F4) were excluded.
Participants had well-preserved immune function without signs of AIDS. Thirteen participants were not yet taking antiretroviral therapy (ART) and had either a stable CD4 cell count and HIV RNA below 500 copies/ml or a CD4 cell count greater than 500 cells/mm3 (median 687 cells/mm3). The other 37 participants were on ART with undetectable HIV RNA and a median CD4 count of 576 cells/mm3. Everyone on ART was taking tenofovir/emtricitabine (the drugs in Truvada), mostly with efavirenz (Sustiva; 41%), raltegravir (Isentress; 27%) or rilpivirine (Edurant; 21%) as their third antiretroviral.
Historically, people with HIV and HCV co-infection and people of African descent have not responded as well to interferon-based therapy for hepatitis C. Immune deficiency related to HIV may interfere with response to interferon, and black people are less likely to have the favourable IL28B CC genetic variant associated with good interferon responsiveness (about 85% in this study had unfavourable IL28B variants). But HIV infection and race/ethnicity do not seem to have much effect on interferon-free treatment.
All participants in this open-label study were treated with co-formulated sofosbuvir/ledipasvir (400/90mg) for 12 weeks, and were followed for 24 weeks after the end of treatment.
Anu Osinusi from NIAID presented interim results from ERADICATE at the EASL International Liver Congress in April. At AASLD, Shyam Kottilil presented final results for the primary endpoint of sustained virological response (SVR), or continued undetectable HCV RNA, at 12 weeks after completing treatment (SVR12), considered to be a cure.
At 12 weeks post-treatment, all patients in the ART-untreated group (100%) and all but one in the ART-treated group (97%) had undetectable HCV RNA, for an overall SVR12 rate of 98%.
The single participant with virological failure was a 63-year-old African-American woman with HCV 1b, mild fibrosis and a CD4 count of 395 cells/mm3 receiving rilpivirine/tenofovir/emtricitabine (Eviplera or Complera). She had undetectable HCV viral load at the end of 12 weeks of treatment but relapsed two weeks later. One additional participant again had detectable HCV viral load at week 36 (24 weeks post-treatment), with the same genotype.
HCV viral load declined steeply and rapidly in both ART-untreated and ART-treated participants. The ART-untreated group did not experience any clinically significant changes in HIV viral load during hepatitis C treatment. One person on ART experienced HIV viral breakthrough after missing antiretrovirals for four days, but re-suppressed HIV on the same regimen. CD4 cell counts and CD4 percentages did not change significantly in either group.
Looking at adverse events, there were no deaths, drug-related serious adverse events or treatment discontinuations for this reason in either group. Side-effects reported by at least 5% of participants included nasal congestion, sore throat, fatigue, diarrhoea, nausea, pain, headache and tooth infections. Grade 3-4 laboratory abnormalities were rare.
Sofosuvir/ledipasvir is known to raise tenofovir levels, but an extensive analysis of kidney function parameters – including creatinine level, creatinine clearance, glomerular filtration rate and beta-2 microglobulin – did not reveal any notable abnormalities. Three people developed protein in their urine.
"Treatment of chronic hepatitis C in HCV/HIV coinfected patients with sofosbuvir/ledipasvir was effective and well-tolerated, suggesting HIV infection may not be a major determinant of treatment outcome with sofosbuvir/ledipasvir therapy," the researchers concluded.
Townsend KS (Kottilil S presenting) High efficacy of sofosbuvir/ledipasvir for the treatment of HCV genotype 1 in patients coinfected with HIV on or off antiretroviral therapy: results from the NIAID ERADICATE trial. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 84, 2014.