Two new studies published in JAMA focus on the need for interferon-free treatment to avoid potential toxicities in patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1). The researchers found that interferon-free drug regimens could be consistent with achieving high rates of sustained virologic response — a lack of detectable HCV RNA for a minimum of 12 weeks after treatment completion.
A JAMA release notes that Hepatitis C virus and HIV-1 co-infections are common mostly due to similar routes of transmission, eg: injection drug use, blood transfusion, and/or sexual contact. Since development of effective antiretroviral therapy regimens, hepatic (liver-related) disease has become a leading cause of illness and death in HCV/HIV-1 co-infected patients, who also have greater risk of progression to liver cirrhosis and hepatitis or liver-related death than do individuals with HCV but not HIV-1.
Adding to the complexity of treatment, Interferon-based HCV treatments introduce significant toxicities, which limits their usefulness; leaving a significant unmet need for an efficacious, interferon-free treatment.
In their study, which was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014, Mark S. Sulkowski, M.D., Medical Director, of the Viral Hepatitis Center and Professor of Medicine at Johns Hopkins University in Baltimore and his team of research colleagues assessed the effects of three oral direct-acting antiviral (3D) drug “cocktail” of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin, in 63 HCV genotype 1-infected adults with HIV-1 co-infection. The subjects included patients with cirrhosis, and were randomly assigned to either 12 or 24 weeks of treatment. These patients had neither received prior HCV treatment nor had history of prior treatment failure with peginterferon plus ribavirin therapy.
The investigators observed rapid plasma HCV RNA suppression was in patients receiving 3D plus ribavirin, and 58 of 63 patients (92 percent) had an HCV RNA below the lower limit of quantitation at treatment week two. After either 12 or 24 weeks of treatment with 3D plus ribavirin, 29 of 31 patients (94 percent) and 29 of 32 patients (91 percent) respectively had achieved SVR12 (sustained virologic response at post-treatment week 12), respectively, with the difference between treatment groups not statistically significant.
The most common side effects and adverse events experienced by study subjects included fatigue (reported by 48 percent), insomnia (19 percent), nausea (18 percent), and headache (16 percent). Adverse events were generally mild, with none reported as serious and none led to discontinuation of treatment.
The researchers summarize that in their open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 treated for 12 or 24 weeks. They deduce that further phase 3 studies of this regimen are warranted in coinfected patients.
In another JAMA published study, conducted from June 2013 to September 2014 at the Clinical Research Center of the National Institutes of Health, Shyam Kottilil, M.D., Ph.D., of the University of Maryland School of Medicine and the Institute of Human Virology, Baltimore, and a multi-institution, international team of colleagues evaluated rates of SVR in 50 patients co-infected with HCV genotype 1 and HIV who had never previously been treated for HCV, following treatment with the antiviral agents ledipasvir and sofosbuvir. The study’s patients, who did not have hepatic cirrhosis, were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks.
The Original Investigation study, published online before print February 23, 2015, entitled “Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection“ (JAMA. Published online February 23, 2015. doi:10.1001/jama.2015.1373 clinicaltrials.gov Identifier:NCT01878799), is coauthored by Anu Osinusi, MD, MPH; Kerry Townsend, BA; Anita Kohli, MD, MS; Amy Nelson, RN; Cassie Seamon, RN; Eric G. Meissner, MD, PhD; Dimitra Bon, MS; Rachel Silk, RN; Chloe Gross, RN; Angie Price, NP; Mohammad Sajadi, MD; Sreetha Sidharthan, BS; Zayani Sims, BS; Eva Herrmann, PhD; John Hogan, MD; Gebeyehu Teferi, MD; Rohit Talwani, MD; Michael Proschan, PhD; Veronica Jenkins, MD10; David E. Kleiner, MD, PhD; Brad J. Wood, MD; G.Mani Subramanian, MD, PhD; Phillip S. Pang, MD, PhD; John G. McHutchison, MD; Michael A. Polis, MD, MPH; Anthony S. Fauci, MD; Henry Masur, MD; Shyam Kottilil, MD, PhD; — variously representing the Division of Infectious Diseases, Institute of Human Virology at the University of Maryland at Baltimore; the National Institute of Allergy and Infectious Diseases, National Institutes of Health’s Laboratory of Immunoregulation at Bethesda, Maryland; Gilead Sciences Inc. off Foster City, California; the NIH Clinical Center, National Institutes of Health Critical Care Medicine Department at Bethesda, Maryland; the Clinical Research Directorate/Clinical Monitoring Research Program at Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc), Frederick National Laboratory for Cancer Research, Frederick, Maryland; the Department of Microbiology and Immunology at the Medical University of South Carolina College of Medicine in Charleston; the Institute of Biostatistics and Mathematical Modeling at Johann Wolfgang Goethe University in Frankfurt, Germany; Unity Health Care Inc. of Washington, DC; the Biostatistics Research Branch of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Bethesda, Maryland; Family and Medical Counseling Services, Washington, DC; the Department of Pathology at the National Cancer Institute in Rockville, Maryland; and the Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute at Bethesda, Maryland.
Forty-nine of the study’s 50 participants (98 percent) achieved sustained viral response 12 weeks after treatment cessation of. One patient experienced relapse at week four following treatment, upon which further analysis found that person had a genetic mutation associated with resistance to inhibitors such as ledipasvir.
The most common adverse events reported were minor in nature, including nasal congestion (16 percent of patients) and myalgia (14 percent; pain in the muscles or within muscle tissue). There were no discontinuations or serious adverse events attributable to the study drugs.
The researchers conclude that results of their their open-label, uncontrolled, pilot study show for the first time, to their knowledge, association of interferon- and ribavirin-free therapy with high SVR rates in patients co-infected with HCV and HIV, and warrant larger studies that would include patients with cirrhosis and with lower CD4 T-cell counts in order to understand whether the results of this study generalize to all patients co-infected with HCV and HIV.
In an accompanying editorial entitled “Hepatitis C and HIV Co-infection: Closing The Gaps“ (doi:10.1001/jama.2015.1111 ), Camilla S. Graham, M.D., M.P.H., of the Viral Hepatitis Center, Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts, notes that Liver disease represents the second leading cause of death in HIV infected persons, observing that the high SVR rates in these two studies suggest that future barriers to preventing unnecessary deaths attributable to HCV may be related to health care system failures.
Dr. Graham says clinician caregivers of patients with HIV infection are skilled in selection of regimens, drug interaction management optimizing adherence, and providing harm reduction counseling — skills that she says are exactly what’s necessary in treating patients with hepatitis C and to ensure that successes achieved in research trials are being replicated in clinical practice. She points to another sobering finding in the Sulkowski et al. study that two of the three patients who failed to achieve SVR in the 24-week group were reinfected with a new strain of HCV within 12 weeks after treatment completion, and both patients had reported unprotected intercourse with a sexual partner after treatment. A meta-analysis of studies examining HCV reinfection found that persons with HIV/HCV co-infection had a 23.6% reinfection rate.13 Individuals who are most at risk for reinfection will need to be cured to achieve decreases in the incidence of HCV infection, an idea termed “cure as prevention.”
She further comments that clinicians who treat patients with hepatitis C must facilitate harm reduction measures as well as provide antiviral treatment in order to achieve the ultimate goal of hepatitis C eradication, and that cost-effectiveness studies that model the value of cure as prevention are needed to demonstrate that resources are well spent in treating persons with a high risk of reinfection. Dr. Graham says many clinicians also have experience advocating for their patients, a skill that may be as valuable now as it was in the early days of HIV, noting that with current concern about the high of these drug regimens, it’s of critical importance that patients living with hepatitis C and the value of treating this disease remain top of mind.
Previous Related Content From JAMA: “Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Co-infection” (July 23/30, 2014) can be accessed at:
http://ja.ma/1ESyOWw