HIV/HCV: Closing the Gap

Patients who are co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have long represented a special population of patients with a unique set of challenges and barriers to HCV treatment access.  FDA identifies HIV/HCV co-infected patients as a population with an unmet medical need due to the more rapid progression of liver disease reported in the highly-active antiretroviral era and the lower reported sustained virologic response (SVR) rates to pegylated interferon and ribavirin (PEG/RBV) treatments.

In the days of interferon and ribavirin, HIV/HCV patients faced significant barriers to therapy, including high rates of psychiatric disease and substance use, competing co-morbidities and greater treatment complications. The past few years have brought a shift in the HCV treatment paradigm to oral, combination direct-acting antiviral (DAA) therapies, which offer a greater than 90 percent cure for all. This exceptional medical advancement has closed the gap of HCV treatment response for HIV/HCV patients. In fact, current U.S. and European HCV guidelines report that the treatment of HIV/HCV and hepatitis C infection should not differ. As HIV becomes less relevant for HCV treatment efficacy, there remain differences between these populations that are important to consider.

When left untreated, HIV/HCV co-infected patients face more rapid progression of their liver disease to cirrhosis and the associated complications, including hepatic decompensation and hepatocellular carcinoma. The recent D:A:D cohort reported that liver disease remains a leading cause of death in patients living with HIV and that HCV infection is independently associated with all-cause mortality.1 Furthermore, a recent model of liver disease in HIV/HCV patients suggested that waiting until these patients havestage F2 or more severe fibrosis to achieve cure increases the risk of hepatitis C-related mortality.2 For this reason, the AASLD/IDSA HCV treatment and management guidelines identify HIV/HCV patients as high priority for HCV treatment access, regardless of liver disease stage. This is a critically important point when interacting with payors who are denying access to HCV treatment for patients with lower stages of liver fibrosis. In our clinic, we consider every HIV/HCV patient for HCV treatment regardless of liver disease stage, but access has not been as universal as we would have hoped for this high-risk population. For those patients with decompensated liver disease, transplantation prior to therapy is recommended because the wait times are more favorable when obtaining an HCV-positive organ for most United Network for Organ Sharing regions.

Although historically HIV/HCV patients experienced lower SVR rates with PEG/IFN, trials of DAA combination therapies have convincingly shown that this is no longer the case. There are now four Phase 3 trials of oral DAA regimens in HIV/HCV patients that have reported the same SVR as those reported in HCV mono-infected patients, regardless of prior treatment experience and presence of cirrhosis.3,4 Similar to HCV monoinfected patients, HIV/HCV patients can expect greater than 95 percent cure rates when treated with DAA combination therapies. Based on these data, the U.S. and European guidelines recommend that HIV/HCV patients be treated the same as patients without HIV infection.

In addition to achieving similar cure rates with DAA combination therapy, Phase 3 studies have found that adverse events and treatment discontinuations are the same for HIV/HCV and HCV-infected patients. To date there is no evidence that HIV/HCV patients have differences in baseline resistance to DAAs or response rates than DAA combination therapies do bring a challenge for HIV/HCV patients that does not exist to the same extent for HCV mono-infected patients: drug interactions. Drug interactions with antiretrovirals and DAAs are common, complex and can result in limited HCV treatment options, especially for HIV/HCV patients on more complex salvage HIV regimens. Communication between a patient’s HCV provider and their primary HIV provider is of the utmost importance in choosing an HCV regimen and preventing drug interactions. Yet as more DAAs are approved by FDA and because the efficacy of these regimens are similar, even this current challenge will be overcome.

One challenge that we will face in the management of HIV/HCV patients is reinfection in those patients with ongoing risk behaviors. Cohort studies suggest that HIV coinfection increases the risk of hepatitis C transmission, especially in HIV-infected men who have sex with men. Recent data have demonstrated the real and significant risk of HCV reinfection in the co-infected population with rates as high as 21.8 percent as compared with their mono-infected cohort who demonstrated rates of 1 percent and 8 percent in low- and high-risk groups, respectively.5 While these studies only reflected small sample sizes, the rates of reinfection were high enough to indicate that education regarding reinfection and risk behaviors will be critical at the end of treatment. Furthermore, when treating a patient whose sexual partner is known to be HCV infected, attention to education and encouraging the partner to seek hepatitis C treatment is important to decrease the risk of reinfection.


The DAA era in HCV therapeutics has revolutionized the way we approach the management of patients co-infected with HIV/HCV


The DAA era in HCV therapeutics has revolutionized the way we approach the management of patients co-infected with HIV/HCV. DAAs have rendered HIV less relevant in the consideration of HCV therapy efficacy and safety, but the population is still unique given the accelerated natural history of liver disease and the complex drug interactions related to concomitant antiretroviral therapy. While drug interactions will still remain, the ability to address these with either ARV switches or the increasing number of available highly efficacious DAA regimens limits the impact on access to therapy. While HCV eradication significantly decreases the risk of liver-disease-related complications, the risk of progression of liver disease due to other liver injuries is less clear. The management of HIV/HCV patients post cure should focus on monitoring for signs of ongoing liver injury (ARV toxicity, steatosis) as well as education and screening for reinfection in those patients with ongoing risk. For those patients who suffered from severe liver disease, long-term follow up for hepatocellular carcinoma screening and cirrhosis management will remain.

Dr. Naggie has received funding from Abbvie, Achillion, BMS, Gilead Sciences, Vertex Pharmaceuticals, Janssen Pharmaceuticals and Merck. She has lectured for IAS-USA and serves on the IDSA Clinical Affairs Committee and the AASLD/IDSA HCV Guidance Committee.

Dr. Austin Chan has no conflicts to disclose.

References
1. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, Kowalska JD, de Wit S, Law M, el Sadr W, Kirk O, Friis-Moller N, Monforte Ad, Phillips AN, Sabin CA, Lundgren JD; D:A:D Study Group. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014 Jul 19;384(9939):241-8.
2. Zahnd C, Salazar-Vizcaya LP, Dufour JF, Mullhaupt B, Wandeler G, Kouyos R, Bertisch B, Rauch A, Keiser O. Impact of Deferring HCV Treatment on Liver Related Events in HIV+ Patients. On behalf of the Swiss HIV and HCV Cohort Studies, Institute of Social and Preventative Medicine, University of Bern, Bern, Switzerland. University Hospital Bern, Bern, Switzerland. University Hospital Zurich, Zurich, Switzerland.
3. Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, Bon D, Silk R, Gross C, Price A, Sajadi M, Sidharthan S, Sims Z, Herrmann E, Hogan J, Teferi G, Talwani R, Proschan M, Jenkins V, Kleiner DE, Wood BJ, Subramanian GM, Pang PS, McHutchison JG, Polis MA, Fauci AS, Masur H, Kottilil S. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV coinfection. JAMA. 2015 Mar 24-31;313(12):1232-9
4.Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, Slim J, Bhatti L, Gathe J, Ruane PJ, Elion R, Bredeek F, Brennan R, Blick G, Khatri A, Gibbons K, Hu YB, Fredrick L, Schnell G, Pilot-Matias T, Tripathi R, Da Silva-Tillmann B, McGovern B, Campbell AL, Podsadecki T. Ombitasvir, paritaprevir codosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015 Mar 24-31;313(12):1223-31.
5.Hill A, Simmons B, Saleem J, Cooke G. Five–Year Risk of Late Relapse or Reinfection With Hepatitis C After Sustained Virological Response: Meta-analysis of 49 Studies in 8534 Patients. CROI Presentation, Abstract #654, February 23 – 26, 2015, Seattle, Washington.

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