Dr. Dieterich is Professor of Medicine in the Division of Liver Diseases, Director of Continuing Medical Education in the Department of Medicine, and Director of Outpatient Hepatology at the Icahn School of Medicine at Mount Sinai in New York City. He also holds appointments in the divisions of Gastroenterology and Infectious Diseases at the Icahn School of Medicine. Dr. Dieterich's clinical work and research focus on HCV and HBV infection, often in people also infected with HIV. He has served on several committees of the AIDS Clinical Trials Group, including the Steering Committee of the Opportunistic Infections Core Committee. A PubMed search linking his name to HCV returns 71 articles.
Mascolini: Do DAAs -- direct-acting antivirals -- work in people with HIV as well as they do in HIV-negative people?
Dieterich: Absolutely, exactly the same. It's incredible. Ever since the beginning of the DAA era in 2011, all trials in HCV/HIV-coinfected patients show that DAAs work just as well as in people infected only with HCV1,2 (Table 1). What's more interesting is that in the real world it looks like DAAs work even better in coinfected patients than they do in trials.
|Table 1. Two Trials of DAA-Only Regimens for HCV/HIV Coinfection|
|ERADICATE Trial1||C-WORTHY Trial2|
|Study participants (all HCV treatment-naive)||13 noncirrhotic HIV/HCV-G1 patients not taking antiretrovirals 37 noncirrhotic HIV/HCV-G1 patients taking antiretrovirals||59 noncirrhotic HIV/HCV-G1 patients taking raltegravir regimen|
|Treatment||Sofosbuvir/ledipasvir for 12 weeks||MK-5172/MK-8742 with or without ribavirin for 12 weeks|
|Response||13 not taking antiretrovirals: 13/13 EOT, 10/10 SVR12|
37 taking antiretrovirals: 30/30 EOT, 22/22 SVR4
|29 taking ribavirin: 29/29 EOT, 28/29 SVR4|
30 not taking ribavirin: 27/30 EOT, 26/29 SVR4
|Other findings||No CD4 change during HCV treatment No discontinuations due to adverse events||Mean CD4 change from baseline - 61.7 with ribavirin, +46.9 without ribavirin No discontinuations due to adverse events|
EOT, end-of-treatment response (HCV RNA below lower limit of quantitation); G1, genotype 1; SVR4 or SVR12, sustained virologic response 4 or 12 weeks after treatment ends.
Mascolini: Why do you suppose that is?
Dieterich: I think HIV patients probably take their medicine better. I'm presenting some data at the DDW [Digestive Diseases Week] meeting [May 4-6, 2014, Chicago] that shows one of the positive predictors of response to HCV treatment with faldaprevir is being HIV positive.
Mascolini: Is enough DAA research being done in HCV/HIV-coinfected people?
Dieterich: There's never enough research. But one huge step forward is that Merck is not separating out HIV patients in their phase 3 trials. HIV patients are included in overall analyses as well as in analyses stratified by HIV status.
Mascolini: How should clinicians who treat HCV infection decide whether to treat HIV-coinfected people with HCV drugs available now or wait for simpler DAA-only combinations?
Dieterich: Some patients can be treated now with sofosbuvir/ribavirin, such as Child-Pugh B and C cirrhotics, though we shouldn't be treating those patients without liver transplant planning. Clinicians can prescribe sofosbuvir/ribavirin for HCV genotype 2 and 3 patients now. In selected patients who are Child-Pugh A or better and who don't have any potential drug interactions, clinicians could use simeprevir/sofosbuvir in coinfected patients, and we've been doing that in some HIV patients.
Mascolini: How close are we to having licensed interferon/ribavirin-free combinations?
Dieterich: Sometime between August and October 2014 for coformulated sofosbuvir/ledipasvir. For coformulated ABT-450/ABT-267, we should know by December.
Mascolini: If a coinfected person has taken drugs for neither infection, how should clinicians decide whether to start treatment for both infections simultaneously or to start with HCV or HIV?
Dieterich: It's probably not a good idea to begin treating both infections simultaneously because of the potential for drug interactions or more side effects. Usually we recommend starting antiretroviral therapy first so we have a better quantity and quality of T cells when we start HCV therapy.
Mascolini: If an untreated person with HIV has a moderate viral load and relatively high CD4 count, does it make sense to try to knock out the HCV infection first with 12 weeks of therapy?
Dieterich: A very small study from the NIH found an SVR12 of 100% in coinfected patients treated with sofosbuvir/ledipasvir for 12 weeks when not on antiretrovirals (Table 1).1 In the future it's probably not going to make any difference whether people are on antiretrovirals or not, but for now I prefer starting antiretrovirals before HCV therapy. And with sofosbuvir/ledipasvir, it looks like adding ribavirin doesn't make any difference. For ABT-450/ABT-267, it looks like adding ribavirin makes a difference only with HCV genotype 1a.
Mascolini: Two or three years from now, will anyone with HCV be taking interferon or ribavirin?
Dieterich: There always might be a tiny percentage of people, perhaps 1% to 5%, with multiple failures and with resistance to DAAs who will be candidates for interferon or ribavirin.
Mascolini: What are the treatment options for coinfected people with cirrhosis in whom previous treatment failed?
Dieterich: If they're Child A cirrhotics, you could use simeprevir/sofosbuvir, provided they're screened for esophageal varices and for hepatocellular carcinoma and screened for transplant. If they're Child B or C, they need to be evaluated for liver transplant, and sofosbuvir/ribavirin is clearly the treatment of choice.
Mascolini: Are some coinfected people at such an advanced stage that DAAs are not going to be help them?
Dieterich: I don't think there is a stage that's too advanced for DAAs to help, unless it's metastatic liver cancer. Screening for liver cancer with ultrasound and alpha-fetoprotein is very important, and I think most HIV clinics are not screening enough or at all. Screening for esophageal varices with endoscopy is also crucial.
Mascolini: When simple DAA-only regimens become available, will HIV clinicians still want to refer their HCV-coinfected patients to hepatitis specialists? Or will they be able to start prescribing for most coinfected patients themselves?
Dieterich: They can do it themselves, as long as they know how to spot cirrhosis and what to prescribe. It's perfectly appropriate for noncirrhotic patients to be treated in the HIV clinic.*
Mascolini: In your experience talking with HIV clinicians, do you think they're getting up to speed on DAA therapy and reaching a comfort level in prescribing them?
Dieterich: I think they're eager to start using DAAs, but they're still having trouble pulling the trigger. I don't know why. I've been trying for years to get HIV providers to treat hep C, and there are only a few who do. Everybody is interested now that DAAs are becoming available, but not many HIV clinicians are writing prescriptions yet. I don't think there are enough treaters to treat all the hep C that's out there. We need to increase our treatment base.
Mascolini: DAAs are expensive. Are public and private insurance paying for them?
Dieterich: They are paying for DAAs, and I think they'll continue to do so. DAAs are very cost-effective. It's very expensive to die from liver disease, and it's very expensive to get a liver transplant. So treating hep C can be incredibly cost-effective. When you figure quality-adjusted life-years, compared with colonoscopy, Pap smears, mammograms, and cholesterol therapy, treating hep C with all-oral DAAs is one of the most cost-effective things you can do because of the downside risk of liver failure.
Mascolini: Is there anything else you want to add about what HIV clinicians should know about DAAs or about HCV coinfection in general?
Dieterich: It's important for patients with cirrhosis to get referred to a liver center. Cirrhosis is relatively easy to diagnose, but HIV clinicians have got to remember how to do it: If a patient's platelets are less than 110,000 per mcL, if their albumin is less than 3.5 g/dL, if they have any physical signs of liver disease, they need to get referred.
HIV clinicians also need to be screening all their hepatitis B surface antigen-positive patients for hepatocellular carcinoma, especially patients who are hep C infected, because they're at increased risk of liver cancer. Tenofovir and emtricitabine are so effective in treating hep B, we've forgotten who among our patients is surface antigen-positive. And those patients are at extra risk for liver failure.
* The American Association for the Study of Liver Diseases (AASLD) launched ACT-First, a comprehensive online guide for first-line HCV treaters.
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