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Managing hepatitis C virus–HIV liver transplant recipients with the new direct-acting antivirals

are we glimpsing a brilliant future behind our shoulders?

Fagiuoli, Stefano; Puoti, Massimo; Rizzardini, Giuliano

doi: 10.1097/QAD.0000000000000891
Editorial Comment
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aDepartment of Gastroenterology, Hepatology and Liver Transplantation, Papa Giovanni XXIII Hospital, Bergamo

bDepartment of Infectious Diseases, Niguarda Cà Granda Hospital

cDepartment of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy

dSchool of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa.

Correspondence to Giuliano Rizzardini, MD, Director, Department of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy. Tel: +39 02 39043490; fax: +39 02 39042568; e-mail: rizzardini.giuliano@hsacco.it

Received 28 August, 2015

Accepted 15 September, 2015

The indication to liver transplantation for HIV/hepatitis C virus (HCV) coinfected population is still debated [1]. Indeed, graft and patient survival rates have been worse than in monoinfected recipients. Moreover, patients with HIV/HCV coinfection have been shown to be more likely to experience organ rejection than monoinfected with either HCV or HIV alone, highlighting the crucial issue of the differential diagnosis between cellular rejection, acute HCV recurrence, and biliary and vascular problems in the interplay between HCV and HIV in liver transplantation recipients [2]. The new era of direct-acting antivirals (DAAs) is bound to offer encouraging opportunities in the management of such patients, in both the pretransplant and the posttransplant setting.

The article titled Successful sofosbuvir-based therapy in HIV/HCV co-infected liver transplant recipients with recurrent HCV infection’ from Grant et al.[3], published in the current issue of AIDS, highlights a relevant issue in the context of the new DAAs for the treatment of HCV infection among HIV coinfected liver transplantation recipients: indeed, there are no data available in such population.

Current American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSL) and European Association for the Study of Liver (EASL) [4,5] recommendations report identical approaches for treating both HCV monoinfected and HIV/HCV coinfected patients. A number of recent studies have shown that coinfected patients, previously referred as one of our ‘special populations’, can now hold the same expectations in term of sustained virological response (SVR) as monoinfected individuals (Table 1).

Table 1

Table 1

The phase III, multicenter ION-4 study (ledipasvir/sofosbuvir in HIV/HCV coinfected patients with genotype 1 or 4) showed an SVR 12 of 96%. Cirrhotics had only slightly lower SVR rates, as in monoinfected patients. Even if the usage of many antiretrovirals was considered as an exclusion criteria, raltegravir usage, which is very common among HIV transplant recipients, was allowed in this study; in two patients, tenofovir dose adjustment and discontinuation were required [6].

The TURQUOISE-I study (ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in G1 coinfected individuals) showed SVR rates ranging from 90 to 94%. Only minor differences emerged depending on the type of antiretroviral therapy (ART) regimen utilized [7].

The ALLY-2 study (daclatasvir and sofosbuvir 12 and 8 weeks for HIV/HCV coinfected patients, including both treatment-naive and treatment-experienced) showed excellent SVR in the 12-week arms (96 and 97%), whereas the 8-week duration emerged as not as effective in this population (75–76%) [8].

The C-EDGE study (grazoprevir/elbasvir for 12 weeks in HIV/HCV naïve coinfected patients) showed a similar excellent overall SVR rate was 95% [9].

The main consideration emerging in treating the HIV-HCV coinfected patients with DAAs is clearly drug–drug interactions. Due to the potential for drug-drug interaction with calcineurin inhibitor many HIV transplant recipients are currently treated with Integrase Strand Transfer Inhibitors-based regimens.

Based on the data available in the literature, we can summarize several considerations:

  1. Patients receiving ritonavir as part of combination ART should require a switch of current ART or withholding ritonavir morning dose from the combination ART if they are treated with ombitasvir/paritaprevir/ritonavir along with dasabuvir regimen. This regimen also requires dose adjustment of calcineurin inhibitors if concurrently administered.
  2. The reported ledipasvir-mediated increases in tenofovir levels, particularly if patients are receiving boosted protease inhibitors need attention. A general recommendation, at present, might be to avoid ledipasvir in patients with CrCl less than 60 ml/min or those receiving tenofovir with ritonavir.
  3. Sofosbuvir shows an excellent compatibility with our antiretroviral regimens, allowing boosted protease inhibitors, efavirenz, raltegravir, rilpivirine, as well as the tenofovir/emtricitabine backbone.
  4. Simeprevir is an HCV protease inhibitor, and thus, more drug interactions should be expected with antiretrovirals and other medications when such drug is in the medication panel. Indeed, simeprevir should not be coadministered with HIV protease inhibitors or most of the non-nucleoside reverse-transcriptase inhibitors (NRTIs; rilpivirine being an exception).

The EASL recommendation includes a very helpful guidance table highlighting the drug–drug interactions with different pharmacological classes.

Therefore, it is important to ‘negotiate’ with patients a switch to a more manageable regimen such as NRTIs with raltegravir or dolutegravir or NRTIs and rilpivirine. However, it must be said that one might be limited by an individual patient's known HIV resistance profile or fear (by provider, patient, or both) of trying a new, unproven regimen.

We must add that the combination simeprevir–sofosbuvir has been studied in coinfected populations only in real-life studies. However, the results of this small series are definitely encouraging with a per-protocol SVR 12 similar to that observed in HIV seronegatives. The single patient experiencing acute cellular rejection because of a sharp drop in tacrolimus (TAC) blood levels after suspension of the sofosbuvir–simeprevir regimen had a concomitant relapse in heroin use, raising the suspicion of a compliance issue rather than a simeprevir-related drug–drug interaction: even more, because simeprevir usually reduces TAC blood levels and its withdrawal should eventually cause an increase of TAC levels.

Patients with HIV/HCV coinfection should no longer be regarded as ‘special’; however, one should have to pay attention to the drug–drug interactions.

The newer available and coming DAA regimens (daclatasvir and sofosbuvir, ledipasvir/sofosbuvir, grazoprevir/elbasvir) appear to be more manageable in terms of drug–drug interaction and will probably be the backbone of the future regimens in such populations.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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References

1. Terrault NA, Roland ME, Schiano T, Dove L, Wong MT, Poordad F, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus co-infection. Liver Transpl 2012; 18:716–726.
2. Sawinski D, Goldberg DS, Blumberg E, Abt PL, Bloom RD, Forde KA. Beyond the NIH multicenter HIV transplant trial experience: outcomes of HIV+ liver transplant recipients compared to HCV+ or HIV+/HCV+ coinfected recipients in the United States. Clin Infect Dis 2015; 61:1054–1062.
3. Grant JL, Hawkins C, Brooks H, Palella FJ Jr, Koppe SWP, Abecassis MM, Stosor V. Successful sofosbuvir-based therapy in HIV/hepatitis C virus coinfected liver transplant recipients with recurrent hepatitis C virus infection. AIDS 2015; 30:93–98.
4. AASLD/ISDA HCV Guidance Panel. Hepatitic C guidance: AASLD-ISDA recommendations for testing, managing and treating adults infected with hepatitis C virus. Hepatology. 2015. (In press).
5. European Association for the study of the liver EASL recommendations on treatment on hepatitis C 2015. J Hepatol 2015; 63:199–236.
6. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373:705–713.
7. Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. J Am Med Assoc 2015; 313:1223–1231.
8. Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373:714–725.
9. Rockstroh JK, Nelson MN, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. C-EDGE co-infected: phase 3 study of grazoprevir/elbasvir in patients with HCV/HIV. J Hepatol 2015; 62:0887.
Keywords:

combination antiretroviral therapy; direct-acting antivirals; HIV/hepatitis C virus coinfection; liver transplant

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