Liver International ISSN 1478-3223 REVIEW ARTICLE Optimal therapy of HIV/HCV co-infected with direct acting antivirals J urgen K. Rockstroh 1,2 1 Department of Internal Medicine I, Bonn University Hospital, Bonn, Germany 2 German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany Keywords HIV hepatis C liver disease direct acting antivirals cirrhosis Abbreviations ART, antiretroviral therapy; cart, combined antiretroviral therapy; DAA, direct acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; IQR, interquartile range; PI, protease inhibitors; RBV, ribavirin; SVR, sustained viral response. Correspondence Prof. Dr J urgen Kurt Rockstroh, Department of Medicine I, Bonn University Hospital, Sigmund-Freud-Str. 25, Bonn 53105, Germany Tel: +49 228 287 16558 Fax: +49 228 287 15034 e-mail: juergen.rockstroh@ukb.uni-bonn.de Abstract The development of direct acting antivirals (DAAs) against the hepatitis C virus (HCV) has revolutionized treatment paradigms for HCV in HIV coinfected subjects. In the era of DAAs, HIV/HCV co-infected have the same cure rates of over 90% with interferon (IFN)-free DAA combinations. Therefore, guidelines no longer separate mono- and co-infected subjects. Indications for HCV therapy and DAA drug selection have become the same for all. The only special consideration in HIV/HCV co-infected subjects is the need to check for drug drug interactions between HIV and HCV drugs, especially HIV and HCV protease inhibitors which have a high risk of clinically significant drug interactions. Because of the faster progression of fibrosis and the higher risk of hepatic decompensation in co-infected subjects, even with combination antiretroviral (ART) therapy, the availability of modern HCV treatments needs to be extended and HCV therapy should be discussed in all co-infected. DOI:10.1111/liv.12721 Key points 2.8 Million (IQR 1.6 5.9 Million) HIV infected subjects have HCV-antibodies worldwide. HCV associated liver disease has emerged as a main cause of morbidity and mortality in HIV/HCV co-infection in the era of combined antiretroviral therapy (cart). In the era of DAA there is no longer any separation between mono- and confected for the indications of HCV treatment or drug choice. DAA-based IFN-free combination therapy is the optimal HCV therapy with expected HCV cure rates >90% for genotypes 1 and 3 6. Sofosbuvir and ribavirin are the new gold standard therapy in genotype 2. Before beginning HCV therapy, concomitant HIV therapy needs to be checked for potential drug drug interactions. Background As a result of shared modes of transmission, the prevalence of hepatitis C virus (HCV) is high in with human immunodeficiency virus (HIV) co-infection. Indeed, worldwide, an estimated 2.8 million [IQR (interquartile range) 1.6 5.8 Mill] HIV-infected subjects also have antibodies against HCV, with most infections in Africa and Southeast Asia, emphasizing the need for HCV treatment and management strategies in these areas of the world (1). In Europe, one of four HIV also has chronic HCV, with much higher rates of co-infection in Eastern and Southern Europe than in Central and Northern Europe (2). Because the natural history of HCV is accelerated in with HIV, and especially in those with advanced immune deficiency and because of the availability of combination antiretroviral therapy, HCV associated liver disease has become a main cause of morbidity and mortality in HIV/HCV infected individuals (3). Unfortunately, pegylated interferon (IFN) and ribavirin (RBV) combination therapy is associated with significantly lower HCV cure rates in HIV/HCV coinfected than in HCV mono-infected subjects (4). This lower efficacy and the severity of IFN/RBV associated adverse events have limited the use of HCV therapies in this special patient population (5). However, in early pilot trials with direct acting antivirals (DAAs), in particular first generation HCV protease inhibitors telaprevir and boceprevir, similar increased cure rates were 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 51
Optimal therapy of HIV/HCV co-infected with DAAs Rockstroh reported in both na ıve and treatment-experienced HIV/ HCV co-infected as well as in with HCV infection alone, with cure rates between 63 and 80% (6 8). With the marketing of IFN-free DAA combinations and potential of cure rates above 95%, as well as shorter treatment without IFN and even without RBV, in the near future telaprevir/boceprevir and IFN may no longer be a component of the HCV treatment and management strategy. Because of the similar sustained viral response (SVR) rates in HCV mono- and HIV/HCV co-infected subjects, major guidelines such as the recent EASL updated HCV clinical practice guidelines, no longer differentiate between HIV/HCV co-infected and HCV mono-infected (9). Indeed indications and treatment choices are now the same. The only remaining issue is the need to check for drug drug interactions between antiretroviral HIV drugs and DAAs. The following review provides practical guidelines on the use of DAAs in HIV/HCV co-infection and discusses who should be treated and when and how to treat. However, it should be kept in mind that progress is being made in HCV therapy at an incredibly fast pace so that treatment strategies are subject to constant change with the development of even more potent new DAA drug combinations. It should also be emphasized that access to these medical advances varies in the different European countries probably because of the high cost of the new DAAs, which is unfortunately a major barrier to these life-saving medications. Practical considerations for HCV therapy in HIV/ HCV co-infection Indication for therapy and patient selection: treat with significant fibrosis HCV treatment can potentially eradicate HCV within a defined period. This is also beneficial to the management of HIV co-infected, thus all co-infected individuals should be considered for treatment when the benefits of therapy outweigh the risks. This must also be considered within the context of the faster progression of liver fibrosis in HIV/HCV co-infection and the improved outcome in treated with direct acting antivirals (DAAs). Indeed, even with successful HIV therapy and persistent suppression of HIV replication, the risk of hepatic decompensation is still higher in HIV/HCV co-infected than in HCV mono-infected (10). Moreover achieving an SVR has also been associated with improved overall survival even in the lower stages of fibrosis (F0 F2) suggesting that HCV therapy provides benefits beyond the cure of HCV and may prevent the progression of liver disease (11). Nevertheless, fibrosis is not likely to progress with stable combined antiretroviral therapy (cart), making a wait and see approach a feasible strategy in HIV/HCV coinfected subjects with little or no fibrosis (F0 F1), especially since HCV drugs with even shorter treatment durations are expected on the market in the near future. For more advanced fibrosis, however, treatment should be considered because fibrosis has already developed and cirrhosis can occur. Because of limited resources, should be prioritized according to need (F3 and F4), an approach which is being adopted in most European countries at present. Figure 1 provides a management algorithm for newly diagnosed HCV. Which should be treated first: HIV or HCV? If chronic HCV is detected early in the course of HIV infection [before ART (antiretroviral therapy)], chronic HCV should be treated because there is no need to consider drug drug interactions. In with a CD4 cell count <500 cells/ll, early ART is recommended to slow the progression of fibrosis. Interferon (IFN)-based HCV therapy has been shown to be more successful in HIV with complete suppression of HIV replication. Therefore, in a patient with HIV/HCV co-infection, the CD4 cell count should be improved with ART before beginning anti-hcv treatment if the CD4 cell count <350 cells/ll. Patients with a CD4 relative percentage >25% who receive IFN-based therapy are more likely to achieve SVR than those with a lower CD4 percentage (12). DAA combinations will clearly be used in the future without IFN and RBV and the treatment duration will be shorter making a strong immune system less important than in IFN-based regimens, because these new HCV treatments are not expected to affect the CD4-count. HCV therapy selection depends on the genotype There are several options for HCV therapy. IFN-free and possibly RBV-free regimens should be chosen when available because of shorter treatment, significantly fewer side effects and improved cure rates (13). However, because of costs, access to the newer HCV drugs may be limited in certain countries or regions. In these cases, HCV drug combinations may be needed because cure rates may be significantly improved compared to PEG-IFN/RBV alone. Tables 1 and 2 summarize the IFN-free and IFN-containing HCV regimens for the different HCV genotypes. Sofosbuvir and RBV is the new gold standard therapy for genotype 2 in both treatment na ıve and treatment experienced. This combination provides a cure for HCV in more than 90% of treated. Indeed in the PHOTON 1 and 2 studies, a SVR was achieved at week 12 with sofosbuvir and RBV in 88 and 89% of HCV treatment na ıve and HIV coinfected subjects with HCV genotype 2 infection respectively (14, 15). Longer treatment (16 weeks) may be needed in with cirrhosis. In all other genotypes, despite quite high average response rates above 80%, sofosbuvir and RBV alone are not the preferred option because of higher relapse rates than with two DAA combinations. However, in case of 52 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Rockstroh Optimal therapy of HIV/HCV co-infected with DAAs Newly diagnosed chronic HCV GT 1 6 infection Perform Fibroscan and/or serum marker and/or liver biopsy F0 F1 * F2 F3 * F4 * In general, treatment can be deferred HCV treatment should be discussed IFN-free HCV treatment needs to be initiated Fig. 1. Management algorithm for HCV of all genotypes. *Metavir fibrosis score: F0 = no fibrosis; F1 = portal fibrosis, no septae; F2 = portal fibrosis, few septae; F3 = bridging fibrosis; F4 = cirrhosis. Table 1. IFN-free HCV treatment options for the various HCV genotypes HCV genotype Treatment Treatment duration in treatment-naive Treatment duration in treatment-experienced 1 & 4 SOF + RBV 24 weeks 24 weeks SOF + SMP 12 weeks (possible extension up to 24 weeks and/or addition of RBV) 12 weeks (possible extension up to 24 weeks and/or addition of RBV) SOF + DCV 12 weeks in non-cirrhotics, 24 weeks in compensated cirrhotics 12 weeks in non-cirrhotics, 24 weeks in compensated cirrhotics 2 SOF + RBV 12 weeks (possible extension 12 16 weeks up to 16 weeks in cirrhotics) 3 SOF + RBV 24 weeks 24 weeks SOF + DCV + RBV 24 weeks in compensated cirrhotics 24 weeks 5 & 6 In the absence of clinical data on DAAs in HCV GT 5 and 6 infection should be treated similar to HCV GT 1 and 4 infection RBV, ribavirin; SOF, sofosbuvir; SMP, simeprevir; DCV, daclatasvir. Table 2. IFN-containing HCV treatment options for all genotypes HCV genotype Treatment Treatment duration in treatment-naive Treatment duration in treatment-experienced 1 & 4 SOF + PR 12 weeks (possible extension up to 24 weeks in cirrhotics) 12 24 weeks SMP* + PR 24 weeks (48 weeks in cirrhotics) 48 weeks DCV + PR 24 weeks if RVR, 48 weeks if non-rvr 24 weeks if RVR, 48 weeks if non-rvr 2 PR IFN-free treatment recommended. If SOF not available: PR 24 weeks if RVR, 48 weeks if non-rvr 3 SOF + PR 12 weeks (possible extension up to 24 weeks in cirrhotics) 12 24 weeks 5 & 6 In the absence of clinical data on DAAs in HCV GT 5 and 6 infection should be treated similar to HCV GT 1 and 4 infection *SMP for 12 weeks only. Also in relapsers. DCV for 24 weeks only. GT 4 only. PR, pegylated interferon + ribavirin; RBV, ribavirin; SOF, sofosbuvir; SMP, simeprevir; DCV, daclatasvir. intolerance to interferon and if other DAAs are not available, a cure is still possible in a high percentage of with the combination of sofosbuvir and RBV. This was especially true in treatment-na ıve genotype three in the PHOTON 2 trial, where 24 weeks treatment was associated with an SVR rate of 89% (15). Sofosbuvir and simeprevir or daclatasvir are clearly the best treatment regimens for with genotypes 1 and 4. Because simeprevir is not active in genotype 3, 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 53
Optimal therapy of HIV/HCV co-infected with DAAs Rockstroh the combination of sofosbuvir and daclatasvir is the best treatment regimen. In the near future, other combinations will become available. A fixed dose of sofosbuvir/ledipasvir will probably be available in November 2014 for genotypes 1 and 4. This combination may be used for a shorter duration of 8 weeks in HCV treatment-na ıve without advanced fibrosis. Initial data from an ongoing pilot trial in 50 HCV treatment-na ıve genotype 1 HIV/HCV co-infected reported significant SVR4 rates of 100% (16). The combination paritaprevir/rtv/ombitasvir, 150 mg/ 100 mg/25 mg QD + dasabuvir, 250 mg BID + RBV twice a day (BID = bis in die) is expected to be licensed in early 2015 for genotypes 1 and 4. First results from this combination from the ongoing TURQUOISE trial have shown high SVR4 rates between 93.5 and 96.9 after 12 and 24 weeks of therapy in HIV/HCV coinfected with HCV genotype 1 infection and no prior HCV therapy respectively (17). Drug drug interactions should be carefully checked Drug interactions are common especially in combinations including HCV protease inhibitors, which are metabolized through the cytochrome 450 pathways like HIV Nonnucleoside reverse-transcriptase inhibitors (NNRTIs) or Protease Inhibitors. Therefore, combinations with HIV drugs must be checked on drug interaction websites such as www.hep-druginteractions.org. Potential drug drug interactions with sofosbuvir, which is not metabolized by the cytochrome p450 pathway, are low. The only antiretroviral drug which should not be co-administered because of significant interactions is tipranavir. Significant interactions exist with simeprevir, which uses metabolization pathways that are similar to those in HIV protease inhibitors and NNRTIs. Indeed at present other than the NRTI backbones abacavir/3tc or tenofovor/ftc, concomitant use is only recommended with raltegravir, dolutegravir or rilpivirine. For the moment only limited data on PK interactions exist for daclatasvir. Atazanavir/r is the only HIV protease inhibitor that has been evaluated to date. Co-administration is possible but the dose of daclatasvir should be adapted to 30 mg per day. The results of pharmacokinetic interaction studies with other boosted HIV protease inhibitors will be presented at the Conference on Retroviruses and Opportunistic Infections meeting in February 2015. Co-administration with efavirenz is possible but because of enzyme induction an increase in the dose of daclatasvir to 90 mg is recommended. Rilpivirine, dolutegravir and raltegravir can be safely co-administered with no change in dose (60 mg per day). Conclusions End-stage liver disease secondary to HIV/HCV coinfection is one of the main causes of mortality in with HIV being treated with ART, because the progression of liver disease associated with HCV infection is accelerated. With the availability of highly active ART, and as live longer, the prevalence of hepatocellular carcinoma is expected to rise. Without early effective HCV treatment, these have a high risk of HCV-related sequelae. Treating HCV in with HIV/HCV co-infection will not only decrease the rate of mortality associated with liver disease and improve the quality of life but it will also improve the outcome of other inflammation-associated comorbidities. IFN and RBV-free therapies are now a reality, promising a cure in most. Indeed, the outcome of treatment in HIV/HCV coinfected and HCV mono-infected subjects is now similar. Unfortunately, the high costs of HCV treatment have limited availability of these new therapies so far. Hopefully as the number of DAA combinations increases and competition grows, prices will fall, allowing broader access to modern HCV therapy. Acknowledgements This study was supported by the DZIF TTU HIV Project 05.803, and the German Center for Infection Research (DZIF). Conflict of interest: JKR has recieved honoraria for speaking at educational events or consulting from Abbvie, Bionor, BMS, Gilead, Janssen, Merck, Tibotec, Tobira, and ViiV. References 1. Easterbrook P. Global burden of hepatitis B and C, and HIV co-infection. International HIV/Viral Hepatitis Co- Infection Satellite Meeting Melbourne, 18 19 July 2014 2. Rockstroh JK, Peters L, Grint D, et al.; EuroSIDA in Euro- Coord. Does hepatitis C viremia or genotype predict the risk of mortality in individuals co-infected with HIV?. J Hepatol 2013; 59: 213 20. 3. 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