Worldwide, currently 35 million people are infected with HIV¹ and 130 million are infected with HCV.² HIV/HCV coinfected persons are known to have accelerated liver disease progression, cirrhosis, and decompensation, compared to HCV monoinfected persons.³ In addition, HIV/HCV patients are frequently diagnosed with hepatocellular carcinoma and are more likely to have multifocal disease.⁴ There has been a recent explosion of direct acting agents (DAAs) for the treatment of HCV infection. The focus of this discussion is to review emerging treatment options and their practical applications.

Newer therapies appear to be equally efficacious in HIV/HCV coinfected and HCV monoinfected patients. This is a critically important difference because previously, HIV/HCV coinfected patients had poorer response rates.^5,6 Current guidelines recommend different medication combinations for different durations, based HCV genotype and HCV treatment history.⁷ The COSMOS trial showed that the combination of sofosbuvir and simeprevir with or without ribavirin (RBV) for 12 or 24 weeks resulted in sustained virologic response (SVR12) rates from 67%-100% for patients with genotype 1 HCV monoinfection.⁸ For patients with HIV/HCV, genotype 1 coinfection, sofosbuvir with pegylated interferon (IFN) and RBV for 12 weeks, sofosbuvir and weight-based RBV for 24 weeks, or sofosbuvir with simeprevir with or without RBV for 12 weeks, are all guidelines-recommended treatment options. These guidelines continue to recommend IFN-based treatment as the standard of care; however data from multiple clinical trials of DAAs support the use of IFN-free, all-oral HCV treatment regimens. As more medications receive approval from the United States Federal Drug Administration, these guidelines will most likely be revised to reflect an increased emphasis on all-oral HCV therapy with interferon containing regimens playing a limited role.

In the PHOTON-1 trial, as reported by Sulkowski and colleagues and reviewed in this issue, patients with HIV/HCV co-infection (182 treatment-naïve and 41 treatment-experienced) with genotypes 1, 2, or 3 given an all-oral regimen of sofosbuvir and RBV for 12 or 24 weeks had SVR12 rates ranging from 67%- 94% with few adverse events. These results are exciting because they are similar to the 68% SVR 24 results in the SPARE trial that looked at 60 genotype 1 HCV monoinfected patients with difficult to treat characteristics (black race, higher fibrosis scores, early to moderate liver cirrhosis) using sofosbuvir with weight based ribavirin for 24 weeks (SVR 24 for the arm with low dose ribavirin was only 48%).⁹

In addition, sofosbuvir does not have significant drug interactions with the cytochrome P450 system, making it an attractive option for HIV patients on antiretrovirals metabolized through the cytochrome P450 system. In PHOTON-1, HIV/HCV patients with genotype 1 HCV infection who received 24 weeks of sofosbuvir and RBV had SVR12 rates of 76%. Preliminary data from the ERADICATE trial were presented at the European Association for the Study of the Liver (EASL) 2014. This study assessed the efficacy of the recently FDA-approved single pill, fixed-dose combination of ledipasvir (NS5A inhibitor) and sofosbuvir in 50 HIV/HCV coinfected patients with genotype 1a and found an SVR12 rate of 100% in patients not on antiretroviral therapy (ART).¹⁰ These data are comparable to the 94%-100% SVR 12 rate observed with ledipasvir/sofosbuvir when given for 8, 12, or 24 weeks among treatment-naïve and treatment-experienced patients with HCV monoinfection, with or without ribavirin.^11-13

At EASL 2014, Sulkowski et al presented data on the C-WORTHY study, an all oral regimen combining MK5172 (HCV NS3/4A protease inhibitor) with MK 8742 (NS5A replication complex inhibitor) with or without RBV for 12 weeks among 59 non-cirrhotic patients with HIV/HCV genotype 1 co-infection and for 8 or 12 weeks among 94 treatment-naïve, non-cirrhotic patients with HCV monoinfection. The C-WORTHY study, included in this review, showed an SVR4 rate of 97% with and 90% without RBV, with 29 and 30 subjects included in the two arms of the study. However, it was observed that the shorter-duration treatment group (8 weeks) among HCV monoinfected patients had a higher relapse rate of 17%. It is also important to note that MK 5172 affects the CYP3A4 enzyme system, which may pose a challenge for HIV/HCV patients on ART.

The TURQUOISE-1 trial presented by Sulkowski and co-workers (reviewed in this issue) showed that an all-oral regimen of paritaprevir (formerly ABT-450)/ritonavir/ombitasvir with dasabuvir and RBV in HIV/HCV coinfected genotype 1 patients had SVR12 rates of 94% with 12 weeks of therapy (N = 31) and SVR 4 rate of 97% with 24 weeks of therapy (N = 3 2, SVR 12 results pending). These data were similar to those reported among 380 treatment naïve and experienced HCV monoinfected genotype 1 patients with compensated cirrhosis in the TURQUOISE-II trial, which assessed the same treatment regimen. SVR12 rates were 92% for patients treated for 12 weeks and 96% for those treated for 24 weeks.¹⁴ In the SAPPHIRE-1 trial, 631 HCV genotype 1 monoinfected treatment-naïve, non-cirrhotic patients were treated with the regimen and had SVR12 rates of 95-98%.¹⁵ This multidrug oral regimen is unique in incorporating ritonavir as a booster agent for the HCV DAAs. Its use in HIV/HCV coinfected patients may require adjustment of ART regimens to avoid ritonavir-related drug-drug interactions.

As reviewed in this issue, Sulkowski and others studied an oral combination of daclatasvir and sofosbuvir among 211 patients with HCV monoinfection. The trial included treatment-naïve patients and those that had previously been treated with telaprevir or boceprevir and pegylated interferon and ribavirin. The study authors reported SVR12 rates of 89-100% across HCV genotypes 1-3, including patients with genotype 1 infection who had previously failed treatment with boceprevir and telaprevir-containing regimens. Ribavirin use and the presence of IL28B variants had no effect on SVR rates. A notable feature of daclatasvir is that it has activity across all genotypes. There is an ongoing study to assess this combination in HIV/HCV co-infection (ALLY-2: Daclatasvir and Sofosbuvir for HIV/HCV Co-Infection)

Vaniprevir, a next-generation HCV protease inhibitor, was evaluated as an add-on to IFN and RBV in 211 non-cirrhotic HCV-monoinfected genotype 1 patients that had previously failed IFN-based therapy. This study by Lawitz et al, reviewed in this issue, had multiple treatment arms, including a control group that received IFN and RBV. Patients in the treatment arms achieved SVR24 rates of 67% to 84%, compared with 19% in the control arm. The regimen still requires a backbone of IFN and RBV, as well as twice daily dosing of vaniprevir. Further investigations are needed in the coinfected patient population – and in a regimen free of IFN

With the advent of all-oral DAAs regimens, justifiable concerns have arisen about HCV resistance and its impact on treatment outcomes.¹⁶ The COSMOS study showed that the presence of the Q80K polymorphism at baseline in HCV genotype 1a was associated with numerically inferior SVR12 results when monoinfected patients were treated with sofosbuvir and simeprevir with or without ribavirin.8 HCV variants with pre-existing polymorphisms associated with drug resistance variants have been detected , although their clinical significance is unclear. In general, HCV protease inhibitors have a low barrier to the development of resistance, whereas polymerase inhibitors (nucleos(t)ide and non-nucleoside) have a higher resistance barrier. In the ION-1 and ION-2 studies, the presence of baseline variants associated with resistance did not have an impact on SVR12 results.^12,13 The S282T variant, associated with reduced susceptibility to sofosbuvir, was not detected when used in combination with ledipasvir, suggesting that combination therapy with the newer HCV direct-acting agents may help protect against emergence of resistance.^12,13,17 While NS3 variants generally decayed over time, the NS5A variants persisted – the clinical implications of these variants are still not clear.^18,19

Some areas still need further investigation. This is especially true for patients with HCV genotype 3 infections (both HCV mono- and HIV-HCV coinfection), for which limited data are available on the use of DAAs. Additional studies should also be performed in underrepresented populations — including blacks, Hispanics, women, and non-genotype 1 patients—to ensure applicability of study results across patient groups.

In summary, the treatment of HCV infection with regimens containing newer DAAs has been shown to be highly effective and safe. There is accumulating evidence that HIV-infected patients respond equally well to these regimens. Multiple new DAAs are likely to be approved in the near future, giving patients and providers additional treatment options. Factors driving optimal HCV treatment regimens include efficacy and tolerability of the drugs, fixed-dose combinations such as ledipasvir-sofosbuvir, consideration of drug interactions, concern for emergence of HCV resistant mutants, and cost. Treatment decisions, including whether to begin HCV therapy with the currently available DAAs or to wait for approval of drugs currently under investigation will have to be individualized and made in discussion with the patient.

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