Latest pharmacotherapy options for treating hepatitis C in HIV-infected patients.

Review

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 08/03/14 For personal use only.

Latest pharmacotherapy options for treating hepatitis C in HIV-infected patients 1.

Introduction

2.

Protease NS3/4 inhibitors

3.

Polymerase NS5B inhibitors

4.

NS5A inhibitors

5.

Expert opinion

Juan Macıás, Karin Neukam, Nicola´s Merchante & Juan A Pineda† Hospital Universitario de Valme, Unit of Infectious Diseases and Microbiology, Sevilla, Spain

Introduction: Hepatitis C virus (HCV)/HIV-coinfected patients are at an increased risk of progression of liver disease. Consequently, they benefit most from sustained virological response (SVR) to treatment against HCV. However, SVR rates to pegylated IFN plus ribavirin are disappointingly low in HIV/HCV coinfection. Nevertheless, therapy against HCV is rapidly changing due to the advent of directly acting antiviral drugs against HCV (DAA). Now, high SVR rates can be obtained in HIV/HCV coinfection with DAA regimens. Areas covered: Data on DAAs in advanced stages of development in HIV/HCV coinfection, those that have entered Phase III clinical trials in this particular subset, are summarized. A search of clintrials.gov was done to identify DAAs entering Phase III trials that included HIV/HCV-coinfected patients. Expert opinion: HCV cure is possible in a high proportion of HIV-coinfected patients with currently available DAA. Caveats of first-generation DAAs are mostly solved by next-generation DAAs. Thus, all-oral regimens under development may be close to the ideal HCV therapy for HIV-coinfected patients. However, the elevated cost of newer DAAs can limit their access. Keywords: direct-acting antiviral drug, hepatitis C virus, HIV, treatment Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Hepatitis C virus (HCV) coinfection is found in approximately 10 -- 30% of the persons living with the HIV, with wide variations around the world [1]. HIV/HCV coinfection results in an increased risk of death [2,3], with very short life expectancy once the first decompensation of cirrhosis ensues [4]. Progression to end-stage liver disease and death can be effectively prevented in HIV/HCV coinfection with therapy against HCV [5]. However, only pegylated IFN plus ribavirin (PegIFN/RBV) were available until very recently to treat HCV infection. PegIFN/RBV in HIV/HCV coinfection offered very limited efficacy, particularly for HCV genotype 1 (G1) and 4 (G4) [6-8]. A new paradigm of treatment against HCV has changed the face of HCV therapy. The development of direct-acting antiviral drugs (DAA) addressed to specific viral targets is bringing unprecedented rates of sustained viral response (SVR). The first-generation NS3/4 protease inhibitors (HCV-PIs) increase the efficacy of PegIFN/RBV, but also add more severe side effects, drug--drug interactions (DDIs) and inconvenience due to a large pill burden [9,10]. In addition, boceprevir (BOC) is only active against G1, whereas telaprevir (TVR) is active against G1 and G4 [9,10]. Next-generation DAA improve the efficacy of TVR or BOC, show better adverse event (AE) profile, less potential DDIs and dosing is usually once-daily [9]. Furthermore, these newer DAA may be combined without PegIFN, thus improving the tolerability of therapy. The aim of this review is to present data on DAAs in advanced stages of development in HIV/HCV coinfection, specifically on those that have already entered Phase III clinical trials (Table 1) including HIV/HCV-coinfected patients. 10.1517/14656566.2014.934810 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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J. Macıás et al.

Article highlights. .

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Sustained virological response (SVR) rates for pegylated-IFN plus ribavirin (PegIFN/RBV) are low for HIV/hepatitis C virus (HCV)-coinfected patients, particularly for those with genotype 1. Boceprevir (BOC) and telaprevir (TVR) provide better SVR rates for HIV/HCV-coinfected patients, but are burdened by side effects and inconvenience. BOC and TVR show relevant drug--drug interactions (DDIs) with some antiretroviral drugs. Newer direct-acting antiviral drugs (DAA) improve SVR rates achieved by BOC or TVR, show better adverse event profile and dosing is usually once-daily. Many of the newer DAA have less potential for DDIs with ART. The increased cost of newer DAA limits the access to them.

This box summarizes key points contained in the article.

2.

Protease NS3/4 inhibitors

Dosage and treatment duration The first DAAs approved by the FDA were BOC and TVR. Both drugs are administered orally in combination with PegIFN/RBV and are burdened by high pill number and multiple dosing. Total treatment duration of BOC or TVRincluding regimens in HIV/HCV-coinfected patients is usually 48 weeks. However, response-guided therapy (RGT) can be applied to TVR-based therapy in HIV/HCV-coinfected patients naı¨ve to treatment or with relapse to previous PegIFN/ RBV showing extended rapid viral response, thus resulting in a 24-week-length course of therapy [11]. A 4-week lead-in of PegIFN/RBV alone is administered before BOC is added to PegIFN/RBV [10,12]. TVR is given during the first 12 weeks of therapy in combination with PegIFN/RBV [10,12]. Stopping rules for BOC are applied at weeks 8, 12 and 24, and for TVR at weeks 4 and 12 [10,12]. Treatment-naı¨ve patients without HIV infection or cirrhosis on BOC plus PegIFN/RBV who are HCV RNA undetectable at week 8 and remain undetectable at week 24 can stop all drugs at week 28 [10]. Ongoing studies are evaluating the feasibility of shorter durations for triple therapy including BOC in the coinfected population [13,14]. The FDA approved the second-generation HCV-PI simeprevir (SMV) in November 2013 as an add-on to IFN-based therapy for patients with chronic HCV G1 infection. SMV has shown good efficacy both with Peg-IFN/RBV and in several interferon-free regimens. However, the current approval does not include the use in IFN-free combinations. SMV is not yet authorized for HIV/HCV coinfection. Triple IFNbased therapy is used for 12 weeks, with PegIFN/RBV alone continued for 12 weeks more for treatment-naive patents and prior relapsers, or 36 more weeks for prior partial and null responders. RGT can be applied to SMV, with the consequent shortening length of therapy [15]. Data from a Phase III clinical trial support RTG also for HIV/HCV-coinfected patients [16]. 2.1

2

Newer HCV-PIs include faldaprevir (FDV), asunaprevir (ASV) and ritonavir-boosted ABT-450 (ABT-450/r). FDV 120 -- 240 mg for 24 -- 48 weeks is being evaluated in a Phase III trial in HIV/HCV coinfection [17]. An accelerated assessment was granted for FDV from the European Medicines Agency (EMA) in November 2013. ASV has being developed only in combination with daclatasvir (DCV); due to this it is discussed together with DCV. ABT-450/r is included in alloral combinations comprising DAAs of different families [18]. Efficacy and safety of NS3A/4 PIs A summary of the main characteristics of HCV-PI evaluated in Phase III clinical trials including HIV/HCV-coinfected patients is given in Table 1. 2.2

Boceprevir The Phase II clinical trial including treatment-naı¨ve patients showed that BOC provided an increase in SVR rate of 30% over placebo (Figure 1A) [19]. AEs were more frequently observed in patients receiving BOC, the most common being anemia (41%), fever (36%) and dysgeusia (28%). Study drug discontinuations due to AEs were observed in 13 (20%) of those individuals who received BOC versus 3 (9%) patients of the placebo group. An intention-to-treat analysis of the 64 treatmentexperienced patients enrolled in the BocepreVIH study reported SVR12 rates of 53% [20]. According to previous response, SVR12 rates were 90% for relapsers, 61% for partial responders and 24% for prior null responders. The vast majority of the patients reported AEs, including gastrointestinal symptoms, skin rash or itching, dysgeusia and neuropsychiatric problems. Twenty (31%) individuals experienced serious AEs. It can be concluded that the efficacy and safety of BOC in HIV/HCV-coinfected patients, either naı¨ve or experienced, is similar to those of HCV-monoinfected patients. Phase III clinical data are awaited from the ongoing studies BIRTH and BOC-HIV [13,21]. 2.2.1

Telaprevir In a Phase II trial on HIV/HCV coinfection, SVR rate was 30% greater for patients receiving TVR compared to those randomized to placebo (Figure 1B) [22]. Two patients suffered ontreatment HCV breakthrough with TVR-resistant variants. The following AEs were more frequent with TVR than with placebo: pruritus (34 vs 5%), rash (29 vs 18%) and anorectal discomfort (13 vs 5%). Hemoglobin < 10 mg/dl levels were observed in 18% of those who received TVR versus 32% of the individuals in the control group. Serious AEs occurred in 5% of those receiving TVR and none of those receiving placebo. The same number in both groups discontinued treatment due to AEs. In an intention-to-treat analysis of the TelapreVIH study [23], in which TVR was administered to 68 experienced patients after a 4-week lead-in phase of Peg-IFN/RBV, an overall SVR12 rate of 80% was reported. SVR12 rates were 100 and 71% among 2.2.2

Expert Opin. Pharmacother. (2014) 15(13)

Latest pharmacotherapy options for treating hepatitis C in HIV-infected patients

Table 1. Direct antiviral agents against hepatitis C virus evaluated in Phase III studies among HIV-coinfected patients. Drug family, mechanism of action

Drug name

Genotype activity

Drug--drug interactions with antiretroviral therapy

Interferon-free regimens

Specific side effects

Telaprevir Boceprevir Faldaprevir Simeprevir

1, 4 1 1, 4, 5, 6 1, 4

Y Y Dose adjustment Y

N N Y Y

Asunaprevir

1 -- 4*

ND

Y

ABT-450

1 -- 4, 6

ND

Y

Anemia, rash, anorectal symptoms Anemia, dysgeusia Transient bilirubin elevations Transient bilirubin elevations, rash, GI symptoms Transient ALT or AST elevations, GI symptoms None specific

Sofosbuvir Dasabuvir

Pangenotypic 1

N ND

Y Y

None specific None specific

Daclatasvir Ombitasvir Ledipasvir

Pangenotypic Pangenotypic Pangenotypic

Dose adjustment ND ND

Y Y Y

None specific None specific None specific


NS5A inhibitors

*In vitro activity against genotype 2 and 3 has been shown in combination with daclatasvir. Y: Yes; N: No; ND: No data.

A.

B. 100

100

90

90

80

80

70

63

60 50 40 29

30 20 10

% Patients with SVR

% Patients with SVR


Protease NS3A/4 inhibitors

74

70 60 45

50 40 30 20 10

0

0 BOC + PegIFN/RBV

Placebo + PegIFN/RBV

Sulkowski et al. Lancet Infect Dis 2013 [19]

TVR + PegIFN/RBV

Placebo + PegIFN/RBV

Sulkowski et al. Ann Intern Med 2013 [22]

Figure 1. Sustained virological response rates in HIV/HCV coinfection Phase II trials involving boceprevir or telaprevir. A. Boceprevir plus pegylated interferon and ribavirin compared with placebo plus pegylated interferon and ribavirin. B. Telaprevir plus pegylated interferon and ribavirin compared with placebo plus pegylated interferon and ribavirin. A. Data taken from [19]. B. Data taken from [22]. HCV: Hepatitis C virus.

prior partial responders and null responders, respectively. Fourteen (20%) individuals experienced grade 4 AEs; however, skin rash was not among these events. The rate of grade 4 anemia was 10% and two patients died, one due to intracranial bleeding

associated with thrombocytopenia and the other from an upper gastrointestinal hemorrhage. A number of Phase III trials including TVR are ongoing [11,24,25]. An interim intention-to-treat analysis of the


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100

89

SVR12 (%)

80

71

67

72

60 40


20 16/18

62/88

20/30

42/58

G1b

G1a

G1a with Q80K

G1a without Q80K

0

Figure 2. Sustained virological response rates after 12 weeks of the end of treatment to simeprevir plus pegylated interferon and ribavirin in the C-212 Phase III trial according to genotype 1 subtype and baseline Q80K variation. Reproduced with permission from [15].

INSIGHT trial has been reported [11]. That analysis involved both naı¨ve and experienced patients completing ‡ 12 weeks of treatment, or with earlier discontinuation [11]. Overall, undetectable HCV-RNA was observed in 72% of the patients at week 12. This accounted for 80% of naı¨ve patients, 72% of relapsers, 83% of partial responders and 57% of null responders. Nine percent discontinued TVR due to AEs. In the UNITE trial, individuals received TVR bid dosing along with Peg-IFN and a fixed RBV dose of 800 mg/day [25]. Naı¨ve patients and previous relapsers with undetectable HCVRNA at weeks 4 and 12 received 12 additional weeks of PegIFN/RBV, while the remaining patients received 36 additional weeks of Peg-IFN/RBV. SVR 12 weeks after the scheduled end of treatment (SVR12) was achieved by 44/67 (66%) treatmentnaı¨ve patients, 16/21 (76%) prior relapsers, 5/8 (63%) prior partial responders and 6/13 (46%) prior null responders. Of the 88 candidates for RGT, 63 (72%) patients received shortened treatment, with 53/63 (84%) achieving SVR12. Ontreatment serious AEs were observed in 20 (11%) patients. In conclusion, interim Phase III trials results suggest that HIV/HCV G1-coinfected patients treated with TVR plus Peg-IFN/RBV achieve high response rates during therapy and SVR rates similar to those observed for HCV-monoinfected patients. TVR bid dosing can be applied to HIV/HCVcoinfected patients, regardless of prior HCV treatment response, and RGT with shortened duration is feasible in both naı¨ve patients and previous relapsers. Safety is similar to that observed in studies conducted in HCV monoinfection. Simeprevir SMV has been evaluated in HIV/HCV G1 coinfection in 106 patients included in the Phase III clinical trial C212 [15]. Nearly 90% of the patients were on ART, and the majority presented undetectable HIV viral load. An overall SVR12 rate of 74% was reported (Figure 2). SVR12 rates stratified by prior treatment status were naı¨ve individuals, 79%; relapsers, for 87%; partial responders, 70%; null responders, 57%. Naı¨ve 2.2.3

4

patients or previous relapsers, both without cirrhosis, were candidates for RGT if they showed HCV RNA < 25 UI/ml at week 4 and undetectable at week 12. Among them, 89% individuals met those criteria for shortening therapy from 48 to 24 weeks. Within this group, the SVR12 rate was 87%. Subjects infected with HCV G1b were more likely to achieve SVR12 than those infected with G1a (Figure 2). Unlike HCVmonoinfected patients receiving SMV, the SVR rate for G1a with and without the Q80K variation at baseline was similar (Figure 2). The effect of G1a plus Q80K on SVR has been stronger in HCV monoinfection trials, reducing SVR close to the rates of PegIFN/RBV alone [26]. Baseline fibrosis had an influence on response, with SVR 80% for F0-F2 and 64% for F3-F4. IL28B had also an effect on SVR: CC 96%, CT 68%, TT 61%. Virological failure on treatment was globally observed in 17% patients and in 39% prior null responders. Of the patients who underwent resistance testing, 79% had emergent resistance mutations, mostly R155K alone. AEs were similar to those observed in HCV-monoinfected patients, including rash (12%), pruritus (20%) and photosensitivity (2%). Neutropenia was found in 21% of the individuals and anemia in 28%. Four patients discontinued therapy due to AEs. Thus, SMV improves previous first-generation HCV-PI, mainly with easier dosing and shorter treatment duration, maintaining similar SVR rates with somewhat less side effects. Faldaprevir The STARTVerso 4 study is a Phase III clinical trial evaluating FDV 120 mg or 240 mg plus Peg-IFN/RBV in 308 HIV/ HCV-coinfected patients [17]. Extensive pharmacokinetic studies guided the design of the trial. Individuals on darunavir/ritonavir (DRV/r), atazanavir/ritonavir (ATV/r) or efavirenz (EFV) were allocated in treatment arms with dose adjustment, FDV 240 mg once a day (q.d.) for EFV and FDV 120 mg q.d. for DRV/r or ATV/r. Those on raltegravir (RAL) were randomized to FDV 120 mg q.d. or FDV 240 mg q.d. Patients on 120 mg FDV were treated for 24 weeks 2.2.4


100 90

88

83

80

72

69

70

73

76

71

71

75

64

60 50 40 30 20 10

s Ye

o N

G 1b

N

G 1a

s Ye

o N

C on

-C

C

ap R

el

ai N

C

se

0 ve

Patients with HCV RNA < LLOQ (%)



Prior treatment

IL28B

Cirrhosis

HCV genotype Baseline Q80K

Figure 3. Baseline factors and sustained virological response rates after 12 weeks of the end of treatment to faldaprevir plus pegylated interferon and ribavirin in the STARTVerso4 Phase III trial. Filled bars: Significant difference between categories; empty bars: No significant difference between categories. Reproduced with permission from [17].

with the triple regimen, while those who received 240 mg FDV were randomly assigned to FDV for 12 or 24 weeks. Subsequently, patients reaching HCV RNA < 25 UI/ml at week 4 and ARN VHC undetectable at week 8 were rerandomized to stop treatment at 24 or 48 weeks. The overall SVR12 rate was 72%. The SVR12 rates according to FDV dose were FDV 120 mg, 71%; FDV 240 mg, 72%. SVR rates were not influenced by FDV duration, HCV subtype, the presence of Q80K variation or cirrhosis at baseline (Figure 3). SVR12 rates were higher for relapsers than for naı¨ve patients (Figure 3). IL28B genotype had an effect on response (Figure 3). Almost all participants experienced AEs, as typically seen with Peg-IFN/RBV. In 19% of the cases, grade 3 or 4 total bilirubin elevations were observed. Twentytwo (7%) patients discontinued all therapy due to AEs. The efficacy and safety of FDV in HIV/HCV G1coinfected patients was similar to that observed in HCVmonoinfected patients. As SMV, FDV improves previous HCV-PI with easier dosing and shorter treatment duration, maintaining similar SVR rates with less side effects. Unfortunately, the manufacturer has withdrawn all pending marketing applications for FDV worldwide and has discontinued further development of this DAA. ABT-450 ABT-450/r is a HCV-PI assessed only in all-oral combinations. Available data come from HCV monoinfection trials evaluating regimens with ABT-450/r, ombitasvir plus dasabuvir with or without RBV. Ombitasvir is an NS5A inhibitor and dasabuvir is a non-nucleoside polymerase NS5B inhibitor. Both of them have only been investigated in combination with ABT-450/r and, thus, are commented only in this section along with ABT-450/r. Based on Phase II results, 2.2.5

the FDA designated the combination as ‘breakthrough therapy,’ which is intended to expedite the development and review of drugs for serious or life-threatening conditions. An open-label Phase III clinical trial recruiting HIV/HCV G1-coinfected patients, naive or experienced, is ongoing [18]. No results have been reported yet. Inclusion of patients with compensated cirrhosis is allowed. ART regimens are limited to combinations of tenofovir (TDF)/emtricitabine (ETC) or TDF/lamivudine (3TC) plus ATV/r or RAL. Individuals are randomized to ABT-450/r/ombitasvir and dasabuvir coadministered with RBV for 12 or 24 weeks. ABT-450/r 150 mg/100 mg is combined in a single pill with ombitasvir 25 mg q.d., together with dasabuvir 400 mg bid plus weight-based RBV. In the 631-patient SAPPHIRE-I study, 96% naı¨ve HCVmonoinfected patients receiving 12 weeks of ABT-450/r, ombitasvir and dasabuvir achieved SVR12 [27]. The majority of patients were infected by G1a. SVR12 rates of subjects infected by G1a were 95% and of those infected by G1b were 98%. Discontinuation rates due to AEs were 0.6%. In the HCV monoinfection SAPPHIRE-II study, 96% of 394 patients who previously failed PegIFN/RBV, including 49% of who were prior null responders, achieved SVR12 with ABT-450/r/ ombitasvir and dasabuvir [28]. SVR12 rates of G1a and G1b were 96 and 97%, respectively. Discontinuation rate due to AEs was 1%. Both SAPPHIRE-1 and SAPPHIRE-2 included only non-cirrhotic individuals. In the TURQUOISE-II Phase III trial, only HCV-monoinfected patients with compensated cirrhosis were included [29]. SVR12 rates were 92% for the 12-week arm and 96% for the 24-week arm. Only 2.1% of patients discontinued treatment due to AEs. The all-oral triple ABT-450/r/ombitasvir and dasabuvir combination shows extremely high SVR rates for a very short


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J. Macıás et al.

length of treatment with apparently negligible side effects, although results of Phase III trials are required to know better the side-effect profile of this combination. Designated breakthrough therapy by the FDA, a very fast approval of the combination is expected. One issue of this regimen is the bid dosing of dasabuvir, because other all-oral DAA combinations have the advantage of a q.d. scheme, as well as the use of ritonavir, which may limit the options for concomitant antiretroviral therapy.

In healthy volunteers, DRV/r and EFV led to significant interactions with SMV, while no relevant influence was observed with RAL, TDF and RPV [42]. The manufacturer does not recommend the coadministration of SMV with other non-nucleoside analog reverse transcriptase inhibitors or HIV-PI [15]. Similarly, FDV levels increase when given with DRV/r and decrease in the presence of EFV [43]. Due to this, dose adjustments were applied according to antiretroviral therapy in STARTVerso4 [17]. FDV did not show clinically relevant DDIs on antiretroviral drugs in STARTVerso4 [44,45].

2.3

DDIs between protease NS3/4 inhibitors and antiretroviral drugs

3.

The vast majority of the data available on DDIs between BOC or TVR and antiretroviral agents is derived from healthy volunteers. The clinical meaning remains unknown and data on HIV/HCV patients are urgently needed. There is evidence that the coadministration of BOC with RAL and rilpivirine (RPV) can be considered safe, while concomitant use of BOC with etravirine (ETV) or maraviroc (MVC) may be a possible option [30-33]. In contrast with the results from a DDI study in healthy volunteers [34], the coadministration of HIV-PI did not have an effect on HCV treatment response or HIV RNA control among patients receiving BOC in the P05411 clinical trial [19]. According to treatment guidelines, recommended combinations of antiretroviral drugs during BOC-based therapy include RAL, RPV and ETV, along with TDF and ETC or abacavir (ABV) and 3TC [10,35,36]. The FDA recommends not combining BOC with HIV-PI [37], while the EMA acknowledges that ritonavir-boosted atazanavir (ATV/r) may be used in patients without data suggesting resistance to HIV PIs and under strict surveillance of HIV RNA control [38]. Similar to what is observed with BOC, important DDIs have been observed between TVR and HIV-PI [39]. However, the influence of ATV/r on pharmacokinetics of TVR, and vice versa, was less intense than that observed with other HIV-PI [39]. A pharmacokinetic substudy of INSIGHT revealed that, among those patients who received ritonavir-boosted darunavir (DRV/r), no individual met HCV treatment stopping rule or experienced HCV or HIV virologic breakthrough during TVR administration. While TVR and DRV concentrations decreased, the plasma levels were higher than the lowest quartiles in historical studies. Additionally, there is evidence that coadministration of TVR with RAL [40], MVC [33], RPV or ETV [41] is safe; however, dose adjustments of MVC may be necessary and need to be evaluated. Guidelines suggest RAL or ATV/r along with TDF/ETC or ABV/3TC as first-choice antiretroviral drug combinations for patients starting BOC- or TVR-based therapy, while ETV or RPV could be regarded as alternative [10,35,36]. The QT interval should be monitored in patients receiving RPV along with TVR, particularly those exposed to other drugs that prolong that interval, as methadone [36]. Also, TDF/ETC or ABC/3TC plus EFV can be used along with TVR; however, the daily dose of TVR should be increased to 3375 mg [10,35].

Sofosbuvir Sofosbuvir (SOF) is the first direct-acting nucleotide polymerase inhibitor that has been approved by the FDA. SOF targets the highly conserved active site of the HCV-specific NS5B polymerase, acting as a non-obligate chain terminator, an effect that is independent of the viral genotype. SOF has a high genetic barrier to resistance. It is administered at a single daily dose of 400 mg without food requirements [46]. It has no influence on CYP3A/4 metabolism and no significant drug interactions with ART [47]. Preliminary data of the efficacy and safety of SOF in HIV/ HCV-coinfected patients have been recently reported [48]. The PHOTON-1 study was a single-arm, open-label trial that included 182 HIV/HCV-infected patients with G1, G2 and G3 who had not been previously treated against HCV. All patients received SOF plus weight-based RBV. Duration for naı¨ve individuals was 24 weeks for G1 (n = 114) and 12 weeks for G2 (n = 26) and G3 (n = 42). G2 or G3 experienced patients (n = 41) received SOF plus RBV for 24 weeks. Cirrhosis was present in only 4% of G1- and G2-naı¨ve patients and in 14% in the G3-naı¨ve group. Among G2/3 experienced patients, baseline cirrhosis was diagnosed in 24%. Highest SVR rates were observed in naı¨ve or experienced G2-infected patients, followed by patients with G1 (Figure 4). Naı¨ve G3-infected subjects, treated for 12 weeks, showed lower SVR rates than experienced individuals with G3, who received therapy for 24 weeks (Figure 4). SOF was well tolerated and safe in combination with multiple antiretroviral regimens for HIV that included EFV, ATV/r, DRV/r, RAL, RPV and TDF/ETC. Based on these promising results, the FDA has expanded SOF indication to include HIV/HCVcoinfected patients [46]. SOF in different all-oral combinations has proven elevated efficacy and excellent safety. SOF together with SMV [49] or with the NS5A inhibitor ledipasvir (LDV) [50] achieved very high SVR rates among difficult-to-cure patients, including patients with cirrhosis and previous null responders. HCV infection can be cured in just 6 weeks with SOF plus LDV plus a non-nucleoside polymerase NS5B inhibitor or a HCV-PI [51]. INF-free regimens based on SOF have raised the standard of HCV therapy to expect eradication in most patients.

6


3.1


Patients with HCV RNA < LLOQ (%)



100 88

90 80

92

88

75 67

70 60 50 40 30 20 10 0 G1 Duration (24 s)

G2 naive (12 s)

G2 exp (24 s)

G3 naive (12 s)

G3 exp (24 s)

Figure 4. Sustained virological response to the all-oral sofosbuvir plus ribavirin combination in the PHOTON-1 Phase III trial in every study arm. Data taken from [48].

4.

NS5A inhibitors

Daclatasvir DCV is the NS5A inhibitor most advanced in clinical development. DCV is a highly selective HCV NS5A replication complex inhibitor active against all HCV genotypes. It is administered at a single daily dose of 60 mg. DCV has been evaluated in combination with PegIFN/RBV, both alone or in quadruple combination with the HCV-PI ASV [52-54]. DCV has been examined as part of different all-oral regimens combined with ASV [54,55], ASV plus BMS-791325 (a nonnucleoside HCV polymerase inhibitor) [56], SOF with or without RBV [57] and SMV [58]. In HIV/HCV-coinfected patients, two Phase III clinical trials [59,60] with DCV are ongoing. In the COMMAND-HIV study, patients with G1 receive DCV plus PegIFN/RBV for 24 weeks followed by PegIFN/RBV 24 -- 48 weeks depending on the ontreatment response [59]. In the DIMMENSION study, individuals with G1 and G2/3 are treated with DCV plus PegIFN lambda/RBV for 12 weeks after which PegIFN lambda/RBV is given during 12 additional weeks for G2/3 or during 12 -- 36 weeks, depending on the initial response, for G1 [59,60]. In addition, a pilot study trying a quadruple combination with DCV plus ASV and PegIFN/RBV in previous null responders is also ongoing [61]. No data have been reported on these studies at the date of writing this review. DCV is a substrate for the CYP3A4 and P-glycoprotein, and moderately inhibits P-glycoprotein and OATP1B1. The pharmacokinetic DDIs between DCV and three antiretroviral agents (ATV/r, EFV and TDF) have been assessed in healthy volunteers [62]. ATV/r increased exposure to DCV requiring a dose reduction of DCV to 30 mg q.d. when coadministered with ATV/r. On the contrary, EFV reduced DCV levels, which could be solved increasing DCV doses to 90 mg q.d. Finally, there was no clinically relevant interaction between 4.1

DCV and TDF. There are no data regarding DDIs with other first-line antiretroviral agents such as DRV/r or RAL, though DDIs with RAL are not expected. The combination DCV plus PegIFN/RBV has been examined in HCV monoinfection in placebo-controlled, randomized, Phase II studies and it has entered Phase III trials. DCV 60 mg q.d., the standard dose, plus PegIFN/RBV for 24 -- 48 weeks showed significantly higher SVR rates than PegIFN/RBV plus placebo for G1, 64 versus 36% [52]. The combination was also very efficacious in a pilot evaluation in G4 [52]. For G2, SVR rates were 83% for DCV plus PegIFN/RBV during 12 weeks compared to 63% for placebo plus PegIFN/RBV during 24 weeks [53]. SVR rates for G3 did not improve PegIFN/RBV: DCV plus PegIFN/RBV for 12 weeks, 72% versus placebo plus PegIFN/RBV, 70% [53]. DCV was well tolerated and did not add side effects to PegIFN/RBV, being diarrhea, headache and nausea the most common AEs and rarely leading to drug discontinuation. All-oral DCV-based combinations have shown inconsistent results in HCV-monoinfected patients. DCV plus SOF with or without RBV matches other IFN-free regimens, with a low pill burden, q.d. dosing, high response rates and good tolerability [57]. By contrast, DCV plus ASV, with or without RBV, is only suitable for G1b, as G1a-infected individuals show high rates of breakthrough with this regimen [54,55]. The addition of BMS-791325, a non-nucleoside NS5B inhibitor, to DCV plus ASV yields high SVR12 rates in G1 infection [56]. However, the double combination of DCV 30 mg q.d. plus SMV fails again in G1a, with high rates of breakthrough [58]. The dose of DCV 30 mg was chosen for the combination with SMV due to pharmacokinetic interactions between both DAA. DCV 30 mg dosing might have been suboptimal and it could explain the lower-thanexpected rates of SVR12 found with this combination. DCV 60 mg q.d. plus SMV is under investigation. DCV is


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under review by FDA and EMA and is expected to be approved during 2014. Ledipasvir LDV is being developed in all-oral regimens with SOF [50,51,63-66]. The fixed-dose combination (FDC) SOF 400 mg/LDV 90 mg is administered orally as a single tablet q.d. The antiviral efficacy, safety and tolerability of SOF/ LDV FDC administered for 12 weeks in treatment-naive and treatment-experienced patients with HIV and HCV G1 or G4 coinfection are being examined in an ongoing open-label Phase III trial [63]. Individuals failing the 12-week course of SOF/LDV will be retreated with 24 weeks of SOF/LDV plus RBV [63]. There is no data available on pharmacokinetic interactions between LDV and antiretroviral therapy. As with DCV, some interactions with antiretroviral drugs requiring dose adjustment might be expected. The three ION studies are randomized, open-label, Phase III clinical trials evaluating SOF/LDV FDC for 8, 12 or 24 weeks, with and without RBV, among 1952 G1-infected patients [64-66]. Patients who were treatment-naive or who had failed previous treatment, including PI-based regimens, were included. Of the 1518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 96% achieved SVR12. Response was neither influenced by prior treatment experience nor by the addition of RBV. Virologic failure was observed in 2.4% patients, mostly due to relapse. Fewer AEs were observed in the RBV-free arms compared to the RBV-containing arms in all ION studies. AEs observed in SOF/LDV without RBV were generally mild and included fatigue and headache. The FDA has assigned the SOF/LDV FDC a breakthrough therapy designation. SOF/LDV FDC approval by the FDA has been requested in 2014. SOF/LDV FDC provides high SVR rates with a simple, safe and short course of therapy, while eliminating the need for PegIFN/RBV.


4.2

of HCV and eradicate the HCV epidemic. This is only going to be possible if large screening campaigns in higher-risk individuals and treating those with HCV infection will be required to eradicate HCV infection worldwide, a fact that would be feasible with the newer DAAs. Widespread HCV testing and treatment will hopefully end the HCV epidemic. One challenge is that drug companies place HIV/HCV DAA research in later stages of development; thus, data on DAA use for HIV/HCV lags far behind HCV monoinfection. There is a need for an earlier investigation of DAA for these patients. However, the biggest challenge is going to be access to approved DAA. SOF is marketed in USA and the European Union and SMV in USA at prohibitive prices for most patients and public health systems, if a large-scale use of these drugs is wanted. The advent of a further generation of DAA, perhaps all-oral regimens including DCV or ABT-450, might ease the access to treatment through more competitive prices. In the meantime, the scenario is set for more inequalities in health care. Until highly effective and safe DAA regimens become available to use in nearly all HIV/HCV-coinfected patients, there is a need for selecting those at greatest risk of clinical progression. This is a task that has been imposed by regulatory authorities in western public health systems. However, the best timing of current therapy also concerns patients and physicians. Aside from the timing of treatment, an additional way to optimize the use of DAA in clinical practice is to develop tools for an accurate prediction of response. The pretreatment likelihood of SVR might be applied to tailor DAA combinations and duration of therapy. Thus, easy-to-treat patients, with a high probability of SVR, could be managed with short courses of all-oral regimens including just one DAA plus RBV. At the other end of the spectrum, very hard-to-cure patients might need triple DAA combinations or even quad therapy including PegIFN/RBV.

Declaration of interest 5.

Expert opinion

HCV cure is possible in a high proportion of HIV-coinfected patients with currently available DAA. However, safety and DDIs with ART are concerning for TVR or BOC. In addition, first-generation HCV-PIs are burdened with a large pill load, multiple dosing, complex management rules and the need of prolonged therapy. Next-generation HCV-PIs come to solve some of these issues. All-oral SOF-based regimens may be close to the ideal HCV therapy, although activity against HCV G3 varies according to combination used and the patient profile. In addition, some recommendations on SOF-containing regimens are based on Phase II trials with very low number of patients. The aim of HCV therapy is to halt and revert liver disease progression. This is critical for HIV/HCV-coinfected patients, whose main cause of death is end-stage liver disease. The ultimate goal, at a population level, is to stop the spread 8

J Macias has been an investigator in clinical trials supported by Roche, Bristol Meyers Squibb, Gilead and Abbott Pharmaceuticals. He has received lecture fees from Roche, Gilead, Boehringer Ingelheim, Merck Sharp & Dohme and Bristol Meyers Squibb and Merck Sharp & Dohme. JA Pineda reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead, Merck Sharp & Dohme, Schering-Plough, JanssenCilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals and Boehringer Ingelheim, and has received lecture fees from GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, Janssen-Cilag, Boehringer Ingelheim and Schering-Plough. K Neukam has received lecture fees from Roche, Merck Sharp & Dohme and Janssen. N Merchante has received lecture fees from



GlaxoSmithKline, Roche, Abbott, Bristol-Myers Squibb, Merck Sharp & Dohme and Gilead. The authors have no other relevant affiliations or financial involvement with any Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


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Affiliation Juan Macıás1,2 MD PhD, Karin Neukam1,2 PharmD PhD, Nicola´s Merchante1,2 MD & Juan A Pineda†1,2 MD PhD † Author for correspondence 1 Hospital Universitario de Valme, Unit of Infectious Diseases and Microbiology, Avda. de Bellavista. 41014 Sevilla, Spain Tel: +34 955015684; Fax: +34 955315795; E-mail: [email protected] 2 Seville Institute of Biomedicine (IBiS), Seville, Spain

12


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