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Summary from CROI 2012 for Hepatitis Co-infection
HCV direct acting antivirals (DAAs) demonstrated to work in HIV/HCV coinfection: so how are treatment paradigms in HIV/HCV coinfection changing now?
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Jurgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany
Correspondence:
Prof. Dr. J.K. Rockstroh
Department of Medicine I
University of Bonn
Sigmund-Freud-Str. 25
53105 Bonn
Germany
Introduction
The advent of the so called direct acting antivirals (DAAs) for treatment of hepatitis C mono infection have significantly changed treatment paradigms for HCV therapy and promise cure of HCV infection in around two thirds of treatment naïve HCV-genotype-1 infected patients undergoing triple therapy with a HCV protease inhibitor together with pegylated interferon (PEG-IFN) and ribavirin (RBV). Not only have sustained virological success rates increased dramatically but in addition shortened treatment durations of 24 weeks have become feasible in the so called early rapid responders (ERVR) (defined as a negative HCV-RNA 4 weeks after starting triple therapy). The use of these new promising compounds in HIV coinfected individuals with chronic HCV so far has been however, rather limited due to the lack of data in the coinfected patient population as well as additional challenges such as the multiple drug-drug interactions between HIV and HCV drugs. Therefore the oral hepatitis session which was correctly named "Breakthroughs in hepatitis" was awaited with quite some excitement as for the first time SVR12 rates in HIV/HCV coinfected patients were presented for the 2 HCV protease inhibitors currently commercially available. In addition increasingly at CROI more space is reserved for research around HCV mono infection. Clearly the presentation of the first HCV nucleotide plus ribavirin based interferon-free regimen in HCV genotype 1 patients was another exciting highlight of this remarkable oral hepatitis session at CROI 2012 in Seattle.
Efficacy and safety of telaprevir in HIV/HCV coinfection
Within this pilot study 60 HIV/HCV genotype 1 coinfected, HCV treatment naïve subjects without HIV treatment indication (part A) were randomized to either telaprevir (TVR) 750 mg every 8 hours + pegIFN-α2a 180 mg/week + RBV 800 mg/day for 12 weeks followed by 36 weeks of pegIFN-α2a + RBV (TVR/PEG/RBV group) or placebo + pegIFN-α2a/RBV for 48 weeks (1). In part B coinfected patients on antiretroviral therapy (either Efavirenz or boosted atazanavir plus tenofovir + 3TC or FTC) were again randomized 2:1 to either TVR 750 mg every 8 hours + pegIFN-α2a 180 mg/week + RBV 800 mg/day for 12 weeks followed by 36 weeks of pegIFN-α2a + RBV (TVR/PEG/RBV group) or placebo + pegIFN-α2a/RBV for 48 weeks. The TVR dose was increased to 1125 mg every 8 hours when the ART regimen included EFV. This SVR12 analysis was performed on all 60 dosed patients (part A, 13; part B, 47:24 on an Efavirenz containing ART regimen, 23 on an atazanavir/r containing regimen). Overall, 88% of patients were male, 69% white, mean age was 46 years, 68% had genotype 1a, 83% had a baseline HCV RNA ≥800,000 IU/mL, and 10% revealed advanced liver fibrosis based on liver biopsy. The primary objective of the trial was to determine the proportion of patients with HCV RNA undetectable after 12 weeks of TVR/PEG/RBV as well as to study the safety of the triple regimen in HIV/HCV coinfected individuals. Secondary objective was to assess efficacy of TVR/PEG/RBV for 12 (SVR12) and 24 weeks after last dose (SVR). Overall, undetectable HCV RNA at weeks 4 and 12 was achieved in 63% of telaprevir treated patients compared to 4.5% on placebo. The SVR12 rates for the different study arms are depicted in figure 1.
The obtained delta in SVR12 rates of 29% between triple therapy and the PEG-IFN/RBV control arm underlines that also in HIV/HCV coinfection triple therapy substantially increases chances of cure in this challenging patient population. After EOT only one relapse occurred in the telaprevir arms and two in the control arm. 3 TPV/PR patients in part B experienced HCV viral breakthrough. No HIV breakthrough was noted in any of the treatment arms. Discontinuations due to adverse events occurred in 3 patients (8%) in the TVR/PR groups vs 0 in the placebo group. Rash, pruritus, nausea, vomiting, fever, anorexia and dizziness were more frequent in patients who received TVR/PR than in controls. No case of severe rash was seen and noteworthy and no patient in the study discontinued study drug because of rash. No significant changes in CD4 decrease or in HIV RNA level were observed in part B patients who received either ART regimen compared to controls.
In summary, in this first pilot trial on efficacy and safety of the oral HCV protease inhibitor telaprevir in combination with PEGG/RBV significantly higher SVR12 cure rates could be observed in HIV/HCV coinfected patients receiving triple therapy. The surprising high cure rate in the control arm of 45% however suggests that overall relatively easy to treat patients with good baseline treatment outcome prediction factors were included into this pilot trial. Indeed there were hardly any patients with more advanced liver disease included and HIV infection was either well controlled or even so well controlled in the natural course of disease that no HIV therapy was required altogether. Therefore, caution still needs to be expressed with regard to HIV/HCV coinfected patients with more advanced fibrosis stages as this patient population remains unstudied so far. Also it should be highlighted that all patients were treated for 48 weeks so that no information on the eagerly awaited treatment response guided shorter treatment durations are available for coinfected individuals. The question whether there are differences in treatment outcome in coinfected versus monoinfected patients is difficult to answer in the lack of a randomized comparative study and crucially depends on the baseline characteristics of the patients studied. First use of telaprevir in coinfected patients (n=20) treated in New York at the Division of Liver Diseases at Mount Sinai School of Medicine suggest lower early on-treatment responses to telaprevir in HIV/HCV co-infected than in HCV mono-infected patients (n=63), but the differences were not statistically significant in this small study (2). Nevertheless the sharp increase in cure rates under triple therapy mandate that this new treatment option is considered correspondingly in HCV genotype-1 patients.
CROI: Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR12 Interim Analysis - (03/7/11)
Efficacy and safety of boceprevir in HIV/HCV coinfection
Within this multi-center, double-blinded, international trial, 100 patients with untreated HCV genotype 1 infections and HIV RNA <50 copies/mL were randomized in a 2:1 ratio to receive peg-IFN-2b 1.5 mg/kg/wk)+RBV (600 to 1400 mg/day, according to weight) + boceprevir (BOC) 800 mg 3 times daily, or peg-IFN+RBV+placebo for 44 weeks (3). All had a 4-week lead-in of peg-IFN+RBV. ARV regimens that included NNRTI, zidovudine, or didanosine were not permitted. Most patients were on a boosted PI based ART regimen (84% in the boceprevir arm and 91% in the placebo arm). Few patients (11 in the boceprevir arm and 4 in the placebo arm) received raltegravir; one patient in each of the arms was on a maraviroc based ART. Patients were stratified by: cirrhosis/fibrosis (yes vs no) and baseline HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). The majority of patients included however were non-cirrhotic (95%), white (82%), male (69%) with a median age of ~43 years. Most study participants had a high baseline HCV RNA (88%) and a HCV genotype 1a (65%). Almost all patients (97%) had a baseline HIV-RNA <50 copies/ml. The median CD4 count was 577/μl in the boceprevir arm and 586/μl in the placebo arm. The primary efficacy endpoint was the achievement of sustained virologic response, undetectable plasma HCV RNA 24 weeks after the end of treatment. Secondary endpoints and planned interim analyses included proportion of subjects with undetectable HCV RNA at treatment week 4, 8, 12, 24, and treatment week 48 (end of treatment). Of the 100 patients enrolled into the study 2 patients in the BOC arm did not receive medication; thus, 34 control and 64 experimental patients were treated. The virological response rates over time are depicted in figure 2.
Looking at the delta of 34% in SVR rates between patients receiving triple therapy versus just PEG-IFN/RBV alone, again underlines the dramatic increase in cure rates which can be achieved with the addition of an HCV protease inhibitor. Discontinuation due to adverse events occurred in 20% and 9% in the BOC and control groups, respectively. There were 9% and 53% HCV treatment failures in the BOC and control groups respectively. Compared to the control group, BOC patients were more likely to have decreased appetite, pyrexia, dysgeusia, vomiting, asthenia, anaemia, and neutropenia. Anaemia being among the most important side effects observed in HCV mono-infection studies was noted in 41% of boceprevir treated patients versus 26% of patients in the control arm. Use of erythropoietin was noted in 38% of boceprevir treated patients and 21% in the placebo arm. 6% of patients in both arms respectively received blood transfusions during HCV therapy. Under particular consideration of recently forwarded dear Dr-letters as well as FDA and EMA press releases highlighting clinically relevant drug-drug interactions between HIV boosted protease inhibitors and boceprevir the main safety concern was whether the drug interactions potentially would have influenced HIV replication control in this study. By week 48, 3 and 4 patients in the BOC and control groups, respectively, had HIV RNA virologic failure, mostly near the end of HCV therapy or even after ending treatment. Therefore, no signal of a higher rate of HIV breakthroughs in boceprevir treated patients was found in this study contrasting the observed significant drug-drug interactions which are summarized and discussed in the next section.
In summary, in this first pilot trial on efficacy and safety of the oral HCV protease inhibitor boceprevir in combination with PEGG/RBV significantly higher SVR12 cure rates could be observed in HIV/HCV coinfected patients with triple therapy. Preliminary safety data of B/PR in co-infected patients showed a profile consistent with that observed in mono-infected patients and does not suggest increased toxicity in HIV/HCV coinfected patients.
CROI: Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients - (03/7/11)
Can we combine boceprevir with boosted HIV protease inhibitors?
As outlined above, prior to CROI, Merck sent out a "Dear Health Care Provider" letter, dated 06 Feb 2012 bringing awareness to newly found relevant drug-drug interactions between the HIV boosted protease inhibitors atazanavir/r (ATV/r), darunavir/r (DRV/r) and lopinavir/r (LPV/r) and boceprevir. This letter was followed by a FDA safety announcement on the 8th of February and an EMEA press release on the 17th of February. The full results of these drug interactions were described here at CROI in the poster section as a late breaker poster (first time ever at CROI) (4). The study presented was a single-center, 3-part, open-label, drug-interaction study in 39 healthy adult subjects. Subjects received boceprevir (800 mg three times a day) on days 1 to 6. After a 4-day washout, subjects received ATV/r (300/100 mg every day), LPV/r (400/100 mg twice a day), or DRV/r (600/100 mg twice a day) on days 10 to 31. Subjects received concomitant boceprevir (800 mg three times a day) on days 25 to 31. Blood samples were collected for the pharmacokinetic assessment of HIV-PI, ritonavir, and BOC. Safety assessments included ECG, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Co administration of BOC with the HIV-PI/r was generally well tolerated; there were no serious adverse events. The effect of ATV/r, LPV/r and DRV/r co-administration on PK of Boceprevir is summarized in Table 1.
Co-administration with ATV/r does not alter boceprevir AUC, but coadministration with LPV/r and DRV/r decreases boceprevir AUC 45% and 32%, respectively. Clearly this is of concern as significantly lowered boceprevir concentrations could increase risk for HCV virological failure and resistance development. Pk data from monoinfection studies so far however have not been able to establish an association between boceprevir level and SVR rate further complicating clinical interpretation of lower boceprevir levels. Next to the observed changes in boceprevir levels there was also an impact from boceprevir on boosted HIV protease inhibitor levels which is outlined in table 2.
Indeed, boceprevir coadministration reduces the exposure of ATV, LPV, and DRV by 35%, 34%, and 44%, respectively, and reduces trough concentrations 49%, 43%, and 59%, respectively. Mean ATV Cmin decreased from 693 ng/mL to 357 ng/mL; mean LPV Cmin decreased from 6,730 ng/mL to 3,805 ng/mL; mean DRV Cmin decreased from 3,220 ng/mL to 1,321 ng/mL. Obviously these reductions are raising concerns that particularly in HIV patients with prior virological resistance and accumulation of resistance mutations this could lead to virological HIV breakthrough. And although this was not noted at an increased rate in boceprevir treated patients (see above) currently it is not recommended to combine the respective boosted HIV protease inhibitors with boceprevir. Clearly the lack of observed increased HIV breakthroughs could reflect the own anti-HIV activity of PEG-IFN which has been shown to lower HIV-RNA by an average of 0.8 log in HIV-patients not on HIV therapy and might compensate for some of the diminished anti-HIV activity of the corresponding HIV protease inhibitor. There also should be a word of caution in how far PK data from healthy volunteers can be extrapolated to HIV infected subjects with liver disease. Particularly in more advanced liver disease higher boceprevir levels would appear very likely compared to healthy controls. EMEA has stated that in general the combination of boosted atazanavir and boceprevir is not recommended but may be considered on a case-by-case basis if patient has no prior HIV drug resistance and is suppressed. Currently it appears best to avoid the corresponding combinations until more data becomes available. Also it should be mentioned that combination of boosted atazanavir and telaprevir has been shown to work well and therefore could be an alternative in patients who need to remain on a boosted PI. Various studies are currently further exploring combination of boceprevir and various antiretrovirals which hopefully will help to better define suitable ART partners. As boosted atazanavir had no impact on boceprevir it would also be possible to study different dosages of atazanavir to try to reach higher atazanavir levels compensating for the observed decrease under concomitant boceprevir administration.
CROI: PHARMACOKINETIC INTERACTION BETWEEN THE HCV PROTEASE INHIBITOR BOCEPREVIR AND RITONAVIR-BOOSTED HIV-1 PROTEASE INHIBITORS ATAZANAVIR, LOPINAVIR, AND DARUNAVIR - (03/7/11)
What about combining raltegravir and boceprevir?
It is also noteworthy that at CROI for the first time drug-drug interaction data was presented between raltegravir and boceprevir (5). This was an open-label, randomized, two-period, cross-over phase I trial in 24 healthy volunteers. All subjects were randomly assigned to: BOC 800 mg three times a day for 10 days plus a single-dose of RAL 400 mg on day 10 followed by a wash-out period and a single-dose of RAL 400 mg on day 38, or the same medication in reverse order. After observed intake of BOC and RAL with a standardized breakfast, blood samples for pharmacokinetics (PK) were collected during an 8-hour and a 12-hour period, respectively. PK parameters were calculated by non-compartmental analysis (WinNonlin version 5.3). Geometric mean ratios (GMR) and 90% confidence intervals (CI) were calculated for RAL AUClast and Cmax after log-transformation of within-subject ratios. A 90%CI within the 0.80 to 1.25 range indicates no clinically meaningful effect of BOC on RAL PK. The geometric mean (95%CI) of RAL AUClast and Cmax for RAL+BOC vs RAL alone were 4.27 (3.22 to 5.66) vs 4.22 (3.19 to 5.59) mg.h/L and 1.06 (0.76 to 1.49) vs 0.98 (0.73 to 1.31) mg/L, respectively. GMR (90%CI ) of RAL AUClast and Cmax for RAL+BOC vs RAL alone were 1.01 (0.85 to 1.20) and 1.09 (0.89 to 1.33). The authors concluded that boceprevir did not affect raltegravir exposure and therefore can be recommended for combined HIV/HCV treatment including boceprevir. This makes raltegravir currently the best partner for boceprevir combination therapy in HIV/HCV coinfection. Obviously this will only be advisable in patients who have not accumulated prior HIV drug resistance as the results of the SWITCHMRK study suggest not to switch from a boosted PI to raltegravir in the presence of prior acquired drug resistance (6).
CROI: Influence of the HCV Protease Inhibitor Boceprevir on the Pharmacokinetics of the HIV Integrase Inhibitor Raltegravir - (03/7/11)
Any news on other relevant drug-drug interactions in the coinfection field?
Indeed there were some interesting studies looking at drug-drug interactions between HIV drugs and some of the newer HCV compounds currently in drug development. In the oral hepatitis session results from two open-label, randomized, 2-panel, 3-way crossover studies conducted in healthy subjects to investigate pharmacokinetic interactions between the investigational oral, once-daily HCV NS3/4A protease inhibitor TMC435 and rilpivirine (RPV, TMC278) or tenofovir (given as tenofovir disoproxil fumarate [TDF]) in study TMC435-C123, or efavirenz (EFV) or raltegravir (RAL) in study TMC435-C114 were presented (7). The obtained PK data strongly suggests that dose adjustments are not required when RPV, TDF, or RAL are co-administered with TMC435. Co-administration of TMC435 and EFV however, should be avoided due to the observed decrease in TMC435 exposure in the presence of EFV. So far data on TMC435 and boosted PIs are missing but interactions are likely and inclusion of HIV/HCV coinfected patients on boosted HIV protease inhibitors at this point in the currently running coinfection study was not possible.
In the poster session there was a presentation on drug-drug interactions between daclatasvir the BMS NS5A-inhibitor (BMS-790052) and tenofovir, efavirenz and boosted atazanavir (8). In exploratory ATV/r (n =14) and EFV studies (n =15), subjects initially received BMS-790052 alone at 60 mg once daily on days 1 through 4 (24-h pharmacokinetics, sampling day 4); followed by ATV/r 300/100 mg once daily + BMS-790052 20 mg once daily on days 5 to 14 (pharmacokinetic sampling day 14); or EFV 600 mg once daily on days 5 to18, with BMS-790052 60 mg once daily on days 5 to13 then 120 mg once daily on days 14 to 18 (pharmacokinetic sampling day 18). In the confirmative TDF study (n = 20) subjects received BMS-790052 (60 mg once daily), TDF (300 mg once daily), or both for 7 days in a 3x3 crossover design, with pharmacokinetic sampling at day 7 of each treatment. BMS-790052 and TDF had no clinically relevant drug-drug interactions, and BMS-790052 did not appear to have relevant effects on exposure to concomitant EFV or ATV/r. Dose adjustment for BMS-790052 to 90 mg once daily when co-administered with EFV or 30 mg once daily when co-administered with ATV/r is expected to generate exposures similar to those observed in subjects receiving 60 mg alone. In summary drug-drug interactions exist but can be overcome by drug dose adaptation. The COMMAND study is currently evaluating the efficacy of BMS-790052 in combination with PEG/RBV and all tested ARVS are allowed in the study with BMS-790052 being dose adapted according to concomitant ART.
CROI: The Pharmacokinetic Interactions of HCV Protease Inhibitor TMC435 with Rilpivirine, Tenofovir, Efavirenz or Raltegravir in Healthy Volunteers - (03/7/11)
CROI: Assessment of HIV Antiretroviral Drug Interactions With the HCV NS5A Replication Complex Inhibitor Daclatasvir Demonstrates a PK Profile Which Supports Coadministration With Tenofovir, Efavirenz and Atazanavir/r - (03/9/11)
How to best manage HCV genotype 1 infection in HIV coinfection?
With regard to the highly significant increase in cure rates with triple therapy over PEG/RBV it is clear that treatment recommendations will need to change and recommend triple therapy in coinfected patients just as well as mono-infected patients. Nevertheless pill burden, overlapping toxicities and in particular drug-drug interactions between HIV and HCV drugs still limit the use of these new compounds. Also the rapid development of new HCV drugs which will be easier to take, will be better tolerated and may even allow for interferon-free treatment approaches at least in the majority of patients need to be considered. Therefore, fibrosis stage assessment is of utmost importance to decide whether treatment of chronic HCV is needed now or in the absence of fibrosis can wait until improved options become available. At CROI in the afternoon hepatitis session possible management algorithms were presented which may help to guide treatment decisions (see figure 3) (9,10).
*Metavir fibrosis score: F0=no fibrosis; F1= portal fibrosis, no septae; F2= portal fibrosis, few septae, F3=bridging fibrosis, F4=cirrhosis; Peg, pegylated interferon; RBV, ribavirin; DAA, direct antiviral agent; Il28B, interleukine 28B
adapted from Ingiliz P, Rockstroh J: HIV-HCV coinfection facing HCV protease inhibitor licensing: implications for clinicians. Liver International 2012, in press (10)
Any news in treatment of hepatitis C mono-infection?
Indeed there was a ground-breaking result from a first interferon free therapy with the nucleotide PSI-7977 in combination with ribavirin for treatment of genotype 1 patients (9). PSI-7977 is a potent uridine nucleotide analogue in phase 3 development. Previously at AASLD in November 2011 results from the ELECTRON study, evaluating PSI-7977/RBV for 12 weeks without PEG demonstarted 100% SVR in HCV GT2/3 patients. In order to evaluate the response of this pegIFN-free regimen in patients infected with HCV GT1, 2 additional cohorts were enrolled in the ELECTRON study-GT1 treatment-naïve patients and GT1 prior null responders (defined as <2 log10 reduction in HCV RNA at week 12 of a pegIFN/RBV regimen). Results for the treatment naïve patients will be presented at EASL in Barcelona April 2012. SVR4 Results for the non-responders was presented at this year CROI. Early, on-treatment viral kinetics were similar in the 2 treatment cohorts. By week 2, mean HCV RNA decline from baseline was 5.54 log10 IU/mL in the GT1 null responders and 4.87 in the GT1 treatment-naïve patients (compared to 5.31 log in GT2/3 treatment-naïve patients); 78% of GT1 null responders and 71% GT1 treatment-naïve patients were < LOD (limit of detection 15 IU/mL) at 2 weeks (compared to 80% of treatment-naïve GT2/3 patients). All patients in both cohorts were < LOD at week 4 (i.e., 100% RVR) or last available time point. Within 4 weeks after stopping therapy all but one patient relapsed demonstrating that most likely 12 weeks of this combination are too short to achieve cure from genotype 1 infection in this challenging to treat group of previous non-responders. The only patient who remained undetectable was a female patient with an IL28B genotype with little fibrosis at baseline. PSI-7977/RBV was generally well tolerated, with no treatment-related SAE, discontinuations, or Grade 3/4 laboratory abnormalities. Overall, this is clearly a drawback for those who believed a simple 2 drug regimen would be capable of curing HCV in all patients. Nevertheless, longer treatment durations with this combination or addition of a further HCV DAA may be the answer to obtain better results in interferon-free startegies in genotype 1 patient populations.
CROI: GS-7977 + Ribavirin in HCV Genotype 1 Null Responders: Results from the ELECTRON Trial - (03/7/11)
What were the highlights in acute hepatitis C research?
Since 2000 outbreaks of acute hepatitis C virus (HCV) among HIV-positive men who have sex with men (MSM) have been reported from Europe, the United States, Canada and Australia. Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming. Clinical data regarding the use of ribavirin (RBV) in the treatment of acute hepatitis C (AHC) infection are controversial. In acute hepatitis C mono-infection, early therapy with interferon (IFN) for up to 24 weeks is sufficient to obtain treatment response rates close to 100% (13). At this year's CROI data on the role of ribavirin in therapy of acute hepatitis C in HIV coinfection was presented (14). Overall, 284 HIV+ patients from 4 European countries with diagnosed acute HCV infection were treated early with pegylated interferon (peg-IFN) and ribavirin (RBV) (n = 254) or peg-IFN alone (n = 30). All patients were followed prospectively and evaluated for virological response rates. Fisher's exact test, c2 test, and binary logistic regression model were used for statistical analysis. All patients included into this cohort were male, median age 39 years. Main routes of transmission were MSM (95%) and intravenous drug users (IDU) (3%). In 75% of patients, clinical signs of acute hepatic infection were missing; 68% of patients were infected with HCV GT1, 4.6% with GT2, 10.6% with GT3, and 16.9% with GT4. Median baseline HCV RNA was 939,249 IU/mL and median CD4 T cell count 471 cells/mL; 65% of all patients received HAART. By univariate analysis, there were no statistical differences at baseline for HCV or HIV characteristics between patients with GT 1/4 (group 1) and patients with GT 2/3 (group 2) infection. Median time from diagnosis to treatment start was 9.6 weeks, median treatment duration 26 weeks, median time to first negative HCV PCR was 8 weeks. RBV dose reduction occurred in 10.4%. Treatment was stopped in 17 patients (6%) due to toxicities. Overall sustained virological response rate was 69.7% (198 of 284). Interestingly, sustained virological response rates were significantly higher in genotype 2/3 patients receiving peg-IFN+RBV (31 of 33) than those receiving peg-IFN mono-therapy (6 of 10) (94% vs 60%, respectively; p = 0.02). In multivariate analysis, peg-IFN+RBV combination therapy (p = 0.037) and rapid virological response (p ≤0.0001) were significantly associated with sustained virological response in group 2. In group 1, only rapid virological response (p ≤0.0001) was significantly associated with sustained virological response. The impact of ribavirin however, was difficult to study in the genotype 1 population as only very few patients received PEG-IFN mono therapy and clearly larger numbers of patients on PEG-IFBN monotherapy are needed to sufficiently explore the role of ribavirin in treatment of acute HCV in HIV coinfected patients. Currently the acute HCV consensus recommendations suggest to treat with combination therapy when acute HCV is diagnosed and no drop in HCV viral load of at least two logs is noted within 4 weeks after first HCV diagnosis (15). Overall, a randomized controlled study exploring the role of ribavirin in treatment of acute HCV would be best to provide a definite answer.
In summary, ribavirin appears to be important in the management of acute HCV infection in HIV+ patients at least for GT2/3 infections, almost all patients clear virus with combination therapy. Treatment outcome data from this large cohort also confirm that early antiviral treatment of acute HCV/HIV-co-infected individuals results in virological response rates significantly higher than those obtained in treatment of chronic HCV co-infection and underlines why treatment options in this well-defined clinical situation need to be considered in each individual patient.
In addition interesting work was presented on HIV patients with multiple episodes of acute hepatitis C (16). In this retrospective analysis from 4 major German HIV and hepatitis care centers (Frankfurt, Hamburg, Berlin, Bonn) all patients with sexually acquired multiple (2 to 4) HCV infections were included. Patients had either cleared the virus spontaneously or were sustained virological responders (SVR) to HCV therapy after first infection. Reinfection was defined by one of the following conditions: genotype (GT) switch, clade switch, detectable viral load after SVR, or 6 months of indetectability after spontaneous clearance. Overall, 45 patients were identified from the database who had two to four repeated episodes of acute hepatitis C infection between 2001 and 2011 (98 HCV episodes). All were Caucasian HIV positive MSM. Eleven (38%) patients had IL28B genotype (rs12979860) C/C, 18 (62%) had non-C/C. 40 patients had a SVR, 5 patients had a spontaneous clearance. The median time to the second diagnosis was 34 months (range 10-94). At the time of the second infection, median HCV viral load, ALT, AST and GGT were not statistically different to the first infection.
26 patients switched genotypes. 7 patients cleared spontaneously, 18 had a SVR, and 12 did not respond to treatment and developed chronic HCV. Patients with spontaneous clearance in the first episode were more likely to clear again (p=0.02) and SC patients had more often IL28B genotype C/C (p=0.02) and had a higher CD4 count (p=0.03). There was a non-significant trend to lower HCV viral load and higher ALT levels in spontaneous clearers. Age, cART, genotype switch and time between infections had no influence on spontaneous clearance. Seven patients developed a third infection with HCV genotype 1a (2 GT switch, 2 SC, 5 SVR). One patient cleared the third episode, became reinfected with a genotype 1b clade and cleared again.
In summary sexually transmitted HCV reinfection is not a rare condition in a high-risk MSM population and can occur again after spontaneous clearance or SVR after HCV therapy. Patients with spontaneous clearance and IL28B C/C genotype are more likely to clear a second infection. Reinfection can occur with the same and with a distinct genotype. In conclusion these data do not support the concept of HCV immune protection in HIV-coinfected individuals.
Anything else in HCV?
There was an interesting themed poster discussion on predicting hepatitis C treatment responses on Tuesday which included the presentation of several helpful algorithms for assessment of treatment outcome of a HCV therapy in an HIV/HCV coinfected individual. The inclusion of IL28B variants and liver fibrosis stages using elastometry in prognostic models allows accurate baseline prediction of sustained virological response in HIV patients with chronic hepatitis C virus (HCV) treated with pegylated interferon (pegIFN)+ ribavirin (RBV). A freely available index (www.fundacionies.com/prometheusindex.php?lang=ing) that records 4 parameters (IL28B variants, HCV RNA level, HCV genotype, and liver fibrosis) provided AUROC of 0.87 in a derivation cohort of 245 co-infected patients (17). In the new analysis presented at CROI the authors of the PROMETHEUS index examined the accuracy of the Prometheus index to predict sustained virological response in HCV-mono-infected patients (18). The study population included 422 patients: 245 HIV/HCV-co-infected individuals comprised the derivation cohort and 177 HCV-mono-infected patients were the validation cohort, which represented a 60:40 ratio. The accuracy of the Prometheus score was significantly inferior in HCV-mono-infected (AUROC = 0.77 [IC95 0.70 to0.84]) than in HIV/HCV co-infected (AUROC = 0.87 [IC95 0.83 to 0.92]), p = 0.01. A new model was then explored to test whether HIV status and HCV-1 subtypes could improve the predictive performance. The model tested in the whole cohort confirmed liver stiffness, IL28 favorable allelic variants, HCV RNA level, and HCV genotype as independently associated to sustained virological response (p <0.001). A trend was observed for HIV status (p = 0.09) as a predictor of sustained virological response. Adding information on HCV-1 subtypes to the model slightly increased its predictive accuracy.
Any news on hepatitis B ?
More recently, quantitative HBSAg levels have been introduced as a new marker to indicate possible HBsAg seroconversion. At this year CROI results on this new marker were investigated in a multi-center study at baseline, month 6, and yearly in 104 HIV/HBV-co-infected patients treated with HAART containing TDF with an exceptionally long follow-up of up to 8 years (19). Median follow-up was 56 (8 to 97) months. Indeed high baseline HBsAg levels (p = 0.035) were associated with HBsAg decline in HBeAg+ patients. In HBeAg+ patients, immune reconstitution indicated by higher CD4 count at month 6 and 12 was correlated with HBsAg decline at these time-points (p <0.05). HBeAg+ patients with HBsAg levels at month 6 <100 IU/mL had a 71% probability of HBsAg loss, whereas none of the patients with HBsAg >100 IU/mL achieved HBsAg loss. Estimated median time to HBsAg loss was 18.2 (IQR 9.7 to 27.5) years for HBeAg+ and 41 (2.6 to 83.4) years for HBeAg- patients. It appears that HBsAg levels decline steadily, particularly in HBeAg+ patients, during long-term tenofovir therapy in HIV/HBV-co-infected patients. On-treatment correlation between CD4 count and HBsAg decline indicates a possible role of immune reconstitution in HBsAg loss. Early HBsAg kinetics in HBeAg+ patients were predictive of HBsAg loss.
Summary
· Studies on the efficacy and safety with the HCV protease inhibitors boceprevir or telaprevir in HCV genotype 1 HIV co-infected individuals have clearly demonstrated substantial higher HCV treatment cure rates under triple therapy compared to just pegylated interferon/ribavirin combination therapy alone allowing for cure of hepatitis C in about two thirds of treated patients; increased toxicities including higher anaemia rates and higher rash rates have been reported although overall discontinuation rates due to adverse events remain low and no discontinuation due to rash has occurred in the studies reported so far.
· Under consideration of the fact that frequently used HIV drugs such as NNRTI or protease inhibitors are metabolized by the cytochrome P450 system as well as HCV protease inhibitors the potential for significant drug-drug interactions arises and need to be checked prior to combination of the respective agents; this also holds true for other co-medications also being metabolized by the cytochrome P450 pathway
· The combination of boceprevir with boosted HIV protease inhibitors cannot be recommended at this time due to significant drug-drug interactions; raltegravir can be safely co-administered with boceprevir
· No dose adjustments are required when RPV, TDF, or RAL are co-administered with TMC435. Co-administration of TMC435 and EFV however, should be avoided due to the observed decrease in TMC435 exposure in the presence of EFV.
· The BMS NS5A-inhibitor (BMS-790052) daclatasvir has some drug interactions with HIV antivirals which can be overcome by corresponding dose adjustments of daclatasvir.
· Interferon-free treatment of hepatitis C with PSI-7977/RBV for 12 weeks in previous GT1 non-responders leads to 100% End-of-treatment undetectable HCV-RNA levels but is followed by rapid relapse after stopping therapy in over 90% suggesting that either longer treatment durations or more potent oral combination therapies will be needed for this particularly challenging non-responder population.
· Early antiviral treatment of acute HCV infection in HIV co-infected individuals results in sustained virologic response rates that are significantly higher than those obtained in treatment of chronic HCV co-infection. Ribavirin appears to be important in the management of acute HCV infection in HIV+ patients at least for GT2/3 infections, almost all patients clear virus with combination therapy.
· Sexually transmitted HCV reinfection is not a rare condition in a high-risk MSM population and can occur again after spontaneous clearance or SVR after HCV therapy. Patients with spontaneous clearance and IL28B C/C genotype are more likely to clear a second infection.
References
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Peginterferon Alfa-2a/Ribavirin in HCV/HIVCo-infected Patients:SVR12 Interim Analysis. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 46
2. Martel-Laferriere V, Bichoupan K, Pappas A, Schonfeld E, Stivala A, Vachon M-L, Ng M, Standen M, Dieterich D, Branch A. Early On-treatment Responses to Telapravir Do Not Differ between HIV/HCV Co-infected and HCV Mono-infected Patients. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 754
3. Sulkowski M, Pol S, Cooper C, Fainboim H, Slim J, Rivero A, Laguno M, Thompson S, Wahl J, Greaves W. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 47
4. Hulskotte E, Feng H-P, Xuan F, van Zutven M, O'Mara E, Youngberg S, Wagner J, Butterton J. Pharmacokinetic Interaction between the HCV Protease Inhibitor Boceprevir and Ritonavir-boosted HIV-1 Protease Inhibitors Atazanavir, Lopinavir, and Darunavir. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 771LB
5. de Kanter C, Blonk M, Colbers A, Fillekes Q, Schouwenberg B, Burger D. The Influence of the HCV Protease Inhibitor Bocepravir on the Pharmacokinetics of the HIV Integrase Inhibitor Raltegravir. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 772LB
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8. Bifano M, Hwang C, Oosterhuis B, Hartstra J, Tiessen R, Velinova-Donga M, Kandoussi H, Sevinsky H, Bertz R. Assessment of HIV ARV Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile which Supports Co-administration with Tenofovir Disoproxil Fumarate, Efavirenz, and Atazanavir/ritonavir. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 618
9. Rockstroh JK. Beyond Phase 2: Treating HIV/HCV Co-infected Patients Today. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 72
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12. EJ Gane, CA Stedman, RH Hyland, et al. Once Daily PSI-7977 plus RBV: Pegylated interferon-Alfa not required for Complete Rapid viral response in Treatment-naive Patients with HCV GT2 or GT3. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 34.
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17. Medrano J, Neukam K, Rallon N, Rivero A, Resino S, Naggie S, Caruz A, Calvin A, Mac’as J, Benito JM, Sanchez-Piedra C, Vispo E, Barreiro P, McHutchison J, Pineda JA, Soriano V. Modeling the probability of sustained virological response to therapy with pegylated interferon plus ribavirin in patients coinfected with hepatitis C virus and HIV. Clin Infect Dis. 2010 Nov 15;51(10):1209-16.
18. Medrano J, de Ledinghen V, Pineda J, Resino S, Vispo E, Taupin JL, di Lello F, Pellegrin I, Barreiro P, Soriano V. Baseline Prediction of Response to Pegylated Interferon + Ribavirin in Chronic HCV Using the Prometheus Score. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 761
19. Theodora de Vries-Sluijs*1, R Zoutendijk1, H Zaaijer2, J Mulder3, F Kroon4, C Richter5, B Hansen1, R de Man1, H Janssen1, and M van der Ende1. TDF Treatment for =8 Years Results in Pronounced HBsAg Decline in HBeAg+ HIV/HBV-co-infected Patients 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 53
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