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Hepatitis C Coinfection Studies

By Simon Collins

March/April 2012

Table of Contents


Introduction

CROI 2012: Seattle, 5-8 March 2012

The conference included very encouraging results from the first studies of telaprevir (tradename Incivek, Vertex) and boceprevir (tradename Victrelis, Merck) in people with HIV/HCV coinfection.

Both studies generally showed similar response rates in HIV/HCV coinfection to those seen in HCV monoinfection. Sustained virological response (SVR) results at 12 weeks are highly predictive of SVR at week 24.


Telaprevir: SVR-12 Results in HIV/HCV Coinfection

SVR results at 12 weeks after treatment, from a double-blind, placebo controlled Phase 2 study telaprevir in combination with pegylated interferon (peg-IFN) + ribavirin (RBV) in 60 patients with HIV and HCV genotype-1 coinfection were presented by Douglas Dieterich. [1]

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Patients were randomised to either telaprevir (750 mg every 8 hours) or placebo, plus PEG-IFN alpha-2a (Pegysys) + RBV, (800 mg/day) for 12 weeks followed by 36 weeks of peg-IFN+RBV. This was a two-part study depending on whether patients were using ART (Part B, n=47) or not (Part A, n=13). In the ART arm atazanavir/ritonavir (n=23) or efavirenz (n=24) based regimens were allowed (with an increased telaprevir dose for efavirenz patients).

Baseline characteristics included: mean age of 46 years; 88% male; 27% African American; 68% with subtype 1a and 3% had cirrhosis. HCV RNA was >800,000 IU/mL in 92% and 81% of no-ART and ART groups respectively; median CD4 counts were approximately 500-600 cells/mm3 (range 300 - >1,100).

Undetectable HCV RNA in the combined active vs placebo groups were achieved by 68 vs 4.5%, 82% vs 32%, 63 vs 4.5% and 74% vs 55% at week 4, 12, weeks 4 and 12, and week 24 respectively, see Table1). ART use did not affect response rates. Outcomes by baseline HCV RNA were not presented.

Both safety and tolerability of telaprevir in combination with peg-IFN+RBV was comparable to that previously observed in HCV-mono-infected patients. No severe rashes were reported.


Table 1: Interim HCV RNA BLQ (%) Response Rates With Telaprevir in HIV/HCV Coinfection

N (%) No ART No ART EFV/TDF/FTC EFV/TDF/FTC ATZ/r/TDF/FTC ATZ/r/TDF/FTC
  T/PR PR T/PR PR T/PR PR
N 7 6 16 8 15 8
Week 4 (RVR) 5 (71) 0 12 (75) 1 (12) 9 (60) 0
Week 12 (oRVR) 6 (66) 2 (33) 14 (80) 2 (25) 11 (73) 3 (38)
Week 4 and 12 (eRVR) 4 (57) 0 12 (75) 1 (12) 8 (53) 0
Week 24 6 (86) 2 (33) 12 (75) 4 (50) 10 (67) 6 (75)

T: telaprevir; P: peg-IFN; R: ribavirin. BLQ: undetectable: lower limit of quantification: 25 IUlmL; limit of detection 10-15 IU/mL.


Interactions Between Telaprevir and Antiretrovirals

Interaction data between telaprevir and HIV drugs was also included in the same presentation. Telaprevir concentrations were similar with efavirenz and atazanavir to reference concentrations with mean (90%CI) Cmin, Cavg and Cmax of 93 ng/mL (56, 156), 97 ng/mL (64, 146) and 101 ng/mL (72, 143) with efavirenz and 131 ng/mL (77, 222), 107 ng/mL (70, 165) and 98 ng/mL (69, 140) with atazanavir, respectively.

The mean concentration ratios to reference levels were also close to 100% for levels of efavirenz and atavanavir, indicating the higher efavirenz dose is sufficient to overcome this interaction.

Telaprevir can only be used with boosted atazanavir, efavirenz (with a higher dose of telaprevir -- 1125 mg tid vs. 750 mg tid) or raltegravir. Background nucleosides are tenofovir plus FTC or 3TC.


Boceprevir: SVR-12 Results in HIV/HCV Coinfection

SVR results at 12 weeks after treatment from a randomised double-blind, placebo controlled study of Merck’s boceprevir (BOC) with pegylated interferon (peg-IFN) + ribavirin (RBV) in 98 patients with HIV and HCV genotype-1 coinfection were presented by Mark Sulkowski. [2]

In this study, all patients were on stable antiretroviral treatment (not including NNRTIs, AZT or ddI) with suppressed viral load (<50 copies/mL). ART regimen included atazanavir/r (n=31), lopinavir/r (n=25), darunavir/r (n=17), other PI (n=7), raltegravir (n=10) and other (n=2).

Patients were randomised (2:1) ratio to receive boceprevir 800 mg every eight hours (n=64) or placebo (n=34) plus pegylated interferon-alfa-2b (Peg-Intron) and weight-based RBV (600 to 1400 mg/day). All patients also had a four-week lead-in phase with peg-IFN + RBV.

Baseline characteristics included: mean age of 45 years; 69% male; 82% white. 88% had HCV RNA >800,000 IU/mL and 65% were genotype 1a. Median CD4 counts were approximately 580 cells/mm3 (range 200 - >1,500). Only 4 patients had cirrhosis.

HCV RNA levels were undetectable in 59% vs 23% of patients at week 12 and 64% vs 29% at week 48 in the boceprevir vs control groups with SVR rates 12 weeks after the end of treatment of 61% vs 26% (see Table 2).


Table 2: Interim HCV RNA BLQ (%) Response Rates With Boceprevir in HIV/HCV Coinfection

  B/PR PR
N 64 34
Discontinuation 24 (38%) 18 (53%)
week 4 (pegIFN/RBV lead-in) 3 (4.7%) 3 (8.8%)
week 8 27 (42%) 5 (15%)
week 12 38 (59%) 8 (23%)
week 24 47 (73%) 11 (32%)
week 48 (EOT) 42 (66%) 10 (29%)
SVR 12 37/61 (61%) 9/34 (26%)

B: boceprevir; P: peg-IFN; R: ribavirin.


Important Drug Interactions Between HIV PIs and Boceprevir

A late breaker poster was presented by researchers at Merck reporting significant drug interactions between boceprevir and HIV protease inhibitors (atazanavir, lopinavir and darunavir) in HIV negative volunteers. [3] This highlighted not just the complexity for future HCV treatment in people already on ART, but also the importance of conducting major drug-drug interaction studies prior to coadministration in new studies.

Boceprevir significantly decreased the exposure of the PIs by up to 41-75% for AUC0-last, Cmax, and Cmin [GMR (90% CI)]. Coadministration with boceprevir also decreased the exposure of ritonavir AUCt by 34%, 22%, and 27% in the atazanavir, lopinavir and darunavir groups, respectively. Co-administration with atazanavir/r did not alter boceprevir AUCt, but co-administration with lopinavir/r and darunavir/r decreased boceprevir AUCt 45% and 32%, respectively.


Table 3: Geometric Mean Ratio (90% CI) for Interaction Between Boceprevir and HIV PIs

  AUC0-last Cmax Cmin
ATZ 0.65 (0.55, 0.78) 0.75 (0.64, 0.88) 0.51 (0.44, 0.61)
LPV/r 0.66 (0.60, 0.72) 0.70 (0.65, 0.77) 0.57 (0.49, 0.65)
DRV 0.56 (0.51, 0.61) 0.64 (0.58, 0.71) 0.41 (0.38. 0.45)


Comment

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These results are important for people with HCV genotype 1 who are in need of urgent treatment.

The interaction data between these HCV drugs and antiretrovirals in these studies was luckily not associated with high rates of treatment failure.

For further information on HCV drug interactions please see the excellent online resource produced by the pharmacology team at Liverpool University.

www.hep-druginteractions.org/

UK consensus guidelines for use of these new HCV drugs were recently published online with free access, and although are not HIV-specific, they include a reference to coinfection being a population where their use should be considered. [4]


References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

  1. Dieterich D et al. Telaprevir in combination with pegylated interferon-alfa-2a+RBV in HCV/HIV-co-infected patients: a 24-week treatment interim analysis. Oral abstract 46.

    www.retroconference.org/2012b/Abstracts/42969.htm

  2. Sulkowski M et al. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: end of treatment (week-48) interim results. Oral abstract 47.

    www.retroconference.org/2012b/Abstracts/44725.htm

  3. Hulskotte E et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. Poster late breaker 771LB.

    www.retroconference.org/2012b/Abstracts/45463.htm

  4. Ramachandran P et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther, 2012, 35(6): 647-662. Free full access.

    onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2012.04992.x/full

Links to external websites are current at time of posting but not maintained.




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