{"id":16336,"date":"2012-04-01T15:35:17","date_gmt":"2012-04-01T15:35:17","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=16336"},"modified":"2012-07-19T13:14:25","modified_gmt":"2012-07-19T13:14:25","slug":"hepatitis-c-coinfection-studies","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/16336","title":{"rendered":"Hepatitis C coinfection studies"},"content":{"rendered":"

\"\"Simon Collins, HIV i-Base<\/strong><\/p>\n

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.<\/strong><\/p>\n

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.<\/p>\n

Telaprevir: SVR-12 results in HIV\/HCV coinfection<\/h2>\n

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]<\/p>\n

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).<\/p>\n

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).<\/p>\n

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.<\/p>\n

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.<\/p>\n\n\n\n\n\n\n\n\n\n
Table 1: Interim HCV RNA BLQ (%) response rates with telaprevir in HIV\/HCV coinfection<\/caption>\n
N (%)<\/td>\nNo ART<\/th>\nEFV\/TDF\/FTC<\/th>\nATZ\/r\/TDF\/FTC<\/th>\n<\/tr>\n
<\/td>\nT\/PR<\/td>\nPR<\/td>\nT\/PR<\/td>\nPR<\/td>\nT\/PR<\/td>\nPR<\/td>\n<\/tr>\n
N<\/th>\n7<\/td>\n6<\/td>\n16<\/td>\n8<\/td>\n15<\/td>\n8<\/td>\n<\/tr>\n
Week 4 (RVR)<\/th>\n5 (71)<\/td>\n0<\/td>\n12 (75)<\/td>\n1 (12)<\/td>\n9 (60)<\/td>\n0<\/td>\n<\/tr>\n
Week 12 (oRVR)<\/th>\n6 (66)<\/td>\n2 (33)<\/td>\n14 (80)<\/td>\n2 (25)<\/td>\n11 (73)<\/td>\n3 (38)<\/td>\n<\/tr>\n
Week 4 and 12 (eRVR)<\/th>\n4 (57)<\/td>\n0<\/td>\n12 (75)<\/td>\n1 (12)<\/td>\n8 (53)<\/td>\n0<\/td>\n<\/tr>\n
Week 24<\/th>\n6 (86)<\/td>\n2 (33)<\/td>\n12 (75)<\/td>\n4 (50)<\/td>\n10 (67)<\/td>\n6 (75)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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

Interactions between telaprevir and antiretrovirals<\/h2>\n

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.<\/p>\n

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.<\/p>\n

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<\/p>\n

Boceprevir: SVR-12 results in HIV\/HCV coinfection<\/h2>\n

SVR results at 12 weeks after treatment from a randomised double-blind, placebo controlled study of Merck\u2019s 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]<\/p>\n

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).<\/p>\n

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.<\/p>\n

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.<\/p>\n

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).<\/p>\n\n\n\n\n\n\n\n\n\n\n\n
Table 2: Interim HCV RNA BLQ (%) response rates with boceprevir in HIV\/HCV coinfection<\/caption>\n
<\/td>\nB\/PR<\/th>\nPR<\/th>\n<\/tr>\n
N<\/th>\n64<\/td>\n34<\/td>\n<\/tr>\n
Discontinuation<\/th>\n24 (38%)<\/td>\n18 (53%)<\/td>\n<\/tr>\n
week 4 (pegIFN\/RBV lead-in)<\/th>\n3 (4.7%)<\/td>\n3 (8.8%)<\/td>\n<\/tr>\n
week 8<\/th>\n27 (42%)<\/td>\n5 (15%)<\/td>\n<\/tr>\n
week 12<\/th>\n38 (59%)<\/td>\n8 (23%)<\/td>\n<\/tr>\n
week 24<\/th>\n47 (73%)<\/td>\n11 (32%)<\/td>\n<\/tr>\n
week 48 (EOT)<\/th>\n42 (66%)<\/td>\n10 (29%)<\/td>\n<\/tr>\n
SVR 12<\/th>\n37\/61 (61%)<\/td>\n9\/34 (26%)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

B: boceprevir; P: peg-IFN; R: ribavirin.<\/p>\n

Important drug interactions between HIV PIs and bocepravir<\/h2>\n

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.<\/p>\n

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.<\/p>\n\n\n\n\n\n\n
Table 3: Geometric mean ratio (90% CI) for interaction between boceprevir and HIV PIs<\/caption>\n
<\/td>\nAUC0-last<\/th>\nCmax<\/th>\nCmin<\/th>\n<\/tr>\n
ATZ<\/th>\n0.65 (0.55, 0.78)<\/td>\n0.75 (0.64, 0.88)<\/td>\n0.51 (0.44, 0.61)<\/td>\n<\/tr>\n
LPV\/r<\/th>\n0.66 (0.60, 0.72)<\/td>\n0.70 (0.65, 0.77)<\/td>\n0.57 (0.49, 0.65)<\/td>\n<\/tr>\n
DRV<\/th>\n0.56 (0.51, 0.61)<\/td>\n0.64 (0.58, 0.71)<\/td>\n0.41 (0.38. 0.45)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

comment<\/h2>\n

These results are important for people with HCV genotype 1 who are in need of urgent treatment.<\/strong><\/p>\n

The interaction data between these HCV drugs and antiretrovirals in these studies was luckily not associated with high rates of treatment failure.<\/strong><\/p>\n

For further information on HCV drug interactions please see the excellent online resource produced by the pharmacology team at Liverpool University.<\/strong><\/p>\n

http:\/\/www.hep-druginteractions.org\/<\/a><\/strong><\/p>\n

UK concensus 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]<\/strong><\/p>\n

References:<\/p>\n

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5\u20138 March 2012, Seattle.<\/p>\n

    \n
  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.
    \n    http:\/\/www.retroconference.org\/2012b\/Abstracts\/42969.htm <\/a><\/li>\n
  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.
    \n    http:\/\/www.retroconference.org\/2012b\/Abstracts\/44725.htm <\/a><\/li>\n
  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.
    \n    http:\/\/www.retroconference.org\/2012b\/Abstracts\/45463.htm <\/a><\/li>\n
  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.
    \n    http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1365-2036.2012.04992.x\/full<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Simon Collins, HIV i-Base 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 …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,24],"tags":[66],"class_list":["post-16336","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-hepatitis-coinfection","tag-croi-2012"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/16336","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=16336"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/16336\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=16336"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=16336"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=16336"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}