Does abacavir decrease SVR rates with HCV treatment?

1 April 2008. Related: Conference reports, Hepatitis coinfection, CROI 15 (Retrovirus) 2008.

Simon Collins, HIV i-Base

Three studies from Spain reported on the relationship between nucleoside/tide analogues and response to HCV treatment. [1, 2, 3] Last year at CROI, a poster from French researchers reported that abacavir use was significantly associated with poorer outcome to HCV treatment, through a possible intracellular competition between abacavir and ribavirin. [4]

Jose Mira and colleagues from Hospital University de Valme, Seville presented a retrospective analysis comparing sustained virological response (SVR) rates among HIV/HCV-co-infected patients treated with peg-IFN plus ribavirin, who were taking a NRTI backbone consisting of either abacavir + 3TC or tenofovir + 3TC/FTC. [1]

In an intention-to-treat analysis, sustained virological response (SVR) was seen in 20/70 (29%) individuals receiving abacavir and 83/186 (45%) patients using tenofovir, (p=0.02). NRTI backbone containing TDF was an independent predictor of SVR in the multivariate analysis (adj odds ratio, 95%CI: 2.6; 1.05 to 6.9); p=0.03).

HCV genotype 2 or 3, baseline LDL cholesterol levels =100 mg/dL, lower baseline plasma HCV viral load and undetectable baseline HIV viral load also predicted SVR. The association between abacavir use and lower SVR rate was mainly seen in patients with plasma HCV viral load >600,000 IU/mL, HCV genotype 1 or 4 and in patients who received lower doses of ribavirin. (those less likely to respond to HCV treatment)

Of patients using a daily dose of ribavirin of less than 13.2 mg/kg, 3 (20%) of those under abacavir vs 22 (52%) under tenofovir achieved SVR (p = 0.03), whereas the rates were 31% and 38% (p = 0.4), respectively, in those receiving RBV dose higher than 13.2 mg/kg.

A second retrospective cohort analysis, from Juan J Gonzalez-Garcia and colleagues from the GESIDA 50/06 Study Group looked at all HIV/HCV coinfected patients treated for HCV while on HAART between January 2003 and November 2005 from 35 sites. [2]

Patients were categorised in 2 groups:  tenofovir, used with 3TC or FTC (n = 238); and non-tenofovir (n = 481) that included patients using AZT + 3TC (n =265), d4T + 3TC (n = 164), or abacavir + 3TC (n =52). They excluded patients receiving ddI or tenofovir with AZT/d4T or abacavir from the analysis.

The two groups were well matched in baseline characteristics except for a lower CD4 cell count mean (535 vs 601; p=0.003), exposure to more HAART regimens (7.2 vs 5.7; p <0.001), and a higher mean GOT/GPT quotient (0.84 vs 0.77; p=0.04). Safety analysis revealed no differences between the groups in relation to death, hepatic decompensation and interruption of HCV treatment due to side effects.

Ribavirin dose-reductions were more frequent in non-tenofovir treated patients (12.8 vs 19.5%; p=0.03), particularly in patients treated with AZT (23.2%; p = 0.003). No significant differences were found in the SVR among patients in the tenofovir and non-tenofovir groups, by ITT analysis (45% vs 39%; p= 0.12).

In a multivariate analysis, adjusting for HCV genotype, HCV viral load <500,000 IU/mL, baseline HIV viral load <50 copies/mL, GOT/GPT quotient, and alcohol intake >50 g/day, SVR was positively associated with use of tenofovir (OR 1.70 95%CI 1.05 to 2.77, p=0.03) and negatively associated with use of AZT, related to anaemia (OR 0.60, 95%CI 0.37 to 0.99, p=0.05), detailed in the Table 1.

Table 1: Odds ratios of SVR by nucleoside backbone

*including patients with AZT+3TC+ABC

The study concluded that the use of TDF + 3TC/FTC was associated with an improved response to peg-IFN plus ribavirin, and that, as shown in previous studies, AZT is associated with a worse tolerability and effectiveness.

In the third study, Ana Moreno and colleagues from Hospital Ramon y Cajal, Madrid looked at use of abacavir or tenofovir in 174 HIV/HCV coinfected patients starting their first cycle of peg-IFN plus weight-adjusted ribavirin. Approximately half the patients used Pegysys and half used PegIntron [3]

Most subjects were male (76%), prior intravenous drug users (87%), with a median age of 40 years (28 to 63). The median duration of HCV infection was 21 years, and 102 (59%) had HCV-genotype 1 or 4. 82% were on HAART (49% PI, 32% NNRTI, and 18% triple-nuke). Tenofovir was used in 69 (48%), abacavir in 56 (39%). The mean ribavirin dosage was 14.7+2.4 mg/kg/day.

Baseline CD4 count, and HCV viral load were 513 cells/mm3 and 5.8 log IU/mL respectively, and two-thirds patients entered the study with undetectable HIV viral load.

SVR was reported in 79/174 (45%) patients. After each adjusted regression analysis however, neither abacavir (p = 0.59), tenofovir (p = 0.92), nor triple NRTI use (p = 0.12) had any significant effect on SVR.

By multivariate analysis, HCV genotype 1 or 4 (OR 7.8, 95%CI 2.6 to 22.93, p = 0.0001), and higher baseline HCV RNA levels (OR 3.5, 95%CI 1.7 to 7.3, p = 0.001) or fibrosis scoring (OR 1.7, 95%CI 1.2 to 2.6, p=0.003) remained independently associated with failure to achieve SVR.

The researchers concluded that in their cohort, use of abacavir, tenofovir or triple nucleosides di not significantly influence the rate of SVR in patients receiving peg-IFN + weight-adjusted-RBV.

Comment

The first study from Mira et al. is a merger of data from Madrid and Seville. The data from Madrid were already presented at IAS and AASLD 2007 with similar findings. The study from Moreno et al. is considerably smaller which may explain the negative finding for abacavir.

The GESIDA cohort took a different route by including abacavir in the group of AZT, ddI and d4T – all of which are known to have toxicities limiting treatment efficacy in coinfected patients.

In summary, these data are no surprise and do not tell us much about abacavir.

References:

1. Mira J, et al. Efficacy of pegylated interferon + ribavirin treatment in HIV/HCV-co-infected patients receiving abacavir + lamivudine or tenofovir + either lamivudine or emtricitabine as nucleoside analogue Backbone.15th CROI, Boston 2008. Abstract 1074.
   http://www.retroconference.org/2008/Abstracts/30917.htm
2. Gonzalez-Garcia J, et al. The use of TDF+ 3TC/ FTC is associated with an improved response to pegylated interferon + ribavirin in HIV/HCV-co-infected patients receiving HAART: the Gesida 50/06 study. 15th CROI, Boston 2008. Abstract 1076.
   http://www.retroconference.org/2008/Abstracts/32077.htm
3. Moreno A, et al. Does the choice of NRTI have a significant influence on the outcome of peg-IFN plus Ribavirin among HIV/HCV-co-infected Patients? 15th CROI, Boston 2008. Abstract 1075.
   http://www.retroconference.org/2008/Abstracts/32710.htm
4. Bani-Sadr F et al. Factors associated with virological non-response to peg-interferon + ribavirin therapy in HIV/HCV co-infected patients: the role of abacavir. 14th CROI, Los Angeles, 2007. Abstract 897.
   http://www.retroconference.org/2007/Abstracts/28572.htm