Background
Until recently, treatment for hepatitis C (HCV) consisted of a combination of pegylated interferon (pegIFN) and ribavirin (RBV), combined more recently with boceprevir and telaprevir or with some of the new direct-acting antivirals (DAA)-containing regimens. In HIV/HCV co-infected patients, treatment for HCV is often administrated concomitantly with combination antiretroviral therapy (cART).
Earlier studies have reported contradicting results regarding the effect of an abacavir-based cART regimen (ABC) on HCV treatment response. For example, some studies found ABC has a negative effect on sustained virologic response (SVR) in the presence of HCV therapy [
1‐
3]. This may be because RBV and ABC share intracellular pathways [
4], which could, theoretically, affect RBV drug concentrations and therefore the effectiveness of RBV. However, other studies found no difference in SVR between patients who received an ABC-containing regimen in combination with HCV treatment and those who did not use ABC concomitantly with HCV treatment [
5‐
8]. These discrepancies might be due to the relatively small samples sizes used in the above-mentioned studies. One larger study, conducted by Berenguer et al. has already been carried out and found that ABC was not associated with a lower response to HCV treatment [
9].
This issue of contradicting results regarding the interaction between ABC and RBV remains important for two reasons. First, even in interferon-free regimens, RBV will often be used with a large number of new DAAs. Furthermore, following the introduction of the HIV integrase inhibitor dolutegravir, which is co-formulated with ABC/3TC in a fixed-dose combination, use of ABC with 3TC is expected to increase. Therefore, to validate the results of the earlier large cohort study by Berenguer et al. we aimed to examine the influence of ABC on the response to pegIFN and RBV-containing HCV treatment in HIV/HCV co-infected patients in a large European cohort collaboration comprising data from different European countries.
Discussion
The results of this study, conducted in an unselected cohort of HCV/HIV co-infected patients from different countries in Europe, showed no difference in response to HCV treatment in patients using an ABC-containing regimen compared to those using an FTC + TDF-containing backbone. Overall, 37 % of patients achieved an SVR, compared to 29 % of patients on a boosted PI regimen. The response to HCV treatment did not differ between patients who used cART and those who did not.
Earlier studies have shown contradicting results for the effect of ABC [
2,
3,
6‐
8]. The results of our study, conducted in a large multi-cohort study, validate those of an earlier large cohort study into the effect of cART on HCV treatment outcome [
9]. In our study, the concomitant use of ABC + 3TC or ABC + TDF and HCV treatment did not result in different SVR rates compared to the concomitant of TDF + FTC and HCV treatment, which was most frequently used in this patient population. In terms of the NRTIs used during HCV treatment, in this study AZT in combination with 3TC and d4T in combination with 3TC negatively affected the response to HCV treatment. This negative effect of these NRTIs might be due not only to the interference of d4T with RBV [
11], but also the effect of AZT on lowering haemoglobin levels [
12]. Moreover, according to the guidelines from the European AIDS Clinical Society, d4T and AZT use should be avoided during pegIFN and RBV treatment [
13], as both PEG-IFN and RBV are also commonly known to decrease haemoglobin levels [
14,
15]. In fact, anaemia is frequently observed in patients during HCV therapy [
12] and is often a cause for RBV dose reductions or early discontinuation of HCV treatment, which negatively impacts SVR rates [
16]. On the other hand, lower haemoglobin levels have been shown to be associated with higher SVR rates [
17]. This could reflect adequate weight-based RBV dosing accompanied by more side effects such as declining haemoglobin levels. Although we had no data on RBV dosing, haemoglobin measurements were available for half the patients. Consequently, we were able to calculate changes in haemoglobin levels and to use the decline in haemoglobin levels as a proxy for changes in RBV doses, assuming that a stronger decline in haemoglobin levels might be a marker for higher RBV doses. As a result of including this haemoglobin change in our analyses we observed higher SVR rates in patients with a haemoglobin decline of 2.5 g/dl or more from baseline, which could reflect higher RBV levels. In addition, the results of a sensitivity analysis including patients with a haemoglobin decline of >2.5 g/dl showed that patients using the combination of AZT and 3TC remained less likely to achieve an SVR compared to patients who used FTC + TDF. Although this result was not statistically significant, the effect of AZT on lowering haemoglobin levels could have attributed to higher toxicity and early discontinuation.
Several reports have shown that weight-based dosing of RBV is more effective than flat dosing of RBV, and that adequate dosing of RBV is crucial to maximising HCV treatment response [
18,
19]. Consequently, there has been a shift from flat dosing to weight-based dosing over time, with most patients receiving weight-based RBV from 2006 onwards. To account for this shift and address the lack of information on RBV dosing in our study, we included calendar time of starting HCV treatment.
The composition of cART regimens has changed over time. In recent years, there has been a drop in the use of AZT and d4T in cART regimens; in fact the European AIDS clinical society guidelines no longer recommend inclusion of AZT and d4T in initial regimens [
13]. Moreover, with the introduction of the HIV integrase inhibitor dolutegravir, use of ABC in combination with 3TC is expected to increase in the future. Therefore, to evaluate the impact of these changes over calendar time we included an interaction term between calendar time and NRTI backbones in the logistic regression model. This analysis found no statistically significant interaction and therefore we assumed that the effect of cART regimens on HCV treatment response does not vary with calendar time.
Our study found a significantly lower SVR in patients on a boosted PI regimens compared to those on an NNRTI-based regimen. This confirms previous reports of an association between a PI-based regimen and lower SVR rates [
20]. Furthermore, Berenguer et al. also found that patients on a boosted PI were less likely to achieve an SVR, although this result was statistically non-significant [
9]. The significant difference between a boosted PI-based regimen and an NNRTI-based regimen in our study might be due to differences in patient characteristics in the two groups: patients on a boosted PI-based regimen had significant lower CD4 counts at the time of cART initiation than patients on an NNRTI cART regimen. Since boosted PI regimens are likely to be prescribed to patients who experienced virological failure on earlier cART regimens, these patients may have been infected with HIV for a longer period of time and may have had more advanced HIV disease progression. It is also likely that these patients had been chronically infected with HCV for a longer period of time. As a result, these patients may have had a higher degree of liver damage, as progression to liver disease is common with HCV and known to be accelerated in the presence of HIV [
21,
22], and therefore might have been less likely to achieve an SVR [
23]. To account for the progression to liver disease and for advanced HIV disease, in the final multivariate model we included not only the APRI score, which has been shown to be a reliable marker for predicting hepatic fibrosis in HIV/HCV co-infected patients [
10], but also nadir CD4 cell count. After adjustment for differences in advanced HIV and liver disease, our study still shows a trend towards a lower probability of achieving an SVR in patients on a boosted PI regimen. Furthermore, although not statistically significant, the discontinuation rate of HCV treatment was somewhat higher in patients receiving a PI or PI-boosted cART regimen, compared to patients receiving an NNRTI cART regimen.
The primary aim of our study was to examine the influence of ABC on the response to pegIFN and RBV-containing HCV treatment in patients already receiving cART prior to HCV treatment. However, we also included a group of patients who started cART after receiving HCV treatment. When we compared this group to those who were already using an FTC + TDF-containing backbone prior to starting HCV treatment, we found no statistically significant difference in SVR response rates. An explanation for this finding could be that the group of patients who started cART after HCV treatment were relatively healthy and not yet in need for HIV treatment. This assumption is supported by the large number of these patients with a high CD4 cell count at the time of HCV treatment initiation: median CD4 cell count in this group was 494 cells/mm3 (interquartile range: 387–651).
Finally, the number of new DAAs is increasing and, consequently, the number of treatment options that rule out the need for pegIFN will also increase substantially. In view of this development, the interaction between pegIFN and ABC has become less relevant. Furthermore, as the result of the growing number of treatment options, including DAA combinations without RBV, it is also likely that fewer patients will be treated with a RBV- containing DAA combination in the future, which might limit the clinical importance of the present findings. Nonetheless, we believe knowledge regarding a possible interaction between RBV and ABC remains important as some of the new DAAs may still be used in combination with RBV. Moreover, the high costs of these new DAAs could limit access to these treatment options in some regions, which might result in RBV still being used in combination with ABC in certain settings.
Acknowledgements
Analysis and Writing committee: Colette Smit, Joop Arends, Lars Peters, Antonella d’Arminio Monforte, Francois Dabis, Jürgen Kurt Rockstroh, Robert Zangerle, George Daikos, Christina Mussini, Josep Mallolas, Stephane De Wit, Annelies Zinkernagel, Jaime Cosin, Genevieve Chêne and Dorthe Raben on behalf of the Hepatitis C working group of Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord
Steering Committee - Contributing Cohorts: Robert Zangerle (AHIVCOS),Giota Touloumi (AMACS), Josiane Warszawski (ANRS CO1 EPF/ANRS CO11 OBSERVATOIRE EPF), Laurence Meyer (ANRS CO2 SEROCO), François Dabis (ANRS CO3 AQUITAINE), Murielle Mary Krause (ANRS CO4 FHDH), Jade Ghosn (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8 COPILOTE), Linda Wittkop (ANRS CO13 HEPAVIH), Peter Reiss (ATHENA), Ferdinand Wit (ATHENA), Maria Prins (CASCADE), Heiner Bucher (CASCADE), Diana Gibb (CHIPS), Gerd Fätkenheuer (Cologne-Bonn), Julia Del Amo (CoRIS), Niels Obel (Danish HIV Cohort), Claire Thorne (ECS), Amanda Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt), Santiago Pérez-Hoyos (GEMES-Haemo), Osamah Hamouda (German ClinSurv), Barbara Bartmeyer (German ClinSurv), Nikoloz Chkhartishvili (Georgian National HIV/AIDS), Antoni Noguera-Julian (CORISPE-cat), Andrea Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Norbert Brockmeyer (KOMPNET), Luis Prieto (Madrid PMTCT Cohort), Pablo Rojo Conejo (CORISPES-Madrid), Antoni Soriano-Arandes (NENEXP), Manuel Battegay (SHCS), Roger Kouyos (SHCS), Cristina Mussini (Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose Miró (PISCIS), Antonella Castagna (San Raffaele), Deborah Konopnick (St. Pierre Cohort), Tessa Goetghebuer (St Pierre Paediatric Cohort), Anders Sönnerborg (Swedish InfCare), Carlo Torti (The Italian Master Cohort), Caroline Sabin (UK CHIC), Ramon Teira (VACH), Myriam Garrido (VACH). David Haerry (European AIDS Treatment Group)
Executive Committee: Stéphane De Wit (Chair, St. Pierre University Hospital), Jose Miró (PISCIS), Dominique Costagliola (FHDH), Antonella d’Arminio-Monforte (ICONA), Antonella Castagna (San Raffaele), Julia del Amo (CoRIS), Amanda Mocroft (EuroSIDA), Dorthe Raben (Head, Copenhagen Regional Coordinating Centre), Geneviève Chêne (Head, Bordeaux Regional Coordinating Centre). Paediatric Cohort Representatives: Ali Judd, Pablo Rojo Conejo.
Regional Coordinating Centres: Bordeaux RCC: Diana Barger, Christine Schwimmer, Monique Termote, Linda Wittkop; Copenhagen RCC: Maria Campbell, Casper M. Frederiksen, Nina Friis-Møller, Dorthe Raben, Rikke Salbøl Brandt.
Project Leads and Statisticians: Juan Berenguer, Julia Bohlius, Vincent Bouteloup, Heiner Bucher, Alessandro Cozzi-Lepri, François Dabis, Antonella d’Arminio Monforte, Mary-Anne Davies, Julia del Amo, Maria Dorrucci, David Dunn, Matthias Egger, Hansjakob Furrer, Marguerite Guiguet, Sophie Grabar, Ali Judd, Ole Kirk, Olivier Lambotte, Valériane Leroy, Sara Lodi, Sophie Matheron, Laurence Meyer, Jose Miró, Amanda Mocroft, Susana Monge, Fumiyo Nakagawa, Roger Paredes, Andrew Phillips, Massimo Puoti, Michael Schomaker, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut, Claire Thorne, Carlo Torti, Marc van der Valk, Linda Wittkop, Natasha Wyss.
We thank Catriona Ester from the Stichting HIV monitoring for editing the manuscript.
Competing interests
JA and JR declare that they have received funding: JA was member of Advisory boards at Viiv, MSD, Janssen, Abbvie, Gilead and BMS. JR has receiven honoraria for consulting and/or speaking at educational events from Abbvie, Bionor, BMS, Gilead, Janssen, Merck and ViiV. None of the remaining authors have anything to declare.
Authors’ contributions
CS analysed the data and drafted the manuscript, JA LP JR critically reviewed the analyses and provided clinical input, JA LP JR AA FB, RZ, GD, CM, JM, SW, AZ, JC, GC, DR reviewed and commented on initial and final drafts of the manuscript, all authors read and approved the final manuscript.