Role of viral kinetics under HCV therapy in HIV/HCV-coinfected patients

Angel Luis Ballesteros1, Daniel Fuster1, Ramon Planas2, Bonaventura Clotet1 and Cristina Tural1,*

1 HIV Clinical Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Barcelona, Spain; 2 Hepatology and Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Barcelona, Spain


* Corresponding author. Tel: +34-93-497-88-87; Fax: +34-93-465-76-02; Email: ctural{at}ns.hugtip.scs.es


    Abstract
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are less responsive to anti-HCV therapies and are at a higher risk of toxicity than HCV monoinfected patients. HCV viral kinetics is the basis for the study of response to interferon-based therapy and for predicting sustained virological response (SVR). A lack of early virological response (EVR; undetectable HCV RNA or a decrease of ≥2 log10 from baseline) after 12 weeks of pegylated interferon (peg-IFN) plus ribavirin (RBV) is an equally reliable predictor of lack of SVR in HIV/HCV-coinfected patients and in the monoinfected HCV population. Early stopping rules are particularly important in coinfected HIV/HCV patients, considering their low chances of response in the more difficult-to-treat HCV genotypes 1 and 4 (<30%). Several factors have been involved in this low efficacy, including higher baseline HCV viraemia, slower viral kinetics decay under interferon pressure and a defective immune substratum. A better understanding of HCV viral kinetics under HCV therapy may be the basis for assaying different peg-IFN plus RBV schedules, such as induction or extending strategies, and may help physicians to make tailored decisions for the management of their patients.

Keywords: HCV kinetics , early virological response , peg-IFN efficacy


    Introduction
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
Treatments against hepatitis C virus (HCV) have improved over the past decade with the introduction of pegylated interferon (peg-IFN) formulations in combination with ribavirin (RBV).1,2 However, their efficacy is lower in HIV/HCV-coinfected patients than in patients only infected with HCV.35 Until the development of new anti-HCV drugs, HCV kinetics may support more efficient, customized peg-IFN plus RBV schedules based on the prediction of sustained virological response (SVR).


    Background
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
Neumann et al.6 first reported the effect of daily standard IFN-{alpha} on the dynamics of HCV replication in monoinfected HCV patients. They described a biphasic pattern of HCV decay using a mathematical model.6 The first phase was an initial sharp decay related to the antiviral ‘efficacy’ ({varepsilon}) of IFN in clearing of free virus (c) by blocking viral production and secretion which occurred after a delay of about 8–9 h from the beginning of therapy. The second decay phase showed a more gradual slope in HCV RNA levels, thus representing the rate of killing or clearance of virally infected cells ({delta}). Recently, new results by Herrmann et al.7 showed a third phase of viral decay attributed to the effect of RBV that may be related to restoration of a previously suppressed cellular immune response (M{delta}) (Figure 1).



View larger version (19K):
[in this window]
[in a new window]
 
Figure 1. Representation of mathematical model of HCV viral decay response to HCV-therapy. First and second phases produced by interferon-{alpha} (Neumann et al.6 ). Third phase attributed to ribavirin (Hermann et al.7 ).

 
However, little is known about HCV dynamics under IFN treatment in the setting of HIV coinfection, and the mathematical model of HCV decay is not well defined. Higher baseline HCV viraemias and impaired HCV-specific antibody responses have been well documented in HIV patients,8 but few studies on HCV kinetics are available after the beginning of HCV therapy.911 The lower effectiveness of IFN-based therapies reported in HIV patients35 might be associated with a slower HCV RNA decay in the first and second phases of HCV kinetics,9,10 producing a suboptimal HCV clearance that may also be related to a deficient immunological third-phase response.12


    Viral kinetics as a tool to predict response to antiviral therapy in HCV/HIV-coinfected patients
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
HCV dynamics assess the ability of the infected host to respond to an antiviral therapy. In patients with chronic HCV monoinfection, several studies have provided evidence of the clinical relevance of initial viral dynamics in predicting SVR.13 To date, the most useful information in clinical practice comes from the negative predictive value (NPV) of lack of early virological response (EVR; undetectable HCV RNA or a decrease of ≥2 log10 from baseline) at week 12. Monoinfected HCV patients without EVR after 12 weeks of HCV therapy only have a 3% chance of SVR, and physicians may interrupt peg-IFN plus RBV therapy.2,13 Recent data from the APRICOT study confirmed that the same early stopping rule may also be applied to HIV/HCV-coinfected patients if HCV eradication is the goal of treatment (NPV=98% at week 12).3 A prompt recognition of non-response is important to minimize toxicity, especially in HIV/HCV-coinfected patients.

This is not the case of the positive predictive value (PPV) of EVR at week 12. The outcome of the combination therapy with peg-IFN and RBV is highly dependent on the rapidity of virological response.13 In HIV/HCV-coinfected patients, we have shown that those patients who become HCV RNA-negative during the first 4 weeks of treatment have the greatest chance of achieving SVR (PPV=100% at 24 h, weeks 1 and 4, but dropped to 58.3% at week 12).11 The PPV reported in the APRICOT study was 56% for peg-IFN {alpha}-2a (180 µg/week) plus ribavirin (800 mg/day) at week 12 by using the definition of EVR, but there are no PPV data of EVR at week 4.3 No information is currently available on whether a more restrictive criteria, such as a negative HCV qualitative test (<50 IU/mL) at week 12, may be a more reliable predictor of SVR than an HCV viral decay of ≥2 log10, which may not be enough to guarantee a lack of relapse after peg-IFN and RBV interruption.

Taking into account the low SVR rates reported for difficult-to-treat genotypes 1 and 4 (29% of individuals harbouring HCV genotype 1 in the APRICOT study achieved SVR)3 in HIV/HCV-coinfected patients, we suggest that these patients may be a subset of the population who would benefit from assaying different HCV therapeutic approaches such as induction or extending schedules. The understanding of HCV kinetics under peg-IFN plus RBV therapy may help design reasonable clinical trials.


    Implications of HCV dynamics in HIV patients for new treatment strategies
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
Untreated monoinfected HCV patients present a dynamic equilibrium where virion production is balanced with viral elimination (turnover of 1012 virions/day).14 To date, we also assumed a stable baseline steady-state in the HIV/HCV-coinfected population. However, some authors have described fluctuations in plasma HCV RNA levels following the initiation or interruption of highly active antiretroviral therapy (HAART), hence suggesting an interaction between both viruses.15,16 Our group recently reported a significant, early and transient decrease in plasma HCV RNA levels in some patients after structured treatment interruptions (STI) of HAART in individuals with long-term suppressed HIV replication.16 Further research is needed to confirm these preliminary data17 but they may establish a rationale for assessing the combination of STI with initiation of antiviral HCV therapy.

Few HCV kinetic studies have been performed in the setting of HCV/HIV coinfection under peg-IFN plus ribavirin.911 Different groups have reported a slower first phase of HCV decay (which sometimes is even absent) in HIV patients harbouring HCV genotype 1 by using IFN-{alpha}10 and peg-IFN {alpha}-2a plus RBV.9 The low effectiveness of IFN-based therapies in this first phase of HCV kinetics may be attributed to higher HCV viraemias compared with monoinfected HCV patients, and to the burden of simultaneously having to clear both HIV and HCV. The estimated virion half-life is longer (6.7 h) in HCV/HIV subjects than in monoinfected HCV patients (2–3 h).9,10 The same studies described a steeper second phase of HCV RNA decline. The viral dynamics of HCV genotype 4, an increasingly prevalent genotype in the HIV population of Southern Europe, seem similar to that of genotype 1.18 HIV-induced blunting of HCV-specific immune responses may be responsible for the higher turnover rate of HCV typically seen in HIV coinfection and may also result in a rapid generation of viral diversity (quasi-species), thus leading to viral escape from the host immune surveillance and from anti-HCV therapy. The slower second phase may reflect a suboptimal clearance of HCV-infected cells by anti-HCV treatment, which may explain the reported increased number of breakthroughs and relapses.5

The rationale for induction strategies is based on the association of early viral kinetics during the first weeks with the probability of achieving SVR. With IFN induction schedules, the improvement in viral kinetics during the initial weeks is supported by the finding that the first-phase slope is dose-related19,20 and by the possibility that maintaining a high drug pressure during the second-phase slope may overcome HCV resistance. Layden et al.21 predicted lack of response if {varepsilon} of IFN did not reduce HCV viral loads below a threshold at 24 h, and reported that the first phase of viral parameters significantly affected the decay rate during the second phase. Our group also reported that the difference in HCV viral decline between HIV/HCV-coinfected patients who achieved SVR to peg-IFN {alpha}-2b plus a fixed dose of RBV and those who did not achieve SVR was already seen at 24 h after the first dose and was maintained throughout the 4 initial weeks of HCV therapy.11 Although the improvement in SVR rates with IFN induction strategies is controversial, the prevalence of difficult-to-treat genotypes 1 and 4, and their higher HCV viraemias in HIV patients may justify these strategies. Ferenci et al.22 reported a better outcome of HCV RNA eradication for monoinfected HCV patients harbouring genotype 1 with the use of higher daily doses of IFN-{alpha}. Nevertheless, induction approaches need a close monitoring of tolerance and adverse events, since the possible improvement of virological efficacy must be balanced with an increased number of discontinuations. In a pilot study including HIV/HCV-coinfected patients, Rockstroh et al.23 attributed the lack of therapeutic benefit of a high initial daily dose of IFN-{alpha} to poor tolerability. However, taking into account the safety profile of new peg-IFN formulations, it may be interesting to assess the benefits of higher induction doses of peg-IFN in HIV populations with high viral loads (>500 000 IU/mL) of HCV genotypes 1 or 4.

The different pharmacokinetic properties of the two commercially available formulations [peg-IFN {alpha}-2b (Pegintron; Schering-Plough) and peg-IFN {alpha}-2a (PEGASSYS; Roche)] are also important in the design of new strategies [absorption half-lives ~4.6 and 50 h, respectively; terminal elimination half-lives (t1/2) ~40 and 80 h, respectively].24 Therefore, a twice-weekly administration should be considered for peg-IFN {alpha}-2b to avoid suboptimal serum concentrations before the 1 week dosing interval.25

The rationale for longer treatment strategies is supported by the slower HCV dynamics that may explain the high relapse rates reported in HIV-infected patients.5 We analysed the changes in HCV viral load during the first 12 weeks of peg-IFN {alpha}-2b therapy in five out of 21 HIV/HCV-coinfected patients who achieved EVR but not SVR (transient responders). We observed that a decay of more than 2 log10 in those transient responders was only achieved at 12 weeks of therapy instead of at 4 weeks, as was the case in patients who achieved both EVR and SVR.11 It is not known whether extending therapy in this subgroup of patients may increase the chances of achieving a SVR. Few publications have dealt with this objective even in monoinfected HCV patients. Buti et al.26 reported successful results of nine monoinfected HCV late responders treated with extended therapy of a peg-IFN {alpha}-2b plus RBV combination. In the coinfected HCV/HCV population, previous studies found a high rate of relapse in HCV genotype 3 patients treated for 24 weeks with peg-IFN {alpha}-2b plus RBV (35%), leading the authors to suggest a longer course of HCV therapy.5 The highest rate of end treatment response (ETR) (64%) with a maintained SVR (62%) in HCV genotype 3 reported in the APRICOT study3 supports extending HCV therapy from 24 to 48 weeks in HIV/HCV-coinfected patients, although the proper duration of HCV therapy in these patients needs to be confirmed in large-scale, well-designed, randomized clinical trials.

In HIV patients, a defective immune system may explain the lack of HCV kinetic efficacy during the second and third phases. The modulation of host factors related to cellular immunity may be required for treatment efficacy and HCV viral clearance. Immunological studies observed that T cell responses may take many months to emerge and peak after the onset of treatment, despite the fact that HCV RNA levels become undetectable,27 hence justifying longer treatment strategies. Interferons are natural mediators of host defence and their possible antifibrotic effect is claimed as an additional reason for extending therapies.28 Moreover, RBV is considered to be responsible for the recently described third phase of viral decay (M{delta}) by enhancing HCV-specific T helper 1 immune responses.7 Thus, insufficient RBV dosages (800 mg/day) usually used in trials in HCV/HIV patients may also be involved in breakthroughs or relapses after HCV therapy, and higher doses of RBV (1000–1200 mg/day) should be tested.


    Conclusions
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
The study of HCV dynamics is a useful tool for establishing a tailored HCV therapy in HIV patients. Until other anti-HCV drugs become available, there is a need to improve SVR rates based on new peg-IFN plus RBV schedules. HCV kinetic studies are important to evaluate the efficacy and optimize the safety of these schedules. Finally, new drug research focused on their own antiviral potency (e.g. anti-HCV protease inhibitors) or even in boosting the efficacy of current therapeutic agents (e.g. immunomodulatory peptides) will also need to be tested in comparative kinetic studies.


    References
 Top
 Abstract
 Introduction
 Background
 Viral kinetics as a...
 Implications of HCV dynamics...
 Conclusions
 References
 
1 . Manns MP, McHutchison JG, Gordon S et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.[CrossRef][ISI][Medline]

2 . Fried M, Shiffman M, Reddy R et al. Peg-interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med 2002; 347: 975–82.[Abstract/Free Full Text]

3 . Torriani FJ, Rodriguez-Torres M, Rockstroh JK et al. (APRICOT Study Group) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV patients. New Engl J Med 2004; 351: 438–50.[Abstract/Free Full Text]

4 . Carrat F, Bani-Sadr F, Pol S et al. ANRS HC02-RIBAVIC study team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 15: 292 (23), 2839–48.[CrossRef]

5 . Pérez-Olmeda M, Núñez M, Romero M et al. Pegylated IFN-{alpha}2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients. AIDS 2003; 17: 1023–8.[CrossRef][ISI][Medline]

6 . Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998; 282: 103–7.[Abstract/Free Full Text]

7 . Herrmann E, Lee J-H, Marinos G et al. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 2003; 37: 1351–8.[CrossRef][ISI][Medline]

8 . Cribier B, Rey D, Schmitt C et al. High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV. AIDS 1995; 9: 1131–6.[ISI][Medline]

9 . Torriani FJ, Ribeiro RM, Gilbert TL et al. Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection. J Infect Dis 2003; 188: 1498–507.[CrossRef][ISI][Medline]

10 . Talal AH, Shata TM, Markatou M et al. Virus dynamics and immune responses during treatment in patients coinfected with hepatitis C and HIV. J Acquir Immune Defic Syndr 2004; 35: 103–13.[Medline]

11 . Ballesteros AL, Franco S, Fuster D et al. Early HCV dynamics on Peg-interferon and ribavirin in HIV/HCV co-infection: indications for the investigation of new treatment approaches. AIDS 2004; 18: 59–66.[CrossRef][ISI][Medline]

12 . Barnes E, Harcourt G, Brown D et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 2002; 36: 743–54.[CrossRef][ISI][Medline]

13 . Davis GL. Monitoring of viral levels during therapy of hepatitis C. Hepatology 2002; 36: 5 Suppl 1, 145–51.[CrossRef]

14 . Nguyen TT, Sedghi-Vaziri A, Wilkes LB et al. Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection. J Viral Hepat 1996; 3: 75–8.[ISI][Medline]

15 . Puoti M, Gargiulo F, Roldan EQ et al. Liver damage and kinetics of hepatitis C virus and human immunodeficiency virus replication during the early phases of combination of antiretroviral treatment. J Infect Dis 2000; 181: 2033–6.[CrossRef][ISI][Medline]

16 . Tural C, Gómez G, Martinez MA et al. Impact of highly active antiretroviral therapy interruption strategies in plasma hepatitis C virus kinetics in human immunodeficiency and hepatitis C virus coinfected patients. In: Abstracts of the XV International AIDS Conference, Bangkok, Thailand, 2004. Abstract WeOrB1326. IAS International AIDS Society, Geneva, Switzerland.

17 . Cooper CL, Cameron DW. Review of the effect of highly active antiretroviral therapy on hepatitis C virus (HCV) RNA levels in human immunodeficiency virus and HCV coinfection. Clin Infect Dis 2002; 35: 873–9.[CrossRef][ISI][Medline]

18 . Halfon P, Neumann AU, Bourliere M et al. Slow viral dynamics of hepatitis C virus genotype 4. J Viral Hepat 2003; 10: 351–3.[CrossRef][ISI][Medline]

19 . Lam NP, Neumann AU, Gretch DR et al. Dose-dependent acute clearance of hepatitic C genotype 1 virus with interferon alfa. Hepatology 1997; 26: 226–31.[ISI][Medline]

20 . Jessner W, Gschwantler M, Steindl-Munda P et al. Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study. Lancet 2001; 358: 1241–2.[CrossRef][ISI][Medline]

21 . Layden JE, Layden TJ, Reddy KR et al. First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline. J Viral Hepat 2002; 9: 332–3.[CrossRef][ISI][Medline]

22 . Ferenci P, Brunner H, Nachbaur K et al. Combination of interferon induction therapy and ribavirin in chronic hepatitis C. Hepatology 2001; 34: 1006–11.[CrossRef][ISI][Medline]

23 . Rockstroh JK, Mudar M, Lichterfeld M et al. Pilot study of interferon alpha high-dose induction therapy in combination with ribavirin for chronic hepatitis C in HIV-co-infected patients. AIDS 2002; 16: 2083–5.[CrossRef][ISI][Medline]

24 . Zeuzem S, Welsch C, Herrmann E. Pharmacokinetics of peginterferons. Semin Liver Dis 2003; 23 Suppl 1: 23–8.[CrossRef][ISI][Medline]

25 . Formann E, Jessner W, Bennett L et al. Twice weekly administration of peginterferon {alpha}2b improves viral kinetics in patients with chronic hepatitis C genotype 1. J Viral Hepat 2003; 10: 271–6.[CrossRef][ISI][Medline]

26 . Buti M, Valdés A, Sánchez-Ávila F et al. Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders: report of 9 cases. Hepatology 2003; 37: 1226–7.[CrossRef][ISI][Medline]

27 . Barnes E, Harcourt G, Brown D et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 2002; 36: 743–54.[CrossRef][ISI][Medline]

28 . Shiffman ML, Hofmann CM, Contos MJ et al. A randomized, controlled trial of maintenance interferon for treatment of chronic hepatitis C non-responders. Gastroenterology 1999; 117: 1164–72.[ISI][Medline]





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
55/6/824    most recent
dki142v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Ballesteros, A. L.
Articles by Tural, C.
PubMed
PubMed Citation
Articles by Ballesteros, A. L.
Articles by Tural, C.