Blood, 15 May 2001, Vol. 97, No. 10, pp. 3318-3319
CORRESPONDENCE
To the editor:
Hepatitis C virus RNA dynamics during antiretroviral therapy
In a recent issue, Yokozaki et al published a report in which
they demonstrated that highly active antiretroviral therapy (HAART)
induces a decline in hepatitis C virus (HCV) viremia in hemophiliac
patients with HIV-HCV coinfection. They concluded that coinfected
patients should be treated with HAART before starting the treatment
with interferon and ribavirin.1 HIV-HCV coinfection is
common and affects more than one third of all HIV-infected persons
worldwide. HIV-coinfected patients have higher HCV RNA levels and a
higher risk of rapid progression of HCV liver disease, with increasing
risk of cirrhosis. Chronic HIV infection mimics an opportunistic
disease because the natural history of HCV infection is accelerated in
HIV patients.2 Because the prognosis of HIV disease has
been modified by HAART, the need to treat HCV coinfection is now a
significant issue. In contrast to the findings of Yokozaki et al,
several reports failed to demonstrate any activity of HAART on HCV
viral load.3 Improvement in immune status during effective antiretroviral therapy is generally not sufficient to reduce HCV viral
titers, although a paper reported that HAART therapy has a beneficial
effect on fibrosis in patients with HIV.4 In fact, treatment with HAART may result in increased HCV replication, higher
alanine aminotransferase (ALT) levels and aspartate aminotransferase (AST) levels, and greater liver damage. This may mean that treatment of
hepatitis should precede HAART. Other studies showed that HAART had no
effect on HCV RNA levels or on ASTs and ALTs.5 Moreover, a
study of antiretroviral therapy in coinfected patients showed higher
aminotransferase levels in coinfected patients and more hepatotoxicity
overall (54% of HIV/HCV versus 39% HIV), although 88% of coinfected
patients did not experience severe hepatotoxicity during antiretroviral
therapy. Ritonavir accounted for more than 50% of cases of severe
aminotransferase toxicity, and indinavir accounted for more than 50%
of cases of hyperbilirubinemia.6
Recently, we published a preliminary report on the outcome of an
aggressive therapeutic schedule of daily alpha interferon (IFN) in
coinfected patients.7 In our previous study performed in
immunocompetent patients,8 we demonstrated that daily IFN administration is more effective than three times a week
administration. The need for a more aggressive therapy in
HIV-HCV patients is justified by the worse clinical course. We
demonstrated that, even in patients with undetectable HIV RNA, HAART
therapy did not modify the HCV RNA levels, which responded poorly to an
aggressive IFN therapy. Our results indicate the difficulty to treat
with IFN HIV-HCV coinfected patients, because side effects restrict the
compliance to IFN therapy and could affect the adherence to HAART.
Hence, interferon therapy influenced the tolerability of HAART and
could affect long-term antiretroviral response. Further problems may
originate from the use of combination therapy with IFN plus ribavirin
because of the drug interaction (in vitro studies have demonstrated
that ribavirin could affect intracellular phosphorylation of
deoxynucleoside, mainly AZT,9,10 leading to a reduced
therapeutic effect) and the increase of pill burden, which reduces the
adherence to HAART. In conclusion, we do not agree with Yokozaki et al
and suggest that therapy for hepatitis should precede HAART, at least in patients without severe immunodeficiency, because the interferences between the 2 treatments limit the adherence and the response to both therapies.
Raffaele Bruno, Paolo Sacchi, and Gaetano Filice
Correspondence: Raffaele Bruno, Division of Infection and
Tropical Diseases, IRCCS San Matteo Hospital, University of Pavia, Via
Taramelli 5, Pavia 2710, Italy
References
1.
Yokozaki S, Takamatsu J, Nakano I, et al.
Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy.
Blood.
2000;96:4293-4299[Abstract/Free Full Text].
2.
Sulkowski MS, Mast EE, Seeff LB, Thomas DL.
Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus.
Clin Infect Dis.
2000;30:S77-S84.
3.
Zylberberg H, Chaix ML, Rabian C, et al.
Tritherapy for human immunodeficiency virus infection does not modify replication of hepatitis C virus in coinfected patients.
Clin Infect Dis.
1998;26:1104-1106[Medline]
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4.
Benhamou Y, Bochet M, Di Martino V, et al.
Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients: the Multivirc Group.
Hepatology.
1999;30:1054-1058[CrossRef][Medline]
[Order article via Infotrieve].
5.
Rutschmann OT, Hirschel B, Negro F, Perrin LH.
Lack of effect of long-term HAART on hepatitis C (HCV) viremia. Program and Abstracts of the 12th World AIDS Conference, Geneva, Switzerland, June 28-July 3, 1998. Marathon Multimedia: Faribault, MN; 1998: abstract 22238.
6.
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD.
Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection.
JAMA.
2000;283:74-80[Abstract/Free Full Text].
7.
Bruno R, Sacchi P, Filice C, Filice G.
Aggressive daily interferon therapy in HIV-HCV coinfected patients.
J Acquir Immune Defic Syndr.
2000;25:372-373.
8.
Bruno R, Debiaggi M, Sacchi P, et al.
Daily interferon regimen for chronic hepatitis C: a prospective randomized study.
Clin Drug Invest.
1999;18:11-16[CrossRef].
9.
Vogt MW, Hartshorn KL, Furman PA, et al.
Ribavirin antagonizes the effect of azidothymidine on HIV replication.
Science.
1987;235:1376-1379[Abstract/Free Full Text].
10.
Hoggard PG, Kewn S, Barry MG, et al.
Effects of drugs on 2', 3'-dideoxy-2',3'-didehydrothymidine phosphorylation in vitro.
Antimicrob Agents Chemother.
1997;41:1231-1236[Abstract].
Response:
Highly active antiretroviral therapy and interferon
therapy for HIV-HCV-coinfected patients: which should precede?
We thank Drs Bruno, Sacchi, and Filice for their comments
regarding our paper on immunologic dynamics during antiretroviral therapy in HIV-HCV-coinfected hemophiliac patients. In the paper, we
suggested that treatment for HIV-HCV patients should begin with highly
active antiretroviral therapy (HAART) for HIV prior to interferon (IFN)
therapy for HCV because HAART improves the host immune function in the
host by increasing the CD4+ cell count and often results in
decreasing HCV viral load, which is thought to be advantageous for
patients starting IFN therapy. Bruno et al raise the following issues
regarding starting HAART before starting IFN: (a) HAART is
not necessarily associated with HCV viral load, (b) anti-HIV
drugs are more often toxic for hepatocytes in HCV-coinfected
individuals, (c) severe side effects of IFN treatment may
affect the patients' adherence to HAART, and (d) IFN
therapy combined with ribavirin could affect the response to HAART
because of a drug interaction.
Whether HAART reduces HCV load in HIV-HCV patients is still
controversial. Although Samaniego et al initially reported no association between HAART and HCV load,1 after a longer
observation period they did find such an association.2 The
influence of HAART on HCV load may be delayed in relation to
CD4+ cell count recovery. It also may be that the response
varies between patient races3 or between patient
populations (hemophilia patients have no repeated transmission
mode, such is seen in drug abusers or homosexual men). The
duration of infection and pretreatment CD4+ cell count of
patients may also be involved. Our hemophiliac patients had been
infected with HIV before the establishment of screening for clotting
factors and, thus, may have been infected longer and had a lower
CD4+ cell count than HIV-HCV patients described in other studies.
Anti-HIV-drug-induced hepatotoxicity is considered more common among
HCV-coinfected patients, but this may be due to underlying HCV-related
liver disease. Even among those patients experiencing toxic effects,
the elevated transaminase level was transient and no irreversible
outcomes were observed.4 HAART can be administered safely
to HIV-HCV-infected patients, though the patients' transaminase levels should be monitored.
Our hemophiliac patients who are suffering from both diseases are
earnest in seeking treatment. They gave informed consent for the IFN
therapy and were prepared for the side effects. To date, none of our
patients treated by HAART and IFN therapy have ceased treatment due to
side effects. Careful attention to the patient's outlook and careful
serum monitoring by the physician is very important, however.
Once a patient starts HAART, it is continued even after the start of
IFN therapy. In vitro study has suggested that ribavirin inhibits
action of anti-HIV drugs.5 Certainly cotreatment with ribavirin may strengthen the IFN effect but may weaken the underlying effect of HAART. A recent report, however, demonstrated the safety and
effectiveness of this combination during HAART: as many as 50% of the
study patients were sustained responders to treatment with IFN plus
ribavirin.6
HCV-related disease has become a more significant issue than HIV
disease that is well controlled by the establishment of HAART. Due to
the fact that HIV accelerates the progression of HCV disease, a
successful outcome with IFN therapy is critical. IFN therapy for HCV
infection aims at complete elimination of the virus and is short-term,
whereas the aim and duration of HAART for HIV infection are quite
different. Because the outcome of IFN therapy, alternatively successful
viral elimination or not, depends greatly on the initial host and virus
conditions,7 the starting point for IFN therapy must be
optimally advantageous for the host.
Approximately 85% of acutely HCV-infected persons develop chronic,
persistent viremia, suggesting the difficulty of viral clearance even
under normal immune conditions. The remaining persons who fortunately
recover from hepatitis with eradication of HCV show a dominant
Th1-response among CD4+ cells,8 inducing
specific CTL activity.9 Thus CD4+ cells are
central to the cytotoxic immune system, playing an important role in
the eradication of viruses. Actually, in HIV-HCV-infected patients, a
sustained IFN response has been associated with a pretreatment
CD4+ cell count.10 Thus IFN therapy should be
performed under as near- normal immune conditions as possible.
Finally, a standard therapy for HIV-HCV-coinfected patients has not
been established. Which therapy should precede: HAART or IFN? The
answer may depend on the pretreatment host and viral factors such as
the CD4+ cell count and the HCV viral load. More
information or a large study addressing this question is urgently needed.
Shouichi Yokozaki, Junki Takamatsu, Isao Nakano, Yoshiaki Katano, Hidenori Toyoda, Kazuhiko Hayashi, Tetsuo Hayakawa, and Yoshihide Fukuda
Correspondence: Shouichi Yokozaki, Second Department of Internal
Medicine, Nagoya University, 65 Tsurumo-cho, Showa-ku, Nagoya 466-8550, Japan
References
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Samaniego JG, Bravo R, Castilla J, et al.
Lack of benefit of protease inhibitors on HCV viremia in HIV patients.
J Hepatol.
1998;28:526-527[CrossRef][Medline]
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2.
Perez-Olmeda M, Samaniego JG, Soriano V.
Hepatitis C viremia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy [letter].
AIDS.
2000;14:212[CrossRef][Medline]
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3.
Reddy KR, Hoofnagle JH, Tong MJ, et al.
Racial differences in responses to therapy with interferon in chronic hepatitis C.
Hepatology.
1999;30:787-793[CrossRef][Medline]
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4.
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD.
Hepatotoxicity associated with antiretroviral therapy in adults with HIV and the role of hepatitis B or C infection.
JAMA.
2000;283:74-80.
5.
Vogt MW, Hartshorn KL, Furman PA, et al.
Ribavirin antagonizes the effect of azidothymidine on HIV replication.
Science.
1987;235:1376-1379.
6.
Landau A, Batisse D, Duong Van Huyen JP, et al.
Efficacy and safety of combination therapy with interferon-alpha2b and ribavirin for chronic hepatitis C in HIV-infected patients.
AIDS.
2000;14:839-844[CrossRef][Medline]
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Davis RG, Lau JY.
Factors predictive of a beneficial response to therapy of hepatitis C.
Hepatology.
1997;26:122S-127S[CrossRef][Medline]
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8.
Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC.
Detection of Type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity.
Hepatology.
1997;25:449-458[CrossRef][Medline]
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Lechner F, Gruener NH, Urbani S, et al.
CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.
Eur J Immunol.
2000;30:2479-2487[CrossRef][Medline]
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10.
Soriano V, Bravo R, Samaniengo JG, et al.
CD4+ T-lymphocytopenia in HIV-infected patients receiving interferon therapy for chronic hepatitis C. HIVHepatitis Spanish Study Group.
AIDS.
1994;8:1621-1622[CrossRef][Medline]
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