Elevated Liver Enzymes Following Initiation of Antiretroviral Therapy - Source : JAMA vol. 283, 17/05/2000
consu...@pandora.be
To the Editor: Dr Sulkowski and colleagues1 described hepatotoxicity
associated with antiretroviral treatment (ART), but the finding of liver
abnormalities following ART does not necessarily imply drug toxicity. Recent
reports have suggested that protease inhibitor therapy may be associated
with transient "flares" of chronic viral hepatitis, which represent a
reactivation of the host inflammatory response following the "immune
reconstitution" associated with successful ART. Similar inflammatory
reactivations of clinically silent infections have been described for other
opportunistic infections after human immunodeficiency virus (HIV) ART.2
Indeed, anecdotal reports have shown that the flare of hepatitis may be
followed by full clearance of the hepatitis B virus.3, 4
Mild to severe hepatotoxicity may be the initial sign of immune
reconstitution. If ART is discontinued at this point, such cases may be
indistinguishable from those of drug toxicity. Sulkowski et al reported that
in 6 of 31 cases with severe hepatotoxicity, ART was continued without
clinically significant consequences. Unfortunately, no information regarding
the evolution of viral hepatitis markers was provided. Interestingly, an
increase in CD4 cell count was found to correlate with severe
hepatotoxicity. The authors interpreted this result as a possible marker of
better adherence to therapy. However, the correlation of the increase of CD4
cell count and liver function abnormalities would also be expected if these
phenomena were related to an increased host response to hepatitis virus
after an improvement in the immunological status. Indeed, cell-mediated
immunity is considered to play an important role in the clearance of viral
hepatitis infection.
Although this was not the original purpose of the study, it would be of
great interest to know the ultimate evolution of viral markers of these
patients, and whether there was clearance of the hepatitis B or C virus in
any of them. If this were the case, the appearance of liver function
abnormalities after ART might represent an immune reconstitution syndrome
rather than an adverse outcome.
Maria Velasco, MD
Hospital Clinic
Barcelona, Spain
Carlos Guijarro, MD, PhD
Fundación Hospital Alcorcón
Madrid, Spain
1. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated
with ART therapy in adults infected with human immunodeficiency virus and
the role of hepatitis C or B virus infection. JAMA. 2000;283:74-80.
2. Sepkowitz KA. Effect of HAART on natural history of AIDS-related
opportunistic disorders. Lancet. 1998;351:228-230. MEDLINE
3. Carr A, Cooper D. Restoration of immunity to chronic hepatitis B
infection in HIV-infected patient on protease inhibitor. Lancet.
1997;349:995-996. MEDLINE
4. Velasco M, Morán A, Téllez MJ. Resolution of chronic hepatitis B after
ritonavir treatment in an HIV-infected patient. N Engl J Med.
1999;340:1765-1766. MEDLINE
In Reply: We agree with Drs Velasco and Guijarro that serum
aminotransaminase level elevations following the initiation of ART could
reflect immune reconstitution, as we discussed. However, there are a number
of reasons to suspect that the majority of significant liver enzyme
elevations in our study were due to medication toxicity. Liver enzyme
elevations occurred more often in persons receiving a specific drug,
ritonavir, an effect that was independent of effectiveness of the medication
in suppressing HIV replication. In addition, 14% of persons with
ritonavir-associated hepatotoxicity did not have effective suppression of
HIV replication or increases in CD4 cell count, findings that essentially
exclude immune reconstitution in these cases.
Velasco and Guijarro suggest that serial assessment of hepatitis C virus
(HCV) RNA level may reveal decreases in HCV viremia and offer evidence of
immune reconstitution syndrome. For instance, reduction in cytomegalovirus
viremia has recently been demonstrated following highly active
antiretroviral therapy (HAART)-associated immune restoration.1 However,
studies that have examined HCV RNA levels after HAART have failed to find
evidence of HCV-specific immune reconstitution. Rutschmann et al2 and Ragni
and Bontempo3 found that HCV RNA levels increased after initiation of HAART
despite increases in CD4 cell count, and Ragni and Bontempo3 reported that
HCV RNA levels decreased with the discontinuation of HAART.
In addition, immune reconstitution typically refers to the restoration of
antigen-specific effects, and paradoxical worsening of disease activity has
been demonstrated for some pathogens, such as Mycobacterium tuberculosis.4
However, given the current understanding of HCV persistence, one might be
surprised to find many individuals who would develop clinically detectable
disease with restoration of an immune response that was previously
ineffective in containing persistent HCV variants. Furthermore, in our study
the proportion of patients who developed hepatotoxicity in association with
CD4 cell count elevations was not different in HCV-infected (94%) vs
HCV-uninfected (83%) individuals. In fact, 42% of all hepatotoxicity was
observed in HCV-uninfected individuals.
Antiretroviral therapy-associated hepatotoxicity is probably multifactorial
and different mechanisms could dominate in various hosts. For example,
immune reconstitution to another pathogen (eg, hepatitis B virus) could
indirectly affect levels of HCV RNA, and may have been responsible for some
of the cases in our study. We are not aware of any study, including our own,
that was designed to evaluate the mechanism of ART-associated
hepatotoxicity. Until such data are available, investigators will need to
keep an open mind about the subject.
Mark S. Sulkowski, MD
David L. Thomas, MD, MPH
Richard E. Chaisson, MD
Richard D. Moore, MD
Johns Hopkins University School of Medicine
Baltimore, Md
1. O'Sullivan CE, Drew WL, McMullen DJ, et al. Decrease of cytomegalovirus
replication in human immunodeficiency virus infected-patients after
treatment with highly active ART therapy. J Infect Dis. 1999;180:947-949.
2. Rutschmann OT, Negro F, Hirschel B, Hadengue A, Anwar D, Perrin LH.
Impact of treatment with human immunodeficiency virus (HIV) protease
inhibitors on hepatitis C viremia in patients coinfected with HIV. J Infect
Dis. 1998;177:783-785. MEDLINE
3. Ragni MV, Bontempo FA. Increase in hepatitis C virus load in hemophiliacs
during treatment with highly active ART therapy. J Infect Dis.
1999;180:2027-2029. MEDLINE
4. Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4
cell reconstitution after protease inhibitor-containing ART regimen. AIDS.
1999;13:669-676. MEDLINE
GRMSTR
To your health,
Grampa Mike