SMART Study Shows Antiretroviral
Treatment Interruption Is Particularly Risky for Patients with HIV-HBV or HIV-HCV
disease related to coinfection with hepatitis
B or hepatitis C virus (HBV
or HCV) is an increasingly important cause of illness and death among people
A growing body of evidence indicates that CD4-guided interruption
of antiretroviral therapy (ART)
is potentially hazardous, and this may be especially true for HIV-HBV
and HIV-HCV coinfected patients,
according to an analysis from the SMART study published in the December 1, 2008
issue of Clinical Infectious Diseases.
previously reported, SMART included more than 5000 mostly treatment-experienced
participants with a baseline CD4 cell count above 350 cells/mm3. They were randomly
assigned to either start and remain on continuous ART ("viral suppression"
arm) or to interrupt therapy while their CD4 count was above 350 cells/mm3 and
resume when it fell to 250 cells/mm3 ("drug conservation" arm).
study was halted in January 2006 after it became apparent that participants in
the treatment interruption arm not only had a higher rate of AIDS-related opportunistic
disease or death due to any cause, but also were more likely to develop serious
cardiovascular, liver, and kidney disease.
In the present retrospective
analysis, the investigators assessed whether the subgroup of SMART participants
with viral hepatitis coinfection were at increased risk for these endpoints.
were classified as HIV-HBV coinfected if they had positive hepatitis B surface
antigen for more than 6 months, and HIV-HCV coinfected if they tested HCV antibody
positive. Among the total 5472 participants enrolled between January 2002 and
January 2006, 930 patients (17%) were HBV and/or HCV coinfected.
The relative risk of death due
to causes other than opportunistic disease in participants randomized to the treatment
interruption versus the continuous therapy arm was comparable regardless of hepatitis
status (hazard ratio [HR] 1.9 for coinfected and HIV monoinfected participants,
Opportunistic disease or death
occurred at a rate of 3.9 events per 100 person-years in the hepatitis coinfected
group, compared with 2.0 per 100 person-years in the HIV monoinfected group.
This excess risk was due to a
higher rate of non-opportunistic disease deaths among the coinfected participants
The risk of opportunistic disease,
however, was comparable in hepatitis coinfected and HIV monoinfected groups (HR
The 3 leading causes of non-opportunistic
disease death in HIV-HBV and HIV-HCV coinfected participants were unknown cause,
substance abuse, and non-AIDS-defining cancers (there were also several suicides).
on these findings, the researchers concluded, "Interruption of antiretroviral
therapy is particularly unsafe in persons with hepatitis virus coinfection."
HCV- and/or HBV-coinfected participants constituted 17% of participants in the
SMART study, almost one-half of all non-opportunistic disease deaths occurred
in this population," they continued.
Finally, they noted, "Viral
hepatitis was an unlikely cause of this excess risk."
cancer (hepatocellular carcinoma) -- a known complication of chronic hepatitis
B or C -- is not classified as an AIDS-defining malignancy, but like the 3 AIDS-defining
cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer), it is associated
with an infectious organism that may gain an advantage when immune function is
suppressed. Several studies have indicated that ART reduces liver disease progression,
but some antiretroviral drugs have the potential to cause liver toxicity.
SMART, however, liver disease was not a predominant cause of the excess deaths
in the coinfected group. Since HIV, HBV, and HCV can all be spread via injection
drug equipment, injection drugs users -- a group with a higher risk of death due
to various causes -- were overrepresented in the coinfected group. The coinfected
patients were also, on average, older and more likely to be heavy alcohol users.
University School of Medicine, Philadelphia, PA; School of Public Health, University
of Minnesota, Minneapolis, MN; Montreal Chest Institute, McGill University Health
Centre, Montreal, Quebec, Canada; Copenhagen HIV Programme, University of Copenhagen
and Centre for Viral Diseases/KMA, Rigshospitalet, Copenhagen, Denmark; Institute
of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; Medizinische
Universitätsklinik, Bonn, Germany; Royal Free and University College Medical
School, London, UK; Service of Infectious Diseases, Hospital Carlos III, Madrid,
Spain; Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain;
National Centre in HIV Epidemiology and Clinical Research, University of New South
Wales, Sydney, Australia.
L Peters, J Neuhaus, and others. Opportunistic Disease and Mortality in Patients
Coinfected with Hepatitis B or C Virus in the Strategic Management of Antiretroviral
Therapy (SMART) Study. Clinical Infectious Diseases 47(11): 1468-1475. December
1, 2008. (Abstract).