- Fulminant Liver Failure From Acute
HCV Superinfection in a Patient With
HIV, HBV, and HDV Coinfections
Kristin Lee, MD; Paul T. Smith, MD
[The AIDS Reader 10(7):398-401, 2000. © 2000 Cliggott
Publishing Co., Division of SCP/Cliggott Communications, Inc.]
The primary causes of liver disease in injection drug users are
acute and chronic viral infections. Because of shared routes of
transmission, infections with HIV, hepatitis B virus (HBV),
hepatitis C virus (HCV), and hepatitis delta virus (HDV) often
coexist. Furthermore, evidence indicates that the courses of
HBV, HCV, and HDV infections are modified by coinfection
with HIV. Increased rates of HBV replication are seen in
HIV-coinfected patients, while preliminary data suggest that
HCV and HDV are characterized by prolonged viremia in
HIV-infected patients. However, to date, there is little
information regarding the clinical implications of such "quadruple"
infections in patients.
One study from Barcelona, by Buti and Rosendo, followed 86
patients with chronic HBV and HDV coinfection during a period
of 6.5 years in order to assess the natural course of HDV
coinfection and to determine the impact of subsequent
coinfection with HIV and/or HCV on disease progression. Of
the 28 patients who died during follow-up, 18 were injection
drug users infected with HBV, HCV, HDV, and HIV. The
authors concluded that chronic HDV infection can be an
especially severe form of hepatitis among injection drug users
also coinfected with HCV and HIV. Several reports of acute
HCV superinfection in HIV-negative, asymptomatic hepatitis B
surface antigen (HbsAg)-positive carriers with HDV antibodies
show much more severe liver decompensation than occurs in
those without HDV markers.[3,4] It is not clear whether such
observations can be extrapolated to HIV-infected individuals.
We describe a case of acute HCV infection in an HIV-infected
patient with a known history of chronic HBV infection.
The patient, a 36-year-old, Hispanic, HIV-positive male,
presented with a 1-month history of intermittent abdominal
cramping, nausea, vomiting, and watery diarrhea. A recent
workup for diarrhea, which included stool studies for bacteria,
ova and parasites, Cryptosporidium, Microsporidia, and
Cyclospora, was unrevealing. He was referred to his primary
care doctor by his drug treatment program for evaluation of 1
day of lethargy and jaundice. His primary care physician found
him to be ill-appearing, orthostatic, and icteric. He was admitted
for intravenous hydration and further evaluation.
The patient's medical history was significant for HIV infection
since 1987 and for HBV infection since 1990. His risk factors
for both infections were unprotected intercourse with both men
and women as well as a history of intravenous drug use. The
patient had not received antiretroviral therapy during the previous
10 months because of ongoing illicit drug use, but he had had an
excellent earlier response to HAART. One month before
admission, his CD4[+] cell count was 518/µL, and his HIV RNA
was 49,657 copies/mL. He had previous exposure to hepatitis A
virus (HAV), as evidenced by a positive IgG HAV antibody. His
HBV infection had been stable during the previous 3 years, with
chronic, mildly elevated liver transaminase levels (aspartate
aminotransferase [AST], 64 U/L; alanine aminotransferase
[ALT], 68 U/L) 3 weeks before admission. His baseline HBV
serology revealed a positive HbsAg, a positive hepatitis B core
IgG antibody (HbcAb), a positive hepatitis Be antigen (HbeAg),
and a nonreactive hepatitis Be antibody (HbeAb) with a negative
IgM HbcAb. A previous baseline HCV antibody test was
Medications on admission included methadone, olanzapine,
trazodone, paroxetine, and megestrol acetate. His social history
was notable for long-standing intranasal cocaine/crack abuse
despite involvement in both a day treatment and a methadone
maintenance program. Of note is the fact that on admission, the
patient did acknowledge intravenous drug use during the
preceding few months, in which he shared "dirty" needles. He
had previously remained "clean" with regard to intravenous drugs
for several years.
The remainder of the physical examination was significant for
scleral icterus; a soft, nontender abdomen with mild
hepatosplenomegaly; and mild asterixis. Although he was
lethargic, he was fully oriented. Admission laboratory values
revealed markedly elevated liver function tests (AST, 1992 U/L;
ALT, 1841 U/L; total bilirubin, 5.5 mg/dL; direct bilirubin, 3.9
mg/dL; alkaline phosphatase, 143 U/L; albumin, 2.2 g/dL),
elevated coagulation parameters (prothrombin time, 19.1
seconds; international normalized ratio, 2.6); normal electrolytes
and renal function; a complete blood cell count notable for a
platelet count of 86,000/µL; an elevated serum ammonia level of
154 mg/dL; and undetectable serum acetaminophen and
salicylate levels. At this time, the initial diagnosis was acute
chronic hepatitis of unclear origin. Further evaluation included
abdominal ultrasonography, which revealed a normal liver and a
distended gallbladder, and an abdominal CT scan, which
revealed moderate ascites and fatty infiltration of the liver but no
focal hepatic lesions. Repeated hepatitis serology tests confirmed
baseline patterns for HAV and HBV. A repeated HCV antibody
test was negative.
Despite aggressive supportive care, the patient's clinical status
rapidly deteriorated, characterized by progressive hepatic
encephalopathy. Liver enzyme levels peaked on hospital day 4
(AST, 3728 U/L; ALT, 2773 U/L; total bilirubin, 13.7 mg/dL;
direct bilirubin, 9.1 mg/dL; alkaline phosphatase, 145 U/L;
albumin, 1.8 g/dL), as did the prothrombin time at 32.9 seconds.
Cultures of blood, ascitic fluid, and urine remained negative. The
patient became unresponsive and died 8 days following
admission. Subsequent to his death as a result of fulminant
hepatic failure, a serum HCV RNA polymerase chain reaction
(PCR) on day 2 of hospitalization revealed more than 1,000,000
copies/mL of virus, confirming the diagnosis of acute HCV
infection on chronic HBV infection. A second HCV antibody
test on hospital day 5 was reactive. In addition, a total antibody
test for HDV on day 2 of hospitalization was reactive. Hence,
this patient died of acute fulminant hepatic failure secondary to
acute superinfection with HCV in the setting of coinfection with
HBV and HDV. The family refused permission for autopsy.
To our knowledge, this is the first reported case of acute HCV
superinfection in a patient coinfected with HIV, HBV, and HDV
resulting in fulminant liver failure and death. The documented
seroconversion from negative to positive HCV antibody and the
positive PCR (which illustrated HCV RNA viremia) established
the diagnosis of acute HCV infection as a cause of his hepatic
decompensation and death. Based on this patient's clinical
course, an acute HDV superinfection is also plausible. Given the
stability of his chronic HBV infection during the previous several
years, coupled with only a recent relapse of intravenous drug use
-- a known risk factor for HDV acquisition -- it is possible that
his rapid decompensation resulted from acute infections with
both HDV and HCV. In addition, the fact that the patient's IgM
HbcAb remained negative is consistent with a possible acute
HDV superinfection, reflecting suppression of HBV replication
The diagnosis of acute HDV infection is generally problematic
outside of a research laboratory. In fact, for several reasons, we
were unable to determine serologically the timing of HDV
infection in this patient. The large reference laboratory that
performed the HDV total antibody test for this patient was
unable to distinguish IgM from IgG HDV antibody. In addition,
laboratory personnel were not able to quantitate the level of
antibody, which, when elevated, may be suggestive of chronic,
ongoing viral replication.
Given the common route of transmission of these viruses, the
likelihood of multiple infections within a single host is not
improbable. The current standard of care in persons infected
with HIV includes screening for hepatitis B and C viruses,
followed by vaccination against HBV in seronegative patients
and counseling for risk reduction. Given the few reports of
more rapid liver decompensation and increased morbidity and
mortality in patients "quadruply" infected with HIV, HBV, HCV,
and HDV, perhaps screening for HDV should be adopted in this
high-risk group. In addition, patients infected with multiple
hepatotropic viruses likely warrant earlier, more aggressive
diagnostic and treatment approaches. Finally, at this time,
morbidity associated with acute HCV infection can only be
ameliorated by preventive risk-reduction methods and by
ongoing efforts at HCV vaccine development.
1.Horvath J, Raffanti SP. Clinical aspects of the interactions
between human immunodeficiency virus and the
hepatotropic viruses. Clin Infect Dis. 1994;18:339-347.
2.Buti M, Rosendo J. Chronic delta hepatitis: is the
prognosis worse when associated with hepatitis C virus
and human immunodeficiency virus infections? J Med
3.Chu CM, Yeh CT, Liaw YF. Fulminant hepatic failure in
acute hepatitis C: increased risk in chronic carriers of
hepatitis B virus. Gut. 1999;45:613-617.
4.Liaw YF. Role of hepatitis C in dual and triple hepatitis
virus infection. Hepatology. 1997;22:1101-1108.
5.Shaw-Stiffel T. Chronic hepatitis. In: Mandell GL, Bennett
JE, Dolin R, eds. Principles and Practice of Infectious
Diseases. 5th ed. Philadelphia: Churchill Livingstone;
6.1999 USPHS/IDSA Guidelines for the prevention of
opportunistic infections in persons infected with human
immunodeficiency virus. MMWR. 1999;48:32-34.
Dr Lee is an infectious diseases fellow, and Dr Smith is an
instructor in medicine in the department of medicine, division of
international medicine and infectious diseases, Weill Medical
College of Cornell University, New York.
- Hepatology Focus
Update on Hepatitis C Treatment
Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
Medicine, Los Angeles, California
Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
Angeles, California, and
Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
[Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]
Although screening of blood products and other interventions such as
programs have significantly reduced the incidence of acute hepatitis C
in the United States and
elsewhere, there remains a large reservoir of chronically infected
individuals, many of whom are
unaware of their infection. Current estimates suggest a seroprevalence
of 1.8% among Americans,
most of whom are viremic. The clinical burden of chronic hepatitis C
virus (HCV) infection is
expected to increase over the next 2-3 decades as a large cohort of
patients infected between the
1960s and 1980s, primarily as a result of recreational drug use,
develops progressive liver disease.
Between 8000 and 10,000 deaths each year in the United States are
believed to be caused by
infection with HCV -- which is now the most frequent indication for
Even before identification of HCV, interferon-alfa (IFN-alfa) had been
evaluated as a potential
therapy for what had been called chronic non-A, non-B hepatitis.
Further studies using normalization of serum alanine aminotransferase
(ALT) levels and
improvement in liver histology as endpoints demonstrated the efficacy of
IFN-alfa as therapy for
the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
Subsequent advances in
molecular diagnosis have now increasingly allowed establishment of
virologic criteria to evaluate
efficacy of treatment in patients with chronic hepatitis C (see Table).
Definition of Virologic Response in Patients Receiving Therapy for
Chronic Hepatitis C
End-of-treatment response (ETR) refers to absence of viremia (ie, serum
HCV RNA below level
of detection) at completion of therapy. Sustained response (SR)
indicates persistent absence of
serum HCV RNA 6 months or more after cessation of therapy. A study by
coworkers on the long-term clinical outcome in 80 patients with
chronic HCV followed for a
mean of 4 years following therapy highlighted the clinical implications
of a virologic SR. Persistent
absence of HCV RNA from serum was observed in 96% of patients with a
lack of histologic
progression on serial liver biopsy. In addition, ALT levels were
persistently normal in over 90%.
The most recent follow-up biopsy showed normal or near normal histologic
findings in 62% of
these patients. Thus, virologic SR was shown to be associated with both
an absence of detectable
serum HCV RNA and marked histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at
therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
patients who fail to
clear HCV RNA from serum during therapy.
A recent paper by Everson and associates underscores the importance
of HCV RNA testing in
defining treatment response. In patients with marked fibrosis and
cirrhosis, they found a major
discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
to therapy. Two of
7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
cirrhosis cleared HCV RNA
without normalizing ALT. In contrast, only 3 patients (10%) without
significant fibrosis had an
HCV RNA response without normalization of ALT. Thus, clinical trials for
chronic HCV are now
typically reported using virologic response rates.
What then are the current goals of antiviral therapy in patients with
chronic hepatitis C? Immediate
goals are eradication of viral replication and improvement in hepatic
inflammation and fibrosis.
Long-term potential goals include prevention of cirrhosis,
hepatocellular carcinoma, and liver
IFN-alfa 2 was the first agent approved for the treatment of chronic
HCV. Since the initial trials
establishing its efficacy, data regarding treatment duration and dose
have evolved. Currently, 2
forms of IFN-alfa that differ by a single amino acid residue are
approved for treatment of chronic
HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
(Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
million units 3 times each
week for up to 12 months.
When used alone in monotherapy, the alfa interferons have similar
efficacies, with SRs of only 10%
to 20%, with the modestly higher response rates associated with more
Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
between 8% and 20% in
treatment-naive patients. High-dose IFN-alfa has also been studied in
NRs and relapsers, but with
mixed results. With prior NR, SRs achieved with higher doses are only
between 0% and 4%. In
relapsers, SRs range from 20% to 40%. However, side effects are more
troublesome with higher
Because of the low overall response rate to standard IFN-alfa, more
recent studies have focused
on newer regimens, including synthetic IFN (IFN alfacon-1),
"combination" therapy (IFN-alfa 2b
+ ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
of NR have been identified, notably HCV genotype 1, the presence of
cirrhosis, and higher viral
load. In addition, patient's race appears to affect response to IFN,
with African Americans
having an overall low SR to therapy.
A significant improvement in SR resulted from the addition of ribavirin
to standard IFN-alfa.
Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
for chronic HCV because
of its antiviral activity against other RNA viruses.[11-13] Although as
monotherapy it reduces ALT
levels, it does not appear to have a direct antiviral effect and fails
to lower serum HCV RNA
levels. Moreover, results of most studies with ribavirin have found no
improvement in hepatic
histology, although a longer 2-year treatment regimen was shown to
However, in combination with IFN-alfa 2b, ribavirin leads to a
significant increase in SR in
treatment-naive patients. SRs of 31% with 24 weeks and 38% with 48
weeks of combination
therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
relapsers, enhanced SR rates also occur on retreatment using combination
therapy, from 30% to
49%; in prior NRs, SR of 14% has been reported with 6 months of
Histologic improvement was more common among treatment-naive patients
combination therapy. Similar improvement was found in a randomized
controlled trial of
However, the improved SR rates observed with combination therapy are
also associated with
more expense and an increased frequency of adverse effects compared with
monotherapy. Dose-related hemolytic anemia is a particular concern
with ribavirin[11,13] as is
teratogenicity, based on animal studies. The mean drop in hemoglobin
in patients treated with
combination therapy is between 2 and 3 g/dL, although a fall of more
than 4 g/dL has been
observed in about 10% of patients. The anemia may be poorly tolerated in
patients with ischemic
heart disease in particular as treatment is extended to older
patients. Accumulation of ribavirin
metabolites that are not cleared by dialysis occurs in end-stage renal
Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
engineered compound synthesized by combining the most common amino acid
naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
and 30% with
IFN-beta. Although it has greater cytokine induction, antiviral,
antiproliferative, natural killer cell,
and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
an equal mass basis, initial
studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
with chronic hepatitis C
resulted in viral response rates similar to those achieved with standard
More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
reported to result in
virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
Pharmacokinetic studies have provided a rationale for enhanced IFN
dosing. The initial decline in
serum HCV RNA levels seen after a single dose of IFN therapy is believed
to reflect a direct
antiviral effect, whereas the subsequent and more delayed decline in HCV
RNA levels is due to
destruction of infected hepatocytes. An important limitation of the
antiviral effect of standard
IFN dosing is the rapid decline in circulating drug level with
thrice-weekly administration. The short
half-life of the drug and the rapid production of HCV virions diminish
the efficacy of standard IFN
therapy. In an effort to achieve more stable and efficacious IFN
activity, pegylated formulations
have been developed.
The production of a pegylated IFN involves the addition of a nontoxic
long-acting formulation of
interferon using the drug delivery system of pegylation. Polyethylene
glycol molecules are added to
IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
Pegylation is already used in the delivery of other drugs. Its
attachment to IFN-alfa permits
In a recent report, Zeuzem and colleagues indicate that at week 72,
the SR was 39% after 48
weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
compared with a 19% SR in
control patients. Drug discontinuation in these treatment-naive patients
and frequency of dose
reduction were similar in the 2 treatment arms. Heathcote and
colleagues have also reported on
the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
patients. SR was 30% following 48
weeks of therapy with 180 mcg, compared with 8% for patients treated
with standard alfa IFN,
again without a significant increase in side effects with the pegylated
Trepo and colleagues have also reported, in abstract form, initial
studies with pegylated IFN-alfa
2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
weekly for 48 weeks) was
12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
with 0.5 mcg/kg,
1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
As with standard IFN-alfa monotherapy, ribavirin may augment response
rates when combined
with the pegylated IFNs.[26,27] Recent trials will help evaluate further
the role of ribavirin in
augmenting the efficacy of pegylated IFN (see Figure).
Figure. Initial antiviral therapy against hepatitis C virus.*
* Abbreviations: IFN = interferon; CSN = consensus interferon;
interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
pegylated interferon +
There has been continued interest in developing non-IFN-based therapies
for HCV despite the
promise of the pegylated IFNs. A recent study examined the role of human
treating prior NRs with chronic HCV. Although, HCV RNA remained
detectable in all patients
at the end of treatment, 5 (23%) of the 22 treated patients had
persistent ALT normalization at
the end of follow-up. Future studies should determine whether combining
interleukin-10 with other
antiviral agents will increase efficacy in this setting. Interleukin-12
has also been evaluated as
monotherapy, again without clear antiviral benefit.
There is also increasing enthusiasm for targeting HCV molecular
products. For example, ribozyme
gene therapy has the potential to accurately degrade HCV RNA. Human
studies are anticipated.
Treatment options for HCV infection continue to expand. Whereas SRs of
10% were achieved
with IFN monotherapy only several years ago, it may soon be possible to
achieve SR rates greater
than 50% with combination pegylated IFN and ribavirin. Molecular-based,
strategies are also likely to become a reality in the future, although
therapy will remain
interferon-based the next several years.
Table. Response (HCV RNA/ALT*) to Antiviral Therapy
Type of Response
6 Months After
* HCV RNA measured by polymerase chain reaction; ALT = alanine
aminotransferase; HCV = hepatitis C virus.
Positive denotes HCV RNA present in the serum by polymerase chain
abnormal alanine aminotransferase values. Negative denotes no serum
HCV RNA by
polymerase chain reaction and normal alanine aminotransferase
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