Full text of DOI:10.1592/phco.20.19.1499.34859

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Coinfection with HIV and HCV: More Questions than
Answers?
Travis W. Waldrep, Pharm.D., Kimberly K. Summers, Pharm.D., and
Philippe A. Chiliade, M.D.
Chronic infection with the hepatitis C virus (HCV) is a major public health
threat in the United States and worldwide. By sharing some routes of
transmission, persons infected with the human immunodeficiency virus
(HIV) are at risk for coinfection with HCV. As a result, hepatic cirrhosis, end-
stage liver disease, and hepatocellular carcinoma due to chronic infection with
HCV are important causes of both morbidity and mortality in coinfected
patients. The advent of highly active antiretroviral therapy improved the
management of patients with HIV, leading to decreased morbidity and better
survival. As patients infected with HIV live longer, their risk of long-term
sequelae from chronic HCV increases. Coinfection with HIV may be
associated with rapid progression of chronic HCV. In contrast, the effect of
HCV on the natural history of HIV is less clear. Data regarding treatment of
HCV in HIV-coinfected patients are limited.
(Pharmacotherapy 2000;20(12):1499–1507)
OUTLINE
Prevalence of Coinfection
Diagnosis
Molecular Biology of HIV and HCV
Natural History of HCV Infection
Noncoinfected Patients
Prevalence of Coinfection
Approximately 4 million persons or 1.8% of
the United States population have antibodies to
hepatitis C virus (HCV), with approximately 2.7
million chronically infected with HCV RNA.1
The prevalence of coinfection in human
immunodeficiency virus (HIV)-seropositive
persons was conservatively estimated to be
14.1%,2 although rates as high as 56% were
reported, depending on the cohort.3, 4 Between
100,000 and 400,000 of the 800,000–900,000
persons infected with HIV in the U.S. potentially
are coinfected with HCV. Investigators
performed a retrospective, cross-sectional study
of patients enrolled in two national studies in the
adult AIDS clinical trials group.5 This
demographically broad cohort study revealed a
coinfection rate of 35.6%. One observational
open cohort study conducted at a Veterans
Affairs HIV clinic determined a prevalence of
33% among 350 HIV-infected individuals.6
Multivariate analysis identified intravenous drug
use as the major predictor of HCV seropositivity.
Another cohort study found a coinfection rate of
41.3% in over 1600 HIV-infected patients in an
Coinfected Patients
Natural History of HIV in Coinfection
The Impact of HAART in Coinfection
Treatment of Chronic HCV Infection
Noncoinfected Patients
Coinfected Patients
New Treatment Options
Comparing and Contrasting Treatment of HIV and
HCV
Conclusion
From South Texas Veterans Health Care System, Audie L.
Murphy Memorial Veterans Hospital Immunosuppression
Clinic, San Antonio, Texas (all authors); the Departments of
Pharmacology (Drs. Waldrep and Summers) and Medicine,
Infectious Disease (Dr. Chiliade), The University of Texas
Health Science Center at San Antonio, San Antonio, Texas;
and the College of Pharmacy, University of Texas at Austin,
Austin, Texas (Drs. Waldrep and Summers).
Address reprint requests to Travis W. Waldrep, Pharm.D.,
Parkland Health and Hospital Systems, 5201 Harry Hines
Boulevard, Dallas, TX 75235.

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PHARMACOTHERAPY Volume 20, Number 12, 2000
urban HIV clinic.7 Perhaps even more concerning
is the high prevalence of coinfection in the
nation’s correctional facilities. A Texas Department
of Corrections study reported 56% of 1862 HIV-
positive inmates to be coinfected.4 Hence,
coinfection with HCV is prominent in HIV-
infected patients, especially among past or
current intravenous drug users.
who are immunosuppressed. In fact, it was
estimated that 6–12% of HIV-positive persons
who are coinfected with detectable hepatitis C
viremia will not have an antibody response to
EIA due to inability to mount an adequate
immune response.20–22 In high-risk or severely
immunosuppressed persons, a negative EIA
should be confirmed with a more sensitive
qualitative or quantitative polymerase chain
reaction test to detect HCV RNA directly.22, 23
Despite advanced serologic and molecular
tests, histologic examination is still the gold
standard to diagnose the extent of liver damage.23
Persons at greatest risk of progression to cirrhosis
are those with extraportal fibrosis, bridging
inflammation, and necrosis on biopsy.
The two viruses share several risk factors for
transmission, including intravenous drug use,
transfusion of contaminated blood products, and
high-risk sexual behavior. The risk of coinfection
depends on the route of transmission. Because
HCV is spread more efficiently through blood-
borne routes, HIV-seropositive hemophiliacs and
intravenous drug users have a much higher risk
of HCV (60% and 80% frequency, respectively).8, 9
Hepatitis C RNA was detected in body fluids
other than blood, including saliva and seminal
fluid.10 Approximately 8% of homosexual men
who are HIV infected also have antibodies
positive against HCV.11 Conversely, prevalence
rates are reported to be low in studies of long-
term spouses of patients with chronic HCV
infection. Evidence suggests that heterosexual
transmission occurs, yet it is extremely inefficient.12
Seroconversion as a result of occupational
exposures of blood products through accidents
with sharp items occurs at a rate of approxi-
mately 3%.13 The risk of vertical transmission is
relatively low (5%) compared with vertical
transmission of hepatitis B (90%) and HIV
(25%).14, 15 However, coinfection increases the
rate of vertical transmission to approximately
14%.16, 17
Molecular Biology of HIV And HCV
Both HIV and HCV are RNA viruses with high
rates of viral production and mutation. The HCV
is a single-stranded RNA virus of the Flaviviridae
family. It replicates to produce approximately
1012 or 1 trillion viral particles/day, with an
estimated serum half-life of 2.7 hours.24
A
tremendous amount of genetic diversification
exists due to a high mutation rate, which results
from frequent mutations during transcription and
lack of proofreading activity in HCV RNA
polymerase. The large rate of viral production
and high mutation rate explain the existence of a
family of closely related variants or quasi species
existing in a single host. Genetic diversification
of HCV led to a classification system of
genotypes or clades based on Arabic numerals
1–6.25
The HIV is a double-stranded RNA virus of the
Retroviridae family. Similar to HCV, it has a great
deal of genetic variability as a consequence of a
high rate of viral turnover and mutation.
Approximately 109 viral particles are produced
and excreted each day, with a half-life of about 6
hours.26 Replication of HIV also is highly prone
to error, resulting in several mutations and the
existence of a quasi species. The heterogeneity of
both HIV and HCV could explain the persistent
infection by avoidance of immune recognition
and resistance to drug therapy.
Diagnosis
Since most acute HCV and HIV infections are
not recognized, screening methods are an
important part of preventing long-term disease
complications. Due to the high prevalence of
coinfection, all persons infected with HIV should
be screened for antibodies to HCV. Serum
alanine aminotransferase (ALT) is a poor
predictor of underlying liver disease, since
progressive liver disease can occur despite
persistently normal ALT levels.18 Second- and
third-generation enzyme immunoassay (EIA)
tests are 95–99% sensitive for detecting
antibodies to HCV in noncoinfected persons with
risk factors or abnormal serum ALT, and is the
initial screening test in most instances.19
Unfortunately, EIA may produce false-negative
results in recently exposed individuals and those
Natural History of HCV Infection
Noncoinfected Patients
A large percentage of noncoinfected patients
carry the hepatitis C virus for an entire lifetime
without experiencing significant liver damage.27

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COINFECTION WITH HIV AND HCV Waldrep et al
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Approximately 85% of those acutely infected
develop chronic, persistent infection.18, 28 Of
these, 20–30% will develop liver cirrhosis within
20–30 years.29 After developing cirrhosis, the
risk of progressing to hepatocellular carcinoma or
decompensated cirrhosis greatly accelerates.30
Numerous prognostic factors, including host,
virus, and environmental variables, likely
determine who will progress to severe liver
damage and at what rate.
Factors determining the level of hepatitis C
viremia in HCV infection are poorly defined.
Interpatient viral loads are highly variable, and
limited data exist concerning the viral load and
correlation with disease progression. Yet, serum
HCV RNA levels are predictive of response to
treatment in patients infected with HCV alone. A
correlation was seen between low pretreatment
viral loads (< 2 x 106 copies/ml) and virologic
response to treatment with interferon and
ribavirin.31, 32 Other factors associated with
disease progression are age at infection above 40
years, alcohol intake of 50 or more g/day, and
male gender.33, 34
of monitoring for hepatotoxicity in coinfected
patients also is discussed, as well as the increased
rate of liver fibrosis and the possibility of treating
HCV. Although HCV may not be an opportunistic
infection in the classic sense, it plays an
important role in the morbidity and mortality of
coinfected patients.
According to retrospective studies on the effect
of HIV on clinical progression of chronic HCV,
HIV modifies the natural history of HCV
infection.41–43 In a case-control study, 122
coinfected patients were matched according to
age, gender, daily alcohol use, age at HCV
infection, and duration and route of HCV
infection, with a control group of 122 HCV-
positive, HIV-negative patients.41 The rate of
fibrosis progression was determined by dividing
the fibrosis stage (determined by biopsy) by
duration of HCV infection (years). Investigators
found a significantly faster rate to liver fibrosis in
coinfected patients (26 yrs) compared with
patients infected with only HCV (38 yrs). Risk
factors independently associated with more rapid
progression were HIV seropositivity, alcohol
consumption of more than 50 g/day, age at HCV
infection above 25 years, and immunosuppression
(CD4+ ≤ 200 cells/mm3). The trend was toward a
slower rate of fibrosis progression in patients
receiving highly active antiretroviral therapy
(HAART). Unfortunately, only 12% of coinfected
patients were receiving HAART, and a statistically
significant difference could not be determined.
Other findings included the combined effect of
alcohol use and immunosuppression on rate of
fibrosis. The median time to fibrosis was 16
years in coinfected patients with CD4+ counts of
200 cells/mm3 or less who consumed more than
50 g/day of alcohol, compared with 36 years for
those with counts above 200 cells/mm3 who
drank less than 50 g/day of alcohol.
Coinfected Patients
Coinfected patients often have higher HCV
RNA concentrations than those infected with
only HCV.35 A prospective cohort study showed
significantly (p<0.001) higher HCV RNA levels
in 468 coinfected patients (7.19 log10 copies/ml)
than in 501 HIV-negative controls (6.73 log10
copies/ml) regardless of CD4+ cell count.36
Immunosuppression due to HIV enhanced
replication of HCV in other studies as well.37, 38
Research from the Centers for Disease Control
and Prevention shed new light on the problem of
liver disease in patients infected with HIV.39
Investigators examined the causes of death from
the U.S. National Vital Statistics System from
1987–1997 and found a 10% death rate due to
associated liver disease in persons who died with
HIV infection in 1997. Causes of death included
sequelae of chronic liver disease, non-A, non-B
hepatitis, and nonalcoholic cirrhosis. It is
possible that many of these patients were
coinfected with HCV. These observations led the
U.S. Public Health Service–Infectious Disease
Society of America to mention chronic HCV
infection in guidelines for prevention of
opportunistic infections.40 The guidelines stress
the importance of screening for, and prevention
of, HCV and vaccination against hepatitis A and
B viruses in HIV-infected persons. The importance
Natural History of HIV in Coinfection
The effect of HCV on the course of HIV is
disputed due to differences in study design and
lack of data in patients receiving HAART. Studies
reported both an increased risk of progression of
HIV and no effect of HCV on HIV.6, 44–47 In a large
Veterans Affairs cohort, HCV had little influence
on the progression of HIV to acquired imuno-
deficiency syndrome (AIDS) or death.6 This
study included more than 1800 HIV-infected
patients from a large urban population who were
part of a continuing cohort study. Investigators
sought to determine the effect of HCV infection

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PHARMACOTHERAPY Volume 20, Number 12, 2000
on length of survival in patients with HIV
infection. A subset of 350 subjects of the entire
population was tested for antibody to HCV,
resulting in a coinfection rate of 33%. The 115
coinfected patients were matched with
noncoinfected patients according to age, gender,
antiretroviral therapy, baseline viral load, and
CD4+ cell count. Using Kaplan-Meier survival
curves, no differences were seen between groups
for end points of time to AIDS and death from
diagnosis of HIV. These results suggest that HCV
infection had little influence on the severity or
progression of HIV disease in this cohort.
Unfortunately, only 20% of participants were
receiving HAART and had received protease
inhibitors for less than 1 year. Hence, the effects
of HAART on the survival of coinfected patients
could not be assessed. Another prospective
cohort study found similar rates of HIV
progression in coinfected compared with
noncoinfected patients before the HAART era.47
A case-control study evaluated the effect of
HCV infection on immunologic and clinical
progression of HIV.44 Retrospectively, 119
coinfected patients were matched according to
age, gender, and CD4+ count with 119 HIV-
infected, HCV-negative controls. Clinical
progression was defined as developing one of the
following: 30% decrease in Karnofsky score, 20%
loss of body weight, AIDS-defining illness, or
death. Immunologic progression was defined as
a decline in baseline CD4+ cell count by at least
half. The results were somewhat contradictory.
Immunologically, no difference was seen between
coinfected and noncoinfected patients. However,
23.1% of coinfected patients met criteria for
clinical progression, compared with 13.4% of the
HCV-negative group (p<0.002). The authors did
not provide data concerning viral load that would
help confirm clinical progression. Other
limitations of this study were retrospective design
and the fact that patients were followed from the
first clinic visit, not from the time of HIV
diagnosis.
without progressive liver disease. Again,
limitations of this study were absence of viral
load data and lack of HAART in the cohort.
Nevertheless, coinfected patients were 3.6 times
(95% confidence interval [CI] 1.3–10) more
likely to have progressive liver disease than HCV-
negative, HIV-positive patients. The most
convincing evidence to date reveals little
influence of HCV on progression of HIV disease.
This deserves further study.
Observational studies reported an increased
mortality rate in coinfected patients.48, 49 One
report characterized all deaths in a Bronx, New
York, HIV clinic from April 1996–September
1997.48 Thirty-five coinfected patients and 38
noncoinfected patients were matched based on
age at death, alcohol use, duration of follow-up at
clinic, therapy with antiretrovirals, and therapy
with protease inhibitors. Even with small
numbers, a significantly greater number of HCV-
positive patients died (12/38) with CD4+ counts
greater than 200 cells/mm3 than did HCV-
negative patients (1/35, p<0.002). Causes of
mortality were diverse and not directly due to
HIV infection. Five of 12 patients died of
advanced liver disease due to chronic HCV
infection. Another report from an urban clinic
consisting of 1100 patients listed 40 deaths
occurring in 1998 and the first 9 months of
1999.49 Patients who died in 1999 were more
likely to have lower viral loads, higher CD4+ cell
counts, better adherence to therapy, and a
response to HAART compared with those dying
in 1998. The three most common causes of
death in both years were AIDS-associated
wasting, mycobacterial disease, and complications
from HCV. Based on these data, mortality due to
chronic HCV infection continues to be a leading
cause of death in coinfected patients despite
access to HAART.
The Impact of HAART in Coinfection
Combination regimens for HIV have vastly
improved survival, with a reported 64% decrease
in AIDS-related deaths in 1996 and 1997.50 With
improved survival, a number of acute and
chronic toxicities are recognized as a result of
HAART. For example, hepatotoxicity is a
significant concern, especially in coinfected
patients who are predisposed to liver disease.51, 52
Liver toxicity with antiretrovirals has been
known for several years and is not limited to one
class of agents, although most reports implicate
protease inhibitors.53 A prospective study in an
A prospective study evaluated the effect of
HCV and progressive liver disease on the natural
history of HIV infection in hemophiliacs.46
Progressive liver disease was defined as
developing one or more of the following:
sustained elevation in serum bilirubin, ascites,
hepatic encephalopathy, esophageal or gastric
varices, or histologic evidence of cirrhosis or
hepatocellular carcinoma. Coinfected patients
with progressive liver disease had a faster
progression to AIDS and death than those