The HCV and HIV Coinfected Patient: What Have We Learned
Andrew H. Talal, MD, MPH, P. Wilfredo Canchis, MD, and Ira M. Jacobson, MD;
Weill College of Medicine, Cornell university, NYC
Current Gastroenterology Reports 2002, 4:15-22
Current Science Inc. ISSN 1522-8037|
Hepatitis C virus (HCV) infection is an important problem
in individuals who are also infected with HIV. HCV infection
is very common in HIV-infected individuals, occurring in
approximately one quarter to one third of this group,
presumably as a consequence of shared routes of trans-mission
related to virologic and pathogenic aspects of the
viral infections. Although both are single-stranded RNA
viruses and share similar epidemiologic properties, there
are many important differences. Although the quantity of
HIV RNA in plasma is an important prognostic determinant
of HIV infection, this has not been shown with HCV.
A direct relationship is apparent between HIV-related
destruction of CD4 cells and the clinical consequences of
the disease resulting from immunodeficiency. The patho-genesis
of HCV, which occurs as a consequence of hepatic
fibrosis, is much more complex. The hepatic stellate cell,
the major producer of the extracellular matrix protein, is
the main contributor to hepatic fibrosis, but the mechanism
by which HCV induces hepatic fibrosis remains unclear.
Treatment of HCV is increasingly important in HIV-infected
patients due to improved HIV-associated morbidity and
mortality and due to the frequency with which HCV occurs
in patients with HIV-HCV coinfection. Timing of treatment
initiation, management of side effects, and possible effects
of anti-HCV therapy on HIV are among the issues that
need consideration. Also, because several issues concerning
HCV are unique to coinfected patients, further research is
needed to determine optimal management of HCV in
Hepatitis C virus (HCV) and human immunodeficiency
virus (HIV) are similar in many respects. Both viruses
have a single-stranded RNA genome, both have very high levels of viral replication, both cause chronic infection,
and the two viruses share similar routes of transmission.
However, HIV and HCV are also different in many
respects. Many of the differences in the clinical manifestations,
pathogenesis, and treatment of these viruses can be
attributed to differences in the target cell of each virus-
the hepatocyte for HCV and the CD4 + cell for HIV. From
an epidemiologic standpoint, HCV is a leading cause
of chronic hepatitis, cirrhosis, and hepatocellular
carcinoma. In the United States, HCV infection is the
main indication for liver transplantation. Recently, HIV-associated
morbidity and mortality have declined
dramatically as a result of potent antiretroviral therapy.
Concomitantly, the incidence of liver disease is increasing
in HIV-infected individuals, a large proportion of which
can be attributed to HCV infection. The epidemiology,
disease course, and management of HCV are different in
HIV-HCV coinfected individuals compared with HCV-monoinfected
individuals. This review focuses on current
advances in HCV-HIV coinfection, particularly in the
area of HCV pathogenesis in coinfected patients. In
addition, we discuss the epidemiology, diagnosis, and
treatment of HCV in coinfected individuals.
Approximately 3.8 million individuals in the United States
(1.8% of the population) have been exposed to HCV, and
2.7 million of these individuals have detectable HCV RNA,
indicating chronic viral infection . Approximately 200
million individuals worldwide have been exposed to HCV
. The factors most frequently implicated in HCV trans-mission
are blood transfusion before 1990 and intra-venous
drug use, although in some cases no risk factors
can be found [1,3]. In comparison, about 30% of the
800,000 HIV-infected individuals in the United States are
coinfected with HCV as a consequence of shared transmis-sion
routes [4oo]. HIV-HCV coinfected individuals have
increased risk of sexual and maternal-fetal transmission of
HCV virus [5,6]. Maternal-fetal transmission is not
common, having a reported prevalence of 1.7% among
HCV-monoinfected individuals; the rate of transmission is
increased to 19.4% among women coinfected with HIV . Recent studies suggest that, in the era of potent anti-retroviral
therapy, the number of deaths caused by liver
disease in HIV-1-infected individuals has been increasing.
In a cohort of approximately 4000 individuals, liver
disease was the primary cause of non-AIDS death . In a
recently published study that retrospectively examined the
causes of death between 1991 and 1998 in HIV-1-seroposi-tive
individuals, end-stage liver disease was found to be the
leading cause among those who were hospitalized . The
majority of these individuals were HCV positive.
Pathogenesis of HCV
Hepatitis C virus, a member of the Flaviviridae family 
based on its genome sequence, has been classified into at
least six genotypes and more than 50 subtypes. Genotype 1
is the most common in the United States, Europe, and
Japan followed by genotypes 2 and 3. Genotype 4 is found
in the Middle East and in Central Africa. Genotype 5 is
confined to South Africa. Genotype 6 is distributed
throughout Southeast Asia . The mechanisms responsi-ble
for tissue injury in HCV infection are not well under-stood.
HCV cell targets are hepatocytes and possibly
B lymphocytes .
Mortality due to HCV results from progressive hepatic
fibrosis that can lead to cirrhosis and its complications.
The clinical manifestations of HIV infection are usually
systemic, whereas those of HCV relate principally to the
liver. Because of the loss of CD4 + cell function, the primary
consequences of HIV infection result from immuno-deficiency.
As a result of HCV target cell localization in the
liver, the infection is principally concentrated in that
organ. Its clinical manifestations, usually first evident
during late-stage disease, primarily result from the accu-mulation
of hepatic fibrosis and ultimately may culminate
in hepatic dysfunction.
Significance of HIV and HCV RNA determinations
Chronic infection with both HIV and HCV is character-ized
by dynamic equilibrium between virus production
and clearance. Studies of viral kinetics, in which mathe-matical
modeling is applied to the viral decay in response
to antiviral medications or after procedures such as
plasma apheresis that perturb the steady state, have been
helpful in clarifying the viral life cycle. Both HIV and HCV
have very rapid life cycles, with an estimated daily virion
production of 9.3 log 10 to 10.2 log 10 for HIV and 11.6
log 10 to 13.0 log 10 for HCV, indicating that viral turnover
is even faster in HCV than it is in HIV infection .
The viral set point, the quantity of HIV RNA in plasma
6 months after seroconversion, is an important prognostic
parameter in HIV infection. The set point indicates how
likely an individual is to progress to AIDS during the next
5 years . During primary HIV infection the HIV RNA
level increases rapidly as virion production greatly out-paces
virion clearance. During the first 6 months after seroconversion, the immune system is able to gain partial control over viral replication, and the level of HIV RNA in plasma is decreased. During the asymptomatic phase of
the infection, a steady state is achieved in which virion
production equals virion clearance, presumably by the
immune system. However, a progressive destruction of
CD4 + cells eventually results in profound immuno-deficiency.
Without effective treatment, most individuals
become symptomatic during late-stage disease as a conse-quence
of various opportunistic infections. The symptoms
present during late-stage disease usually result from
immunodeficiency, which allows opportunistic infections
to be established.
The relationship between the quantity of HCV RNA in
serum, the pathogenesis of the disease, and the develop-ment
of clinical symptoms is not as straightforward in
HCV infection. The hepatic stellate cell (HSC) is the main
fibrogenic cell type in the liver, and it is the principal
culprit in the pathogenesis of HCV . Many different
stimuli can lead to HSC activation, most notably inflam-mation
in the liver. The hepatic inflammatory infiltrate
within the liver can lead to secretion of transforming
growth factor-o (TGF-o ), which can lead to HSC activation
and secretion of extracellular matrix (ECM) protein .
Although a direct correlation between the quantity of
HCV RNA in serum and HCV pathogenesis has not been
made, the quantity of HCV RNA is one of the five determi-nants
of an increased likelihood of a successful outcome to
antiviral therapy .
Significance of immune response against each virus
We have learned much about the importance of the
immune response against HIV. Although the hope of viral
eradication was harbored by many researchers and practi-tioners
shortly after the development of the HIV protease
inhibitors, time has demonstrated that our efforts at HIV
eradication have been thwarted thus far. However, it does
appear that early initiation of antiretroviral therapy, prior
to seroconversion, may alter the course of HIV as a result of
the retention of potent HIV-specific cellular immune
responses that may delay disease progression. Novel
approaches to the treatment of HIV involve boosting the
immune response through a variety of mechanisms to
achieve immune-mediated virus suppression in the
absence of therapy. This approach has been demonstrated
through "structured treatment interruptions" that have
recently become popular.
The immune response plays an important role in HCV
pathogenesis . A broad and strong anti-HCV-specific
CD4 + immune response is an important determinant of
recovery during the acute phase of HCV [19,20] and in
the prevention of severe HCV recurrence after hepatic
transplantation . Vigorous HCV-specific CD8 immu-nity
further distinguishes individuals with self-limited
HCV infection from individuals with chronic HCV infec-tion
[22,23]. Even in patients with chronic HCV infection, a strong HCV-specific CD4 response may help protect these individuals against progressive liver disease
. Moreover, both CD4 + and CD8 + responses to HCV
structural proteins (core, E1, and E2) are important deter-minants
of a successful outcome to therapy. Through the
destruction of CD4 + cells with reactivity for HCV, HIV
may have a deleterious effect on immune responses in
coinfected patients, which may be one of the reasons why
higher CD4 + T-cell counts and lower HCV viremia
have been associated with improved responsiveness to
interferon (IFN) [24-26]. Because IFN may also result in
a dose-dependent decrease in CD4 + T cells, it is impor-tant
to initiate treatment as early in the course of HIV
infection as possible prior to the onset of severe immuno-deficiency
The central pathogenic mechanisms, whether direct
viral cytotoxicity or the immune response of the host, have
not been conclusively established for either virus, although
each mechanism has been hypothesized to be important
in each viral infection. Recent reports have demonstrated
that the rate of hepatic fibrosis is accelerated in HIV-HCV
coinfected individuals [29oo,30o,31,32o]. Several studies
have evaluated the determinants of hepatic fibrosis in
HCV-monoinfected and HIV-HCV coinfected individuals.
In HCV infection, age over 50 years, consumption of 50 g
or more of alcohol per day, and male gender are indepen-dently
associated with accelerated hepatic fibrosis [33,34].
In HIV-HCV coinfected individuals, HIV infection, alcohol
consumption of more than 50 g/d, CD4 cell count less
than 200 cells/µL, and age over 25 years at the time of HCV
acquisition are all associated with accelerated hepatic
fibrosis . Puoti et al.  found an independent associ-ation
between CD4 + cell count less than 500 cells/mm 3
and increased rate of fibrous septa formation. A recent
study found that chronic use of antiretroviral therapy
containing at least one protease inhibitor, younger age at
the time of HCV infection, low alcohol intake, and high
CD4 count were associated with a reduced hepatic fibrosis
progression rate in HCV-HCV coinfected individuals .
The pathogenic mechanisms by which increased
hepatic fibrosis in HIV-HCV coinfected individuals occurs
have yet to be determined conclusively. However, immuno-logic
differences in HIV-HCV coinfected and HCV-monoinfected
individuals may account for the different
rate of hepatic fibrosis, because the inflammatory response
has been shown to be an important determinant of fibrosis
in humans . In preliminary evaluation we showed that
the number of proliferative and apoptotic liver cells were
increased in HCV-monoinfected and HCV-HIV coinfected
individuals, compared with uninfected individuals .
Upon further study, we found that CD4 + cells are signifi-cantly
decreased and that periportal hepatocyte prolifera-tion
is increased in HIV-HCV coinfected individuals,
compared with HCV-monoinfected individuals .
Deficient cytolytic activity and ineffective CD4 priming of
CD8 responses may lead to dysfunctional CD8 + cells in HIV infection that are deficient in cytolytic activity, impairing
their ability to clear infected hepatocytes, but retaining
their ability to secrete cytokines [38,39]. These cytokines
may lead to hepatocyte injury, resulting in phagocytosis by
Kupffer cells, activation of hepatic stellate cells, and
deposition of hepatic fibrosis (Fig. 1). Our findings suggest
that the resulting hepatocyte injury may also stimulate
de novo hepatocyte proliferation. In HCV, dysfunctional
peripheral blood CD8 + T cells are also characterized by
impaired cytolytic activity. In contrast to the situation in
HIV, antiviral cytokine secretion is diminished in these
cells . However, the existence of dysfunctional intra-hepatic
CD8 + cells in HCV remains to be evaluated.
Finally, a dependence of fibrosis on T-helper 2 responses,
which are disproportionately preserved in HIV patients,
has been documented in IFN-o -deficient knockout mice
 and in schistosomiasis .
Most HIV- and HCV-infected individuals do not develop
symptoms until late in the course of their disease. During
the initial stages of HIV infection, patients usually present
with symptoms similar to those in infectious mononucleosis,
including fever, lymphadenopathy, myalgias, arthal-gias,
and sweating . The clinical consequences of the
infection result directly from immunodeficiency. The
symptoms in acute HCV infection are typically those
seen with other forms of hepatitis: jaundice, scleral icterus,
fatigue, and weakness. However, the occurrence of acute
symptoms may indicate important differences in disease
pathogenesis. For example, whereas the acute seroconver-sion
syndrome occurs in the majority of HIV-infected
individuals, some have suggested that the presence of
symptoms during the acute phase of HCV infection is
associated with an increased likelihood of viral clearance
. The symptoms that usually occur in late-stage HCV
infection (ascites, encephalopathy, prolonged prothrom-bin
time, elevated bilirubin, and decreased serum albumin)
comprise the Child-Pugh scoring system, the most
frequently used measure to assess damage in end-stage
HCV diagnosis in HIV-HCV coinfected individuals
With the realization that HCV is a frequent pathogen in
HIV-infected individuals, the United States Public Health
Service and the Infectious Disease Society of America
issued guidelines in 1999 stating that all HIV-infected
individuals must be screened for anti-HCV antibodies
. With respect to these recommendations, the concern
has been raised regarding the most appropriate screening
test, whether measurement of anti-HCV antibodies, as
determined by enzyme-linked immunosorbent assay
(ELISA), or HCV RNA, as determined by polymerase chain
reaction (PCR). Initially the concern was expressed that
HIV-associated immunodeficiency might result in false negative ELISA results. However, recent investigations have
shown that the predictive value of the anti-HCV ELISA is
significantly better in HIV-HCV coinfected individuals
than it is in HCV-monoinfected individuals . The
third-generation ELISA should be performed to screen for
HCV in HIV-HCV coinfected individuals .
Management of HCV Infection in HIV-HCV Coinfected Individuals
Assessment of disease severity
In HIV-infected individuals, quantitation of the amount of
HIV-1 RNA in plasma is both an important predictor of
disease progression and a measurement of the efficacy of
antiretroviral therapy. Additionally, the peripheral blood
CD4 + T-cell count provides important information
concerning the severity of the disease and the likelihood of
a successful therapeutic outcome . In HCV, the amount
of hepatic fibrosis, as opposed to the level of HCV RNA, is
the most important prognostic factor. However, quantita-tion
of serum HCV RNA and determination of the HCV
genotype are important predictors of the likelihood of
therapeutic efficacy. Liver biopsy is the most specific test
for diagnosis and the assessment of hepatic pathology
, and currently, it is the only method by which to
quantify the amount of hepatic fibrosis. The biopsy is
graded on the amount of inflammation and on the stage of
fibrosis on a 0-to-4 scale [50-52].
Most hepatologists recommend a liver biopsy for histo-logic
assessment of the liver, regardless of aminotransferase
or HCV RNA levels, because there is a poor correlation
between the aminotransferase level and the hepatic histo-logic
features that may result from HCV. For example,
a subgroup of HCV-infected individuals have normal
aminotransferase levels despite clinically significant fibrosis or cirrhosis . To arrest disease progression, we believe that treatment should be more aggressively pursued in patients with stage 2 or stage 3 fibrosis in the liver.
Therapeutic options At least 15 antiretroviral medications directed against
specific portions of HIV have been approved by the US
Food and Drug Administration (FDA). In contrast, agents
used to treat HCV-IFN, IFN modified with polyethylene
glycol (PEG), and RBV-are nonspecific viral agents.
The precise mechanisms of action of IFN and RBV have
not been discerned, but they appear to involve both antiviral
and immunomodulatory effects, and both effects appear to
be important in achieving therapeutic success. In HCV,
several indicators can be used to assess the degree of disease
severity and therapeutic efficacy. These include biochemical
measurements (serum quantitation of alanine aminotrans-ferase),
virologic measurements (HCV RNA), and histologic
measurements (degree of fibrosis and inflammation on liver
biopsy). Because clinical symptoms do not usually present
in chronic HCV infection until the development of end-stage
liver disease, symptomatic improvement cannot be
used as a means to assess therapeutic efficacy. The timing of
a therapeutic response is also important, ie, whether the
response occurs at the end of the treatment period (ETR) or
6 months after treatment is discontinued, with the latter
instance referred to as sustained virologic response (SVR).
Because HCV does not have a nuclear phase during its
replication cycle and does not integrate into the host
genome as HIV does, HCV eradication may be a realistic
therapeutic target. Long-term follow-up studies have
suggested that individuals who achieve an SVR are very
unlikely to have HCV recurrence [54,55]. Combination therapy with IFN and RBV has been the standard treatment for HCV . IFN can decrease the
level of HIV, and it may prolong survival in HIV-mono-infected
individuals . However, IFN attenuates the
CD4 + cell response to HIV when it is combined with
nucleoside analogues . Investigators in a French
prospective study reported that the response to IFN in
chronic HCV infection was not statistically different in
HCV-monoinfected individuals, compared with HIV-HCV
coinfected individuals .
The efficacy of IFN and RBV in HIV-HCV coinfected
individuals has been documented in four published
studies, including a total of 109 individuals (Table 1)
[60,61o,62,63]. All of these studies were conducted in
Europe. Three of the studies included primarily HCV-therapy
naïve individuals. In three of the studies, intra-venous
drug use was the primary risk factor for HCV
disease. The vast majority of study participants had
between 300 and 500 CD4 lymphocytes/mm 3 and were on
antiretroviral therapy. All study participants received
combination therapy with IFN and RBV for 6 to 12 months
and achieved an SVR of 11% to 40%.
Recently IFN has been conjugated to polyethylene
glycol (PEG), allowing weekly dosing and bringing more
sustained IFN levels . Additional improvements in the
sustained virologic response may occur as a result of basing
the IFN and RBV doses on the body weight of the individual
. Studies of the efficacy of PEGylated IFN (PEG-IFN) and
RBV in HIV-HCV coinfection are currently in progress.
Side effects of treatment
Because of the relatively increased frequency of side effects
with PEG-IFN and RBV, the ability to tolerate these medica-tions
is another issue that warrants careful consideration in
HIV-HCV coinfection. RBV is a guanoside nucleoside
analogue with antiviral activity against a variety of RNA and
DNA viruses, not including HIV . In vitro RBV can phos-phorylate
the HIV reverse transcriptase inhibitors, particu-larly
zidovudine and stavudine (D4T), which could result in
vivo in increased plasma HIV RNA [62,63]. However, in
studies to date, significantly increased HIV RNA levels have
not been a major problem in RBV-treated individuals who
were also treated with HIV reverse transcriptase inhibitors.
Anemia and neutropenia, both of which are common
side effects in HCV-infected patients who are prescribed
IFN and RBV, may be particularly problematic in HIV-HCV
coinfected patients. RBV can cause hemolytic anemia,
and IFN can cause bone marrow suppression resulting
primarily in neutropenia but also in anemia. Anemia,
which is more prevalent in HIV-infected individuals
compared with the general population, is usually multi-factorial
in HIV infection. Multiple antiretroviral medica-tions,
including nucleoside analogues that are associated
with bone marrow suppression and HIV infection itself,
can contribute to anemia in these individuals. The use of
growth factors, granulocyte colony stimulating factor or
erythropoietin, may be beneficial in treating these side
effects, particularly in HIV-HCV coinfected patients.
Duration of therapy
In the treatment of HCV, the optimal duration of therapy
has become an important issue. Five independent charac-teristics
have been associated with a sustained virologic
response: genotype 2 or 3, baseline viral load less than 3.5
million copies/mL, no or minimal portal fibrosis, female
gender, and age less than 40 years . Recently, Poynard
et al.  suggested that all HCV-infected individuals be
treated for 24 weeks, at which time HCV RNA should be
determined by PCR. If HCV RNA is detectable, treatment
can be stopped. If PCR is negative and the patient has fewer
than four favorable factors, treatment should be continued
for an additional 24 weeks. Whether the same factors also
predict an increased likelihood of a successful therapeutic
response is yet to be determined, as is the optimal duration
of HCV treatment in HIV infection.
Several studies in HCV-monoinfected individuals have
suggested that an immune response directed against HCV
is important to achieve a successful response to therapy. It
has also been suggested that a higher CD4 + cell count is
associated with improved outcome in the treatment of
HCV in HIV-HCV coinfected individuals. Early initiation
of anti-HCV therapy, prior to decrease of CD4 + T cells,
may improve the efficacy of anti-HCV therapy in HIV-
HCV coinfection. Furthermore, delaying HCV therapy
may necessitate treatment of HIV and HCV simulta-neously
with multiple medications, some of which may
have hepatotoxic effects. Therefore, we believe that
therapy for HCV should be initiated as early as possible
in the course of HIV disease. Additionally, initiation of
anti-HCV therapy early in the course of HIV may decrease
if not halt the progression to cirrhosis. In individuals with
severe immunodeficiency, initiation of antiretroviral
therapy before anti-HCV therapy should be considered to
improve patients' immune status and decrease HIV
replication. Clearly, further investigation is necessary for
a more accurate definition of the timing of treatment of
HCV in HIV-HCV coinfected individuals. In addition,
further studies are needed to evaluate the possible mecha-nisms
by which antiretroviral therapy may prevent
hepatic fibrosis. Given the clinical and epidemiologic
importance of HCV in HIV-infected individuals, addi-tional
research is necessary to more fully discern the ways
in which HCV pathogenesis and immune responses are
altered in the setting of HIV.
References and Recommended Reading
Papers of particular interest, published recently, have been
o Of importance
oo Of major importance
1. Alter M, Kruszon-Moran D, Nainan O, et al.: The prevalence of
hepatitis C virus infection in the United States, 1988 through
1994. N Engl J Med 1999, 341:556-562.
2. Weekly epidemiological record. WHO Rep 1997, 72:65-72.
3. Alter MJ, Margolis HS, Krawczynski K, et al.: The natural
history of community-acquired hepatitis C in the United
States. N Engl J Med 1992, 327:1899-1905.
4. 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,
5. Thomas DL, Villano SA, Riester KA, et al.: Perinatal trans-mission
of hepatitis C virus from human immunodeficiency
virus type 1-infected mothers: Women and Infants Trans-mission
Study. J Infect Dis 1998, 177:1480-1488.
6. Soto B, Rodrigo L, Garcia-Bengoechea M, et al.: Heterosexual
transmission of hepatitis C virus and the possible role of
coexistent human immunodeficiency virus infection in the
index case: a multicentre study of 423 pairings. J Intern Med
7. Yeung LTF, King SM, Roberts EA: Mother-to-infant trans-mission
of hepatitis C virus. Hepatology 2001, 34:223-229.
8. Justice AC, Chang CH, Fusco J, West N: Extrapolating long-term
HIV/AIDS survival in the post-HAART era (abstract
11 5 8 ) . Paper presented at the 39th Annual International Conference
on Antimicrobial Agents and Chemotherapy. San Francisco, CA,
September 26-29, 1999.
9. Bica I, McGovern B, Dhar R, et al.: Increasing mortality due
to end-stage liver disease in patients with human immuno-deficiency
virus infection. Clin Infect Dis 2001, 32:492-497.
10. Major ME, Feinstone SM: The molecular virology of hepatitis
C. Hepatology 1997, 25:1527-1538.
11 . S i mmo n d s P : Clinical relevance of hepatitis C virus geno-types.
Gut 1997, 40:291-293.
12. Cerny A, Chisari FV: Pathogenisis of chronic hepatitis C:
immunological features of hepatic injury and viral persis-tence.
Hepatology 1999, 30:595-601.
13. Ramratnam B, Bonhoeffer S, Binley J, et al.: Rapid production
and clearance of HIV-1 and hepatitis C virus assessed by
large volume plasma apheresis. Lancet 1999, 354:1782-1785.
14. Mellors JW, Rinaldo CR, Gupta P, et al.: Prognosis in HIV-1
infection predicted by the quantity of virus in plasma.
Science 1996, 272:1167-1170.
15. Friedman SL: Molecular regulation of hepatic fibrosis:
an integrated cellular response to tissue injury. J Biol Chem
16. Bissell DM, Roulot D, George J: Transforming growth factor B
and the liver. Hepatology 2001, 34:859-867.
17. McHutchinson J, Gordon S, Schiff E, et al.: Interferon alfa-2b
alone or in combination with ribavirin as initial treatment
for chronic hepatitis C. N Engl J Med 1998, 339:1485-1492.
18. Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C:
immunological features of hepatic injury and viral persis-tence.
Hepatology 1999, 30:595-601.
19. Gerlach JT, Diepolder HM, Jung M-C, et al.: Recurrence of
Hepatitis C virus after loss of virus-specific CD4 + T-cell
response in acute hepatitis C. Gastroenterology 1999,
11 7 : 933-941.
20. Thimme R, Oldach D, Chang, K-M, et al.: Determinants of
viral clearance and persistence during acute hepatitis C virus
infections. J Exp Med 2001, 194:1395-1406.
21. Rosen HR, Hinrichs DJ, Gretch DR, et al.: Association of multi-specific
CD4 + response to hepatitis C and severity of recur-rence
after liver transplantation. Gastroenterology 1999,
11 7 : 926-932.
22. Lechner F, Wong DKH, Dunbar PR, et al.: Analysis of successful
immune response in persons infected with hepatitis C virus.
J Exp Med 2000,191:1499-1512.
23. Takaki A, Wiese M, Maertens G, et al.: Cellular immune
responses persist and humoral responses decrease two
decades after recovery from a single-source outbreak of
hepatitis C. Nat Med 2000, 6:578-582.
24. Boyer N, Marcellin P, Degott C, et al.: Recombinant interferon-alpha
for chronic hepatitis C in patients positive for anti-body
to human immunodeficiency virus. J Infect Dis 1992,
25. Marriott E, Navas S, del Romero J, et al.: Treatment with recom-binant
alpha-interferon of chronic hepatitis C in anti-HIV
positive patients. J Med Virol 1993, 40:107-111.
26. Mauss S, Klinker H, Ulmer A, et al.: Response to treatment of
chronic hepatitis C with interferon alpha in patients infected
with HIV-1 is associated with higher CD4 + cell count.
Infection 1998, 26:16-19.
27. Soriano V, Bravo R, Samaniego JG, et al.: CD4 + T-lympho-cytopenia
in HIV-infected patients receiving interferon
therapy for chronic hepatitis C. HIV-Hepatitis Spanish Study
Group. AIDS 1994, 8:1621-1622.
28. Vento S, Di Perri G, Cruciani M, et al.: Rapid decline of CD4 +
cells after IFN alpha treatment in HIV-1 infection. Lancet
29.oo Benhamou Y, Bochet M, DiMartino V, et al.: Liver fibrosis
progression in human immunodeficiency virus and hepatitis
C virus coinfected patients. Hepatology 1999, 30:1054-1058.
This study evaluated the fibrosis progression rate in 122 HIV-HCV
coinfected individuals compared with a matched cohort of 122 HIV-negative
HCV-infected individuals. The fibrosis progression rate was
defined as the ratio between the fibrosis stage, determined by the
METAVIR scoring system, and the HCV duration. In coinfected and
HCV monoinfected individuals, the median fibrosis progression rate
is 0.153 and 0.106 (P<0.0001) fibrosis units per year, respectively.
HIV seropositivity, alcohol consumption, age at HCV infection, and
severe immunosuppression were associated with an increase in the
fibrosis progression rate.
30.o Soto B, Sanchez-Quijano A, Rodrigo L, et al.: Human immuno-deficiency
virus infection modifies the natural history of
chronic parenterally-acquired hepatitis C with an unusually
rapid progression to cirrhosis. J Hepatol 1997, 26:1-5.
A cohort of 547 HCV-infected individuals (116 HIV-positive and 431
HIV-negative) was observed to evaluate the effect of HIV infection on
the rate of HCV-associated liver disease. The median estimated inter-val
of time from HCV infection to cirrhosis was significantly longer
in HIV-negative than in HIV-positive individuals (23.2 vs 6.9
31. Sanchez-Quijano A, Andreu J, Gavilan F, et al.: Influence of
human immunodeficiency virus type 1 infection on the
natural history of chronic parenteral-acquired hepatitis C.
Eur J Clin Microbiol Infect Dis 1995, 14:949-953.
32.o Puoti M, Bonacini M, Spinetti A, et al.: Liver fibrosis progres-sion
is related to CD4 cell depletion in patients coinfected
with hepatitis C virus and human immunodeficiency virus.
J Infect Dis 2001, 183:134-137.
Liver biopsies from 84 HIV-HCV coinfected and 120 HCV mono-infected
individuals were evaluated to determine variables associated
with increased hepatic fibrosis. This study found a significant associ-ation
between CD4 + cell counts of less than 500 cells/mm 3 and the
presence of many fibrous septa independent of HIV infection,
suggesting that CD4 depletion is independently associated with the
severity of hepatic fibrosis.
33. Poynard T, Bedossa P, Opolon P, et al.: Natural history of liver
fibrosis progression in patients with chronic hepatitis C.
Lancet 1997, 349:825-832.
34. Poynard T, Ratziu V, Charlotte F, et al.: Rates and risk factors of
liver fibrosis progression in patients with chronic hepatitis
C. Lancet 2001, 34:730-739.
35. Benhamou Y, DiMartino V, Colombet G, et al.: Factors affect-ing
liver fibrosis in human immunodeficiency virus and
hepatitis C virus coinfected patients: impact of protease
inhibitor therapy. Hepatology 2001, 34:283-287.
36. Talal AH, Yee H, Dieterich DT: Effect of hepatitis C virus and
HIV-1 on hepatic parenchymal and mononuclear cell
proliferation and apoptosis [abstract]. Gastroenterology 2000,
11 8 : A938.
37. Canchis W, Fiel I, Chiriboga L, et al.: Hepatocyte and infiltra-ting
hepatic lymphocyte proliferation and apoptosis in HIV/
HCV coinfected individuals [abstract]. Hepatology 2001,
38. Zajac AJ, Blattman JN Murali-Krishna K, et al.: Viral immune
evasion due to persistence of activated T cells without
effector function. J Exp Med 1998,188:2205-2213.
39. Appay V, Nixon DF, Donahoe SM, et al.: HIV-specific CD8 + T
cells produce antiviral cytokines but are impaired in cytolytic
function. J Exp Med 2000, 192:63-75.
40. Gruener NH, Lechner F, Jung M-C, et al.: Sustained dysfunction
of antiviral CD8 + T lymphocytes after infection with
hepatitis C virus. J Virol 2001, 75:5550-5558.
41. Fr i edman SL: The virtuosity of hepatic stellate cells.
Gastroenterology 1999, 11 7 : 1244-46.
42. Kamal SM, Rasenack JW, Bianchi L, et al.: Acute hepatitis C
without and with schistosomiasis: correlation with hepatitis
C-specific CD4 + T-cell and cytokine response. Gastroenterology
43. Schacker T, Collier AC, Hughes J, et al.: Clinical and epidemio-logic
features of primary HIV infection. Ann Intern Med 1996,
44. Orland JR, Wright TL, Cooper S: Acute hepatitis C. Hepatology
45. 1999 USPHS/IDSA guidelines for the prevention of opportu-nistic
infections in persons infected with human immuno-deficiency
virus. Morb Mortal Wkly Rep 1999, 48:1-59.
46. Bonacini M, Lin HJ, Hollinger FB: Effect of coexisting HIV-1
infection on the diagnosis and evaluation of hepatitis C
virus. J Acquire Immunodefic Syndr 2001, 26:340-344.
47. Thio CL, Nolt KR, Astemborski J, et al.: Screening for hepatitis
C virus in human immunodeficiency virus-infected individu-als.
J Clin Micro 2000, 38:575-577.
48. Miller V, Staszewski S, Sabin C, et al.: CD4 lymphocyte count
as a predictor of the duration of highly active antiretroviral
therapy-induced suppression of human immunodeficiency
virus load. J Infect Dis1999,180:530-533.
49. Bravo AA, She SG, Chopra S: Liver biopsy. N Engl J Med 2001,
50. Bedossa P, Poynard T, for the METAVIR Cooperative Study
Group: An algorithm for the grading of activity in chronic
hepatitis C. Hepatology 1996, 24:289-293.
51. The METAVIR Cooperative Group: Inter- and intra-observer
variation in the assessment of liver biopsy of chronic hepati-tis
C. Hepatology 1994, 20:15-20.
52. Brunt EM: Grading and staging the histopathological lesions
of chronic hepatitis. Hepatology 2000, 31: 241-246.
53. Stanley AJ, Haydon GH, Piris J, et al.: Assessment of liver
histology in patients with hepatitis C and normal amino-transferase
levels. Eur J Gastroenterol Hepatol 1996,
54. Lau DT, Kleiner DE, Ghany MG, et al: 10-Year follow-up after
interferon-alpha therapy for chronic hepatitis C. Hepatology
55. Marcellin P, Boyer N, Gervais A, et al.: Long-term histologic
improvement and loss of detectable intrahepatic HCV RNA
in patients with chronic hepatitis C and sustained response
to interferon-alpha therapy. Ann Intern Med 1997,
56. Poynard T, Marcellin P, Lee SS, et al.: Randomized trial of
interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks
versus interferon alfa-2b plus placebo for 48 weeks for treat-ment
of chronic infection with hepatitis C virus. Lancet 1998,
57. Rivero J, Faga M, Cancio I, et al.: Long-term treatment with
recombinant interferon alpha-2b prolongs survival of
asymptomatic HIV-infected individuals. Biotherapy 1997,
58. Haas DW, Lavelle J, Nadler JP, et al.: A randomized trial of
interferon alpha therapy for HIV type 1 infection.
AIDS Res Hum Retroviruses 2000, 16:183-190.
59. Causse X, Payen JL, Izopet J, et al.: Does HIV-infection
influence the response of chronic hepatitis C to interferon
treatment? A French multicenter prospective study.
J Hepatol 2000, 32:1003-1010.
60. Landau A, Batisse D, Pickety C, et al.: Long-term efficacy of
combination therapy with interferon-a2b and ribavirin for
severe chronic hepatitis C in HIV-infected patients.
AIDS 2001, 15:2149-2155.
61.o Zylberberg H, Benhamou Y, Lagneaux JL, et al.: Safety and
efficacy of interferon-ribavirin combination therapy in
HCV-HIV coinfected subjects: an early report. Gut 2000,
This trial evaluated the safety and efficacy of combination therapy
using interferon and ribavirin in HIV-HCV coinfected individuals
who were nonresponders or relapsers after treatment with standard
interferon. The sustained virologic response rate in these patients
62. Nasti G, Di Gennaro G, Tavio M, et al.: Chronic hepatitis C in
HIV infection: feasibility and sustained efficacy of therapy
with interferon alfa-2b and ribavirin. AIDS 2001,
63. Sauleda S, Juarez A, Esteban JI, et al.: Interferon and ribavirin
combination therapy for chronic hepatitis C in human
immunodeficiency virus-infected patients with congenital
coagulation disorders. Hepatology 2001, 34:1035-1040.
64. Zeuzem S, Feinman SV, Rasenack J, et al.: Peginterferon
alfa-2a in patients with chronic hepatitis. N Engl J Med 2000,
65. Manns MP, McHutchinson JG, Gordon SC, et al.: Peginterferon
alfa-2b plus ribavirin compared with interferon alfa-2b plus
randomized trial. Lancet 2001, 358:958-965.
66. Roberts RB, Hollinger FB, Parks WP, et al.: A multicenter
clinical trial of oral ribavirin in HIV-infected people with
lymphadenopathy: virologic observations. AIDS 1990,
67. Vogt MW, Hartshorn KL, Furman PA, et al.: Ribavirin antago-nizes
the effect of azidothymidine on HIV replication.
Science 1987, 235:1376-1379.
68. Hoggard PG, Kewn S, Barry MG, et al.: Effects of drugs on
2'3'-didehydrothymidine phosphorylation in vitro.
Antimicrob Agents Chemother 1997, 41: 1231-1236.
69. Poynard T, McHutchinson J, Goodman Z, et al.: Is an Œa la carte'
combination interferon alfa-2b plus ribavirin regimen
possible for the first line treatment in patients with chronic
hepatitis C? Hepatology 2000, 31 : 211-218.