1117
REVIEW ARTICLES
Reciprocal Interactions Between Human Immunodeficiency Virus and Hepatitis
C Virus Infections
Herve Zylberberg and Stanislas Pol From the Service d'Hepatologie, HOpital Necker, Paris, France
Hepatotropic viruses that lead to chronic infection—namely,
hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis
delta virus (HDV), and HIV share the same parenteral, sexual, and vertical (from infected mother to newborn) routes of
transmission [1, 2]. This common epidemiology explains the
high frequency of combined infections by hepatotropic viruses
and HIV. Little is known about interactions between HIV and
HCV infections, while interactions between HIV and HBV
[3-6] or HDV [7-10] have been extensively studied; these
investigations have led to controversial findings, however.
The aim of the present review is to clarify some important
issues dealing with the reciprocal impact of HIV- and HCVassociated infections, including the variations in clinical, biological, histopathologic, and virological natural history of both
infections and the resulting therapeutic and prognostic consequences, on the basis of recent reports.
Impact of HIV Infection on the Natural History of HCV
Infection
HCV and HIV Combined Infection
Acute HCV infection is usually asymptomatic in immunocompetent patients, and the risk of fulminant hepatitis, if any,
appears very low [11] . After exposure to HCV, the risk of
chronic infection is —50%-80%, and such chronic infection
Received 15 March 1996; revised 5 July 1996.
Reprints or correspondence: Dr. Stanislas Pol, Unite d'Hepatologie, H8pital
Necker, 161 Rue de Sevres, 75743 Paris, Cedex 15, France.
Clinical Infectious Diseases 1996; 23:1117-25
© 1996 by The University of Chicago. All rights reserved.
1058-4838/96/2305-0027$02.00
is associated with a 20% risk of cirrhosis. In 20%-50% of
patients spontaneous resolution of HCV infection occurs, characterized by normal aminotransferase levels and long-lasting
positivity for antibodies to HCV but undetectable serum or
liver levels of HCV RNA.
There are no available data indicating an increased risk of
fulminant [12] or symptomatic acute HCV infection in HIVinfected patients. There are also no data that would indicate
an increased risk of progression to chronicity of HCV infection
in HIV-positive patients: in our experience with HCV-antibody-positive hemophiliacs, the prevalence of detectable HCV
RNA was not significantly but slightly higher among HIVpositive patients (77%) than among HIV-negative ones (60%)
[13].
Viremia due to HCV was detectable by PCR in 88.2% of
HCV-antibody-positive patients in a series of 226 HIV-antibody-positive patients [14], a figure similar to that observed
after posttransfusional infection in HIV-negative patients. In a
prospective study comparing HCV load in 150 HCV-antibodypositive patients, mainly intravenous drug users (IVDUs), HCV
RNA was detected in 90.7% of 75 HIV-positive patients and
in 82.7% of 75 HIV-negative patients (NS) [15]. Given the
spontaneously high rate of chronic infection in immunocompetent patients; large series would be necessary to evaluate if
such individuals are at increased risk of chronic infection.
Whether this risk is correlated to immune status (as assessed
by the CD4 cell count), as has been described for HBV, should
be determined.
Prevalence and Significance of Antibodies to HCV
The prevalence of antibodies to HCV in the population of
blood donors is —0.3%-1.5%, depending on the geographic
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Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same routes of
transmission, which explains the high rate of HCV and HIV coinfection (-9%). HIV/HCV coinfection leads to high rates of indeterminate recombinant immunoblot assay patterns and seroreversion;
high levels of viral replication; and a more severe histopathologic course. By contrast, HCV infection
does not seem to accelerate the progression of HIV infection. Interferon a (IFN-a) in coinfected
patients leads to a similar rate of primary responses, but sustained responses are less frequent. The
potential severity of hepatitis C virus infection evidences the need for early diagnosis. Liver biopsy
should be performed for all HCV RNA —positive patients in order to evaluate the activity of the
liver disease. Given the poor efficiency of IFN-a in terms of sustained response in HIV-infected
patients, reinforced therapeutic procedures (long-term administration of IFN-a or combined ribavirin/IFN-a) should be proposed, at least for those patients with severe liver disease.
CID 1996;23 (November)
Zylberberg and Pol
1118
Table 1. Reported prevalence of HCV antibodies in HIV-infected
subjects.
References
Subjects
Percentage with
antibodies to HCV
[14, 21-24]
[17, 18]
[13, 19, 20]
[14, 16]
IVDUs
Homosexual men
Hemophiliacs
All subjects
52-90*
4-8
60-85
8-30t
* HCV RNA was detectable in 88%.
t Results of second-generation testing (the first-generation assays yielded a
rate of 15.6%).
generation RIBA) was noted for 10.7% [15] and 23% [34] of
tested patients, respectively, in two studies of coinfected
patients; a preferential c22 reactivity band suggested that reactivity to c22 is conserved even in HIV-infected individuals,
probably in accordance with a thymus-independent antigen response. Viremia due to HCV was found more frequently in
HIV-antibody-positive than HIV-antibody-negative subjects
with indeterminate RIBA patterns (89% vs. 50%) [34]. This
finding underlines the fact that for HIV-antibody-positive patients, a single negative assay for antibodies to HCV is not
sufficient to definitively exclude HCV infection.
Thus, antibodies to HCV are detected in —9% of HIVpositive patients, as compared with —1% of the healthy population, with frequent seroreversion. The prevalence largely varies
according to risk factor (table 1). Sixty percent to 90% of HCVand HIV-antibody-positive patients have detectable viremia
due to HCV.
Viremia Due to HCV in HIV Infected Patients
-
To overcome the question of specificity and sensitivity of
serological tests for HIV-infected patients—and since the detection of antibodies to HCV is not sufficient for the diagnosis
of HCV infection in these patients, whose liver test results
frequently are abnormal [35] —the direct detection of HCV
RNA appears necessary for confident conclusions and decisions
regarding therapy [36, 37]. Genomic amplification by PCR
indeed allows detection of small amounts of HCV RNA, semiquantitative estimation, and evaluation of the genotype.
A competitive PCR or the amplification of the signal in the
branched DNA (bDNA) assay allows a simple and reproducible
quantification of HCV RNA, with a cutoff of 2.0 X 10 5 genome
equivalents per mL (Eq/mL) for the latter procedure. It has
been clearly demonstrated that these virological parameters,
namely, quantitative viremia and genotypes, have important
clinical and therapeutic implications for immunocompetent patients (vide infra).
Qualitative viremia. As previously mentioned, several
studies confirmed with use of PCR that most HCV-antibodypositive patients had detectable viremia [13, 14]. HCV RNA
has also been detected in HCV-antibody-negative patients, especially immunocompromised ones, at a prevalence rate of
—3% [31]. The precise prevalence of viremia due to HCV in
HCV-negative, HIV-positive patients is unknown.
Quantitative viremia. Most cases of immune deficiency are
associated with a high viral load. In association with HIV
infection, high HCV replication is suggested by the more frequent vertical transmission of HCV to newborns from HIVinfected mothers (-20%) [38, 39] than from HIV-negative
mothers (3%-9%); in HIV-negative mothers, the risk of transmission is clearly related to the level of viremia (> 106 Eq/mL
by the bDNA test) [40]. Higher serum levels of HCV RNA
were noted in 19 HIV-infected patients (median, 141; range,
25-3,980 x 10 6 Eq/mL) than in 40 HIV-antibody-negative
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area. The prevalence of antibodies to HCV in HIV-infected
patients varies according to the risk factor for HCV and HIV
infection and to the serological assays used (table 1); it is —8%
in American studies [14, 16]. Data from the United Kingdom
[17] and Spain [18] indicate a prevalence of 4%-8% among
HIV-positive homosexual males, which is no different from
that among HIV-negative homosexuals. Among hemophiliacs
the prevalence of antibodies to HCV is much higher
(— 60%— 85%) [13, 19, 20], as it is among IVDUs
(-50%-70%) [14, 21-24], whatever their HIV status.
Factors carrying a statistically significant correlation with
the presence of antibodies to HCV in HIV-infected patients
are iv drug use [14] and female sex [23]; by contrast, the
sexual acquisition of HIV is negatively associated with HCV
coinfection, a finding confirming the low rate of sexual transmission of HCV [25-27].
The prevalence of antibodies to HCV in HIV-positive patients was initially overestimated by the frequent false-positive
results of the first-generation assays: although antibodies to
HCV were detected by the first-generation ELISA in 14 of 90
HIV-infected patients (15.6%), these results were confirmed
for only 8 (57.1%) by the recombinant immunoblot assay
(RIBA), thus yielding an 8.8% antibody-positivity rate [24].
On the other hand, the prevalence may be underestimated
by fluctuations or spontaneous disappearance of antibodies to
HCV. In a time-point survey of 262 IVDUs receiving methadone treatment, antibodies to HCV were detected in 64% of
the patients [28]. Analysis of previously collected frozen stored
sera of the same patients showed that 31 other patients had
had antibodies to HCV in the past but lost them in a timedependent fashion, as assessed with successive samples. HCV
seroreversion (defined as a change from positive to negative
status for antibodies to HCV) is 2.5 times more frequently
observed in HIV-positive than HIV-negative patients [28-30].
Diminution or loss of reactivity to HCV antigens has been
previously observed in other immunocompromised patients,
such as those undergoing hemodialysis and kidney or bone
marrow recipients [31-33]. This diminution of reactivity to
HCV antigens leads to an indeterminate RIBA pattern, defined
by reactivity for only one antigen. Such a pattern (with third-
CID 1996;23 (November)
HIV- and HCV-Associated Infections
results showed that genomic diversity of the viral population
(or quasi-species) is an independent factor of therapeutic response [51].
In summary, HCV RNA is frequently detected in HCVantibody-positive patients. HIV infection leads usually to
higher levels of viremia due to HCV. Despite the fact that data
about HCV genotypes in HIV-positive populations are few, we
assume that the changing prevalence over time of genotype lb
will be observed in hemophiliacs, although genotypes 3a and
1 a are mainly observed in IVDUs.
Histopathologic Impact of HIV/HCV Coinfection
Chronic HCV infection in immunocompetent patients exposes them to an overall 20% risk of cirrhosis, and cirrhosis
itself is associated with a 3% yearly incidence of hepatocellular
carcinoma [52]. It has been suggested that some patients (a
minority) may be symptomless healthy carriers of HCV [53].
Compared to those in HBV infection, the mechanisms leading to hepatocellular injury in chronic HCV infection have
not been well characterized [54, 55]. The rapid efficiency of
interferon treatment of HCV infection and the more severe
liver disease that may be associated with immunosuppression
suggest the direct cytopathic effect of HCV. However, the
involvement of immunopathogenic mechanisms in HCV infection is suggested by (1) the absence of correlation between the
viral load (level of HCV RNA or HCV antigens) in liver tissues
and histopathologic activity, (2) the identification of liver and
peripheral blood T lymphocytes (CD4 and CD8) directed
against specific HCV antigens in correlation with disease activity [56], and (3) the association between HCV and autoimmunity.
Most studies [14, 57, 58], if not all, indicate that HIV infection modifies the severity of HCV-related liver disease; however, these studies, which revealed only mild liver injury in
association with HIV infection, provided poor or no histopathologic data. The occurrence of rapidly progressive hepatitis, in
three elderly patients who acquired simultaneously non-A, nonB hepatitis and HIV infection by blood transfusions [59] and
in hemophiliacs who acquired HCV [19, 60], has been reported.
In a study of 255 HCV-antibody-positive hemophiliac patients,
the risk of hepatic decompensation was 21-fold higher among
HIV-coinfected patients [60].
Two recent studies in Spain dealing with large series of
HCV-antibody-positive patients (547 and 76, including 116
and 32 HIV-positive patients, respectively) with parenterally
acquired HCV infection demonstrated that the time elapsed
between acquisition of HCV infection and the development of
liver cirrhosis was significantly lower in HIV-positive subjects
[61, 62]. In our series of 150 HCV-antibody-positive hemophiliacs, 21 underwent a liver biopsy: 5 (of 8) HIV-positive patients
vs. 2 (of 15) HIV-antibody-negative patients had cirrhosis [13].
In our series of 210 HCV-antibody-positive IVDUs, including
60 HIV-infected patients, the incidence of cirrhosis was
,
,
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patients (median, 32; range, 0.1-500 X 10 6 Eq/mL [as determined by competitive PCR]; P = .0001) [41].
In another study, high HCV loads were observed in HIVinfected patients: 50% of 75 coinfected patients (vs. only 1.5%
of 75 HIV-negative patients) had an HCV load of >10 7
Eq/mL [15]. Similarly, the level of HCV RNA was significantly
higher in 17 HIV-positive than 17 HIV-negative hemophiliacs;
it increased more quickly over time and correlated significantly
with the loss of CD4 cells [42]. Among HIV-positive patients,
viremia due to HCV was not significantly different with regard
to clinical status, p24 antigenemia, or HIV viral load [15, 43].
In hemophiliacs with HCV infection, a significant increase in
viremia due to HCV after HIV seroconversion has been described [44]. This higher viral load related to HIV infection
is observed, although not constantly [13, 45], as well with
semiquantitative PCR as with the bDNA test [46]. The impact
of this high level of replication on the severity of liver disease
and on the response to antiviral therapies is very likely deleterious (vide infra).
HCV genotypes. The distribution of HCV genotypes in immunocompetent HCV-antibody-positive patients reflects
mainly the route of contamination. The lb genotype accounts
for two-thirds of posttransfusional or sporadic HCV infections
[47]; by contrast, genotypes la and 3a are the most prevalent
(20% and 40%, respectively, as compared with only 15% prevalence of the lb genotype) in IVDUs, whose viruses probably
were imported from the Far East (i.e., Pakistan and Nepal).
During the last 2 decades, probably in relation with various
surrogate tests, the prevalence of posttransfusional infection
with HCV genotype lb has dramatically decreased, from 80%
before 1975 to 17% after 1987 [47, 48]. This changing relative
prevalence may reflect the introduction of the la and 3a genotypes in blood banks by IVDUs in the 1980s, before screening
began for antibodies to HIV (1985) [48, 49]. It may also be
due, at least in part and in France, to the free screening for
antibodies to HIV that is now offered in blood banks and to
the solicitation of blood donations from prisoners.
More data about HCV genotypes in the HIV-positive population, such as those we have obtained with regard to the general
population and patients undergoing hemodialysis [49], should
be obtained.
Mixed infections have been described and appear to be frequent in hemophiliacs (-40%) and in IVDUs (-10%). In
one of our own studies involving 216 HCV-antibody-positive
hemophiliacs coinfected (46.5%) or not by HIV, mixed HCV
infections were identified in 11 (31.4%) of 34 randomly selected patients tested with equal frequency (5 of the 17
HIV-antibody-positive and 4 of the 17 HIV-antibody-negative
patients) [13]. In another of our studies, dealing with 210 HCVantibody-positive IVDUs, mixed infection was not more frequent in cases of HIV infection (- 10%) [50] . The significance
and impact of such combined infections are not well established, neither for HIV-negative patients nor for HIV-positive
ones [13], but should be evaluated, especially since preliminary
1119
1120
Zylberberg and Pol
Impact of HCV Infection on the Natural History of HIV
Infection
It has been suggested that various cofactors lead to increased
progression of HIV infection, including infectious agents, especially herpesviruses and Mycoplasma species [66]. Most of the
studies dealing with HCV infection in HIV-infected patients
conclude that HCV infection does not seem to accelerate the
progression of HIV infection or at least does not deteriorate
the surrogate markers of progression of HIV (total and CD4
cell count, presence of p24 antigen, and presence of serum /32
microglobulin) [67, 68]. In a study of 226 HIV-positive patients
[14], only 3 (16.7%) of the 18 HCV-antibody-positive patients
vs. 77 (37.4%) of the 208 HCV-antibody-negative patients had
AIDS (P = .04). Most (88.3%) of the HCV-antibody-positive
patients but only 44.1% of the HCV-antibody-negative patients
had a CD4 cell count of ..200/mm 3 (P = .001). The prevalence
of antibodies to HCV decreased in parallel with the CD4 cell
count, but this could reflect only immune dysfunction and ser°reversion.
In a study dealing with 416 HIV-positive patients, including
214 who were HCV-antibody-positive, it appeared that coinfec-
tion by HCV does not influence clinical and immunologic progression of HIV disease [68]. On the whole, HCV infection
does not appear to increase the severity of HIV infection.
Preliminary data suggested that HCV, probably because of
its lymphotropism, is involved in some occurrences of nonHodgkin's lymphoma [69]. Whether and how HCV is related
to lymphoma in patients with AIDS remains to be determinated.
Since in vitro interactions between HBV and HIV [70] and
between HCV and HBV [71] at a transcriptional level—especially by transactivation—have been described, we could not
exclude a similar interaction between HCV and HIV.
Treatment of Chronic Hepatitis in HIV-Infected Patients
Administration of interferon, especially IFN-a, is the only
treatment of proven efficacy for chronic hepatitis C. A standard
treatment (3 million units subcutaneously, thrice weekly for
6 months) induces normalization of transaminase levels and
histologic improvement in one-half of treated patients [72].
Fifty percent of these so-called responders relapse within 6
months after termination of treatment (relapsers), and the other
50% are the so-called long-term responders [73]. Early clearance of viremia (at 1 month) appears to be a good predictor
of primary and sustained response.
Recent studies suggest that responsiveness to IFN-a in cases
of chronic active hepatitis C differs according to HCV replication
and genotype: low pretreatment severity of viremia, low genomic
diversity, and involvement of genotypes other than lb independently correlate with primary and sustained response [48]. Trials
of new protocols that use a different dosage, prolonged administration, and/or a second antiviral agent (ribavirin) are now in
progress in order to try to improve the responsiveness to IFNa [74, 75]. Among long-term responders, HCV RNA is cleared
from most (if not all) patients' serum, liver, and peripheral blood
mononuclear cells and is associated with marked histopathologic
improvement [76, 77]. Nevertheless, the long-term benefit of
antiviral treatment in terms of the overall rate of survival of
immunocompetent patients is not yet evaluable.
Several studies, mainly described in abstract form, have evaluated the response of patients with chronic HCV and HIV
infection to IFN-a [50, 78-94] (table 2); . most of the patients
were IVDUs with high CD4 lymphocyte counts (>200/mm 3 )
and without diagnosed AIDS. Most studies [77-84, 87, 88]
but not all [89] showed a biological or histologic benefit of
IFN-a at the usual dosage (3 million units thrice weekly for 6
months); this benefit did not differ from that noted in HIVnegative patients (i.e., normalization of transaminase levels in
50% of treated patients).
Long-term response (at 1 year) was analyzed in five studies
reported in abstract form [50, 78, 79, 84, 90] (table 3). In three
studies [78, 79, 84] long-term response was observed in —50%
of patients who had a primary response, as observed in HIVnegative patients; in the two other studies the sustained
response was low. In a study of 40 HCV-antibody-positive
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3.5-fold higher among HIV-positive patients than among
HIV-negative ones [50].
All these results indicate that HIV infection accelerates the
natural course of HCV infection, causing an unusually rapid
progression to cirrhosis. Mechanisms that could explain such an
effect are not clear, since HIV infection per se appears to worsen
the histologic characteristics of the liver [63] independently of
other cofactors such as chronic alcoholism, HBV- or HDVassociated infection, and the genotypes involved in HCV infection; it must be an early event since there is no clear difference
in Knodell scores in relation to CD4 cell counts [63a].
An increase in quantitative viremia due to HCV, associated
with immune deficiency, may explain the higher frequency of
cirrhosis among HIV-infected patients: an increase in severity
of HCV viremia is usual in immunocompromised patients (vide
supra), but there is no clear correlation between the level of
viremia and the severity of the liver disease. Nevertheless, an
increase in levels of HCV RNA in persons with coinfection in
whom liver failure developed, as compared with levels in those
whose livers did not fail, has been described [44].
Since we found that the outcome of HCV infection in hemophiliac coinfected patients was more severe despite the lower
severity of their HCV viremia [13], other mechanisms modified
by HIV infection such as variations of cytokine expression,
adhesion-molecule expression, or fibrogenesis— are probably
involved in the histologic deterioration, as has been described
with regard to other immunocompromised patients. In addition,
coinfections with other hepatotropic viruses (HBV and HDV),
especially in IVDUs, should be considered carefully since
reciprocal viral interactions in viral replication have been reported [64, 65].
CID 1996;23 (November)
CID 1996;23 (November)
1121
HIV- and HCV-Associated Infections
Table 2. Results of treatment with IFN-a for chronic hepatitis C in HIV-infected patients: analysis
of primary response.
Reference
Controlled
study
Thrice-weekly
dose(s) (MU)
of IFN-a
Duration (mo)
of IFN-a
treatment
NA
3
5
3
5
3
5
5
3
NA
6
3
6
6
3
9
3
6
[77]
[81]
[82]
Y*
41
17
88
[83]
[89]
Y*
79
18
78
[93]
Primary response
(% of patients)
52t
54 1
43
54
22
38
NOTE. MU = megaunits; N = no; NA = data not available; Y = yes.
* Involved histologic analysis.
t Determined on a histologic basis.
Results of HCV viremia were available.
was a nonrandomized trial including 12 patients with high
CD4 lymphocyte counts; 4 of the 12 patients had a complete
response, occurring within the first 2 months of therapy, but
only 1 (8.3%) had a sustained, complete response after a 12month follow-up.
The second investigation was a pilot study of 14 IVDUs
with chronic active hepatitis (including one with cirrhosis) and
asymptomatic HIV infection (mean [±SD] CD4 count, 584 ±
283/mm 3 ). They were given 9 million units of IFN-a subcutaneously daily for 3 months and then 9, 6, and 3 million units,
respectively, three times weekly for 3-month periods (for a
total treatment period of 1 year). Five (55%) of the nine patients
who completed the treatment period had a complete response,
including four (44.4%) with a sustained response 6 months
after withdrawal of IFN-a.
Histologic improvement in the liver was observed in the six
patients who underwent a second liver biopsy. Serum HCV
IVDUs (20 were HIV-positive [mean CD4 cell count,
350/mm 3 ] and 20 were HIV-negative), a response during therapy with IFN-a (3 million units thrice weekly for 6 months)
was observed in 75% of HIV-negative patients and 30% of
HIV-positive patients. A sustained response during the 3
months following withdrawal of IFN-a was observed in 35%
and 15%, respectively [90].
Among 210 HCV-antibody-positive IVDUs, we treated 16
of the 60 HIV-positive patients and 62 of the 150 HIV-negative
patients with a standard IFN-a regimen (3 million units subcutaneously, thrice weekly for 6 months). A primary response
was observed in 88% of the former and in 55.1% of the latter;
a biological long-term response was noted in none of the 16
HIV-antibody-positive and 25 (32%) of the 62 HIV-antibodynegative patients (P = .01) [50].
Only three studies have been published as full articles
[91-93], and two analyzed the long-term response. The first
Table 3. Results of treatment with IFN-a for chronic hepatitis C in HIV-infected patients: analysis
of long-term response.
Reference
[50]
[78]
[84]
[79]
[91]
[92]
[90]
Controlled
study
No. of
patients
studied
Thrice-weekly
dose(s) (MU)
of IFN-a
Duration (mo)
of IFN-a
treatment
N*
N*
N*
31
20
21
10
12
14
3
3
3
3
6
9
6
3
6
18
6
6
6
6
6
6
20
NOTE. MU = megaunits; N = no; NA = data not available; Y = yes.
* Involved histologic analysis.
t Results of HCV viremia were available.
Response
(percentage of patients)
Primary
Long-term
22.6
NA
45
40
33
55
0
25
27
20
8
44t
30
15
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No. of
patients
studied
1122
Zylberberg and Pol
to IFN-a in patients with HIV infection (mainly IVDUs) and
without such infection (mainly those infected by the lb genotype) [48, 49], despite a higher level of HCV viremia in the
HIV-infected population.
Third, there is little information concerning the consequences
of IFN-a treatment on morbidity and mortality among HIVinfected patients. In a prospective study including 73 HIVpositive patients with chronic viral hepatitis (due to HCV in
54 cases), IFN-a seemed to decrease the occurrence of liver
failure and to increase survival with a Cox's model analysis
[80].
Finally, many patients were concomitantly receiving antiretroviral therapy. A preliminary small-sample-size study suggested that zidovudine could induce remission of chronic active
hepatitis C, probably by enhancement of immune functions
[85]. By contrast, in a large prospective study, zidovudine
showed no statistically significant beneficial effect on hepatitis
C infection [86]. Somes studies provided evidence that INF-a
may have activity against HIV in vivo [95, 96], but this issue
has not been studied in reported trials dealing with therapy for
HCV-infected patients. Ribavirin, a nucleoside analog that has
no clear effect alone on HCV [75] or HIV replication, yielded
encouraging results in combination with IFN-a. Such a combination remains to be tested in HIV-infected patients.
Thus, interpretation of the previously reported data concerning HCV/HIV coinfection should be considered with caution
because (1) most of these studies have been described only in
abstract form; (2) in such patients, who have numerous causes
of hypertransaminasemia [35], the level of transaminase should
not be considered a good reflection of the activity of liver
disease; (3) interactions between HIV and HCV replication at
the lymphocyte level cannot be excluded; (4) the potential
effects of different regimens may differ; (5) HBV coinfection
may occur in the absence of the usual antibody or antigen
markers in serum [97]; and (6) the potential role of hepatitis
G virus in HIV/HCV coinfected patients remains to be determined.
The crucial point now is to define a subgroup of HIV/HCV
coinfected patients who really need to be treated and may
benefit from IFN-a therapy. Indeed, the actual risk of death
related to either HIV infection or liver failure is difficult to
evaluate, and probably only those HIV-infected patients with
severe liver disease need to be treated. In this setting, it will
be necessary to analyze the effects, unknown at present, of
INF-a therapy on a homogenous group of patients with low
CD4 lymphocyte counts (< 100/mm 3 ).
In conclusion, antibodies to HCV are frequently detected in
HIV-infected patients (-9%) and especially in hemophiliacs
and IVDUs. Antibodies to HCV are usually associated with
active infection, as assessed by a detectable level of HCV
viremia. HIV infection increases levels of viremia and thus the
risk of mother-to-child transmission. HIV infection probably
worsens the histologic course of HCV infection and exposes
at least those patients with parenterally acquired infection to
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RNA was detectable in all the patients before therapy; of the
five patients with a complete response, HCV RNA became
undetectable in three (33.3%) at the end of therapy and was
no longer detectable during the follow-up. Three nonresponders
had no detectable serum HCV RNA at the end of therapy, but
HCV RNA became detectable again in two patients during
follow-up.
The third study was a prospective, controlled trial including
78 patients. They were given 5 million units of IFN-a three
times weekly for 3 months, and then 3 million units were given
three times weekly for 9 months to responding patients (as
defined by normalization or decrease of the alanine aminotransferase level by > 50% of baseline values). Responses to treatment were analyzed after 8 months of therapy. Complete response was achieved in 22 (38%) of 57 coinfected patients
vs. 10 (47%) of 21 HIV-negative patients (NS). A positive
correlation was found between CD4 cell count and response
to therapy with IFN-a (vide infra).
Tolerance of treatment was no different from that observed in
HIV-negative patients. As reported for HIV-negative patients, a
transient flulike syndrome occurred frequently. No serious side
effects or occurrences of opportunistic infections have been
reported. Nevertheless, in a few patients (5.2% in a Spanish
study) a dramatic fall (reduction of > 100%) in the CD4 cell
count after initiation of therapy with IFN-a has been described
[93, 94]. Although no clear relationship has been established
between IFN-a therapy and CD4 lymphopenia in this setting,
this rare event emphasizes the need for control of the CD4 cell
count during treatment of HIV-infected patients with IFN-a.
In summary, IFN-a appears to be poorly efficient in HIVinfected patients in standard therapies, but reinforced and prolonged treatments may—as in immunocompetent patients
increase the response rate. Nevertheless, some points should
be further clarified. First, the correlation between responsiveness to IFN-a and immune status was analyzed in few
trials. In a prospective randomized study including 57 HIVand HCV-antibody-positive patients, a positive correlation was
found between CD4 lymphocyte counts and the response to
IFN-a: a complete response was observed in 58% of patients
with a CD4 cell count of >500/mm 3 but in only 34% of patients
with a lower CD4 cell count (P < .01) [93].
Conversely, in a multicentric trial including 79 patients who
had antibodies to both HIV and HCV, a negative correlation
between CD4 lymphocyte counts and response to IFN-a was
observed [83]: patients with <400 CD4 cells/mm' had a paradoxically better response rate than those who had a higher
CD4 lymphocyte count. In a noncontrolled study including 21
patients, no correlation was found between CD4 count or CDC
(Centers for Disease Control and Prevention) stage of infection
and response to IFN-a [84].
Second, none of these studies included viral genotype analyses. In Europe, the predominant genotype among IVDUs is 3a
(vide supra), which has been associated with a fair response
to IFN-a therapy. This fact could explain the similar response
CID 1996; 23 (November)
CID 1996;23 (November)
HIV- and HCV-Associated Infections
Acknowledgments
The authors thank Prof. P. Berthelot and Dr. G. Pialoux for their
helpful advice and Miss D. Jourdat for her expert preparation of
the manuscript.
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