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Introduction
Although
the advent of HAART has resulted in a considerable reduction
in mortality
and morbidity associated with HIV infection,
advances in the management of hepatitis B and C both in the
singly and co-infected patient continue to somewhat lag behind.
This is particularly true for those coinfected with HIV and
HBV or HCV, despite the high incidence of coinfection worldwide.
Liver
disease remains a major cause of mortality amongst HIV-infected
individuals living in developed counties with access to HAART,
as well as being a significant cause of morbidity in coinfected
individuals.
The 3rd International
AIDS Society Conference in Rio de Janeiro included a number of presentations
on coinfection, particularly HCV with new subanalyses of the
APRICOT
trial, and new data on the safety of antiretrovirals
(ARVs) in coinfected individuals. Several epidemiological
studies highlighted the high rates of concomitant HCV and HBV
in HIV-infected subjects and the need for enhanced vaccination
programmes in emerging HIV populations.
Note: Unless otherwise stated, all references
in this article are to the Program and abstracts of the 3rd
International AIDS Society Conference on HIV Pathogenesis
and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil.
Epidemiology of HCV
The difficulties
of instituting risk reduction programmes amongst intravenous
drug users (IDUs) were outlined in a poster
by Aquino et al (WePe10.4P08). Low rates of
HIV infection (approximately 1%) in a Philippine IDU population
led to a reluctance from the local authorities to support
risk management programmes. The authors used HCV testing
as a marker of risky injecting practice and 80% tested positive
for HCV antibody.
Hadi et al performed
a prospective follow-up amongst an IDU population in Pakistan.
Levels of baseline HCV and HIV infection were 42% and 3.4%
respectively amongst the 500 individuals recruited to the
study and the group reported high levels of risky behaviours
such as sharing of injecting equipment. During follow-up
the incidence of HCV and HIV were calculated to be 22 and
1.7 cases/100 person years.
Gabelia et al analysed
the risk factors for HIV
and HCV infection in 2406 adults in Georgia,
including over 900 IDUs. High injecting frequency and sharing
of drug using equipment were strongly associated with HCV
positivity (overall rate in IDUs 58.2%), as was previous imprisonment.
Rates of HIV infection in the IDU population were much lower
at 0.5% and there appears to be a low rate of spread of the
infection in this group. This contrasts with a longitudinal
study in Vancouver suggesting increasing HIV incidence amongst
IDU over the last decade (abstract MoPe10.2P08).
Armenia,
until recently, had no access to ARVs (abstract MoPe11.4C01).
74 HIV-positive patients were screened for eligibility for
therapy (based on CD4 count and symptoms) and 29/74 were diagnosed
with HCV, highlighting the high rates of HCV coinfection in
many regions and the increased risk of complications secondary
to disease progression and drug associated toxicity in the
dual infected population.
An Argentinean
cohort analysis by Fay et al (abstract TuPe1/1C28)
assessed the frequency of HCV antibody positivity in 250 HIV
infected patients between 1997 and 2004. 48% were coinfected
with HCV, 87.5% of whom had evidence of active disease; HCV
RNA detectability was not related to risk group. Genotype
1 was the most prevalent subtype (72%), again not influenced
by risk group. 15% of HCV infected individuals were found
to have a positive HCV RNA but negative antibody leading the
authors to recommend HCV
RNA testing as a screening test in this population.
Finally,
a prospective serological study of 312 individuals attending
an out-patient unit in St Petersburg (abstract TuPe1.1C12)
detected coinfection with HIV and either HCV or HBV in 37%;
in total 27.1% tested positive for HIV-1 antibody and 26.9%
of these had a positive HBV surface antigen and 80.8% a positive
HCV antibody (over 75% of these individuals had a positive
HCV RNA). This study reiterates the frequency of HIV/HCV
coinfection in many populations.
In
contrast, a Romanian study by Benea et al (abstract
TuPe1.1C33) found relatively low rates of HCV infection in
their HIV-positive cohort (6.82%), reflecting the low levels
of IDU-associated infection.
Silva et al (abstract TuPe1.1C36) found that in a cohort of 2005
individuals 48% had not been screened for HCV and of those
who had undergone testing, 10.9% were HCV-positive. All clinicians
should test newly presenting individuals for hepatitis
A, B and C and vaccinate and retest as appropriate.
HCV Therapy
It is
well-established that rates of success when treating HCV are
lower in those coinfected with HIV than in moninfected individuals.
Neumann et al (abstract WePp0304) studied
HCV
kinetics in an attempt to predict rates of
sustained virological response (SVR) in a group coinfected
with HIV and HCV
(genotype 1).
23 patients (11 Caucasian and 12 African-American) were treated
with weekly Pegylated
interferon alpha-2b (PegIntron) dosed at 1.5mcg/kg and 1200mg
ribavarin once daily for 48 weeks.
HCV
RNA quantification assays were performed to
monitor viral kinetics during therapy. The results revealed
a rapid early phase decline in HCV RNA between day 1 and 3
followed by a transient day 3-7 rebound in 22/23 patients.
The day 1-3 decline and the mean decline at day 7 were significantly
greater in Caucasians.
A second
phase decline occurred between week 1 and 4, again significantly
faster in Caucasians; this second decline correlated with
viral load at day 3 (p<0.003).
A number
of factors were found not to correlate with viral kinetics
including age, gender, baseline ALT
and CD4
cell count. Sustained
viral response (SVR) was achieved in 4/21 patients;
absence of SVR could be predicted with 100% negative predictive
values by a viral load > 5 log copies/ml at day 28 or day
3.
High
rates of HCV RNA clearance in response to weekly Peg-IFN (Alpha-2b)
1.5mcg/kg and daily ribavirin (800-1000mg/day) were demonstrated
in an open-label, prospective study amongst 17 HIV/HCV coinfected
individuals in Moscow (abstract TuPe1.1C01).
In this
population 87% were IDUs and approximately 50% were HIV virologically
controlled on HAART. 11 (65%) achieved biochemical and virological
response at 4 weeks (defined as transaminase normalisation
and negative HCV RNA respectively) and 15 (88%) had negative
HCV RNA levels at 12 weeks. The same number had an undetectable
HCV RNA at the end of therapy and of the 9 who were followed-up
to 48 weeks, all remained undetectable. Only 2 (15%) discontinued
therapy prior to 24 weeks. The genotypes were not specified.
In order
to assess the impact of adverse
events (AEs) on rates of treatment success
in HIV/HCV coinfection, Sulkowski et al (abstract
TuPe1.1C19) analysed data from APRICOT.
This
trial compared three therapeutic strategies, pegylated
interferon alfa-2a (PEGASYS) with ribavirin,
peginterferon
alone and standard
interferon with ribavirin, all for 48 weeks
duration. ‘Safety events’ included treatment-related serious
adverse events (AEs), premature withdrawal secondary to AEs,
laboratory abnormalities (neutropenia, thrombocytopenia and
anaemia) and depression; Sustained viral response (SVR) was
defined as HCV RNA <50 IU/ml at the end of follow-up (week
72).
Among
patients treated with peginterferon/ribavarin, treatment-related AEs and
AEs leading to withdrawal of therapy were associated with
the greatest reductions in SVR rates; laboratory abnormalities
and depression
had minimal impact on SVR in this group. These results suggest
that the prevention or treatment of AEs may improve rates
of SVR to HCV treatment.
Another
analysis of APRICOT was presented by Lissen et al
(abstract TuPe1.1C21). Following the superior SVR rates achieved
with peginterferon/ribavirin compared with peginterferon monotherapy
and conventional interferon plus ribavirin, they analysed
the histology of individuals with baseline bridging fibrosis
or cirrhosis.
All individuals fulfilling these histological criteria at
baseline, with paired biopsy samples (15 months or less prior
to randomisation and 56 or more days after treatment) were
included in the analysis. Biopsies were rated using the Ishak-modified
system to assess changes in histological activity index (HAI)
or fibrosis score.
Overall
peginterferon/ribavirin was shown to have the greatest impact
on fibrosis and HAI scores with a mean reduction of 0.2 (SD1.5)
and 2.5 (SD 2.7) respectively. The greatest improvements
were achieved in cirrhotics with a mean reduction in HAI of
3.3 (SD 3.5) and in fibrosis score of 0.6 (SD 1.3). Histological
response (HR) was shown to be independent of SVR; HR was seen
in 80% of individuals with SVR but also in 58% of those who
failed to achieve SVR. The lowest HR was observed in the
peginterferon
monotherapy arm.
This
study supports the use of therapy even in patients with advanced
HCV infection as improvements in HAI and fibrosis can be expected.
The lack of association between histological response and
SVR may support full treatment courses even in individuals
who experience a suboptimal viral response at 12 weeks.
Also
extracted from the APRICOT database, Soriano et al
(abstract TuPe1.1C23) analysed the rates of SVR achieved with
peginterferon/ribavirin in subjects infected with HCV
genotype 4. In HCV monoinfection similar,
relatively poor SVR rates are seen in genotype 1 and 4 infection.
In APRICOT only 7% (60/860) of individuals had genotype 4
and 38% of this group experienced SVR; SVR rates were influenced
by baseline viral titre (27% SVR if >800,000IU/ml and 60%
if <800,000IU/ml).
Overall
the SVR rate in those with genotype 4 was similar to the overall
rate seen in APRICOT (40%) suggesting slightly higher SVR
rates for genotype 4 than genotype 1.
Interferon and HIV Replication
Neumann et al (WePe3.3C17)
studied HIV kinetics in 23 HIV-infected patients coinfected
with genotype 1 HCV (mean CD4 cell count 612 cells/mm3)
receiving peginterferon alpa-2b and ribavirin for 48 weeks.
In the 9 subjects with a detectable HIV RNA there was a steady
decline in HIV viral load during the first week of HCV therapy
and the authors suggest that this is indicative of interferon
suppressing de-novo HIV infection; in vitro studies are ongoing.
Liver Biopsy in Patients with Normal ALT
The question
of whether liver
biopsy is useful in individuals with normal
liver function tests remains controversial. Sanchez-Conde
et al (abstract TuPe1.1C42) performed liver biopsy
in 256 HIV/HCV coinfected subjects over a 5 year period.
9.4% had a persistently normal
ALT (PNALT) defined as two or more normal measurements
within 6 months and their biopsy results were compared with
those in individuals with elevated ALTs. PNALT was found
to correlate with lower fibrosis scores (p<0.001) but approximately
1 in 4 had significant fibrosis (F2), supporting the use of
liver biopsy in patients with PNALT.
Treatment of Acute HCV
Increasing
detection of acute
HCV infection has raised interest in early
treatment. HIV negative individuals have very high rates of
HCV clearance, approaching 100%, when treated with standard
interferon alone.
A group
of 50 homosexual men attending the Chelsea & Westminster
hospital (abstract TuPe1.1C10) were diagnosed with
acute HCV infection (44 during investigation for liver enzyme
abnormalities, 4 following sexual contact with an HCV-infected
partner and 2 during screening at HIV seroconversion). Sequential
HCV RNA measurement was performed at 0, 4,12,24,32 and 48
weeks; 24 weeks therapy with 1.5mcg/kg/week Peg-IFN (alpha-2b)
and weight-adjusted ribavirin was offered to subjects who
after 12 weeks had a positive HCV-RNA or earlier in the face
of a rising RNA level.
12 individuals
became HCV-RNA negative spontaneously; this was significantly
associated with a higher median CD4 count (p=0.029), CD4 count
>500 (p=0.017) and lower HCV RNA level at diagnosis (p=0.017).
Of those offered treatment, 27 accepted and 16 (59%) experienced
SVR; SVR was associated with a higher peak mean ALT (p<0.001)
but not with genotype.
This
study demonstrated a high level of spontaneous HCV
seroconversion but lower rates of SVR compared
to the results achieved in HIV-negative subjects. The factors
associated with spontaneous clearance of HCV-RNA have not
been clearly elucidated.
Grebely et al (abstract
TuPe1.1C18) analysed data from the CHASE Project, a prospective
cohort study in Vancouver in an area with high rates of injecting
drug use. 523/1202 HCV antibody positive subjects underwent
HCV-RNA testing between 1991 and 2004.
Excluding
individuals who had undergone HCV treatment previously the
analysis revealed a negative correlation between HIV infection
and spontaneous HCV clearance (adjusted OR 0.41; p=0.007).
Reinfection
was observed in 5.7% of those achieving spontaneous HCV clearance.
Response to HAART in HCV-infected Subjects
Although
HIV has been shown to accelerate the progression
of HCV, a number of previous studies assessing
the impact of HCV coinfection on HIV disease have yielded
conflicting results. Sullivan et al (abstract
TuPe1.1C05) performed a retrospective, multicentre analysis
of patients commencing HAART between 1998 and 2003. They
analysed changes in viral load and CD4 cell count to test
the hypothesis that viral load reduction during the first
30 days of HAART and CD4 rise during the first year differ
in HIV-positive individuals with and without HCV.
18% of
the 1531 subjects included were coinfected with HCV but this
was not associated with attenuation of virological or immunological
response to HAART; the only patients to experience inferior
response to ARVs were those with coinfection and previously
diagnosed alcoholism.
The difficulties
in assessing the impact of HCV on response to HAART were highlighted
by the CASCADE collaboration (abstract TuPe1.1C13). Pre-HAART
(i.e. pre-1996) data from 22 HIV-seroconvertor cohorts were
pooled to assess the effect of HCV on time from seroconversion
to death and on virological
response to HAART.
6053
seroconvertors were included, 1405 of whom died. 22%, 25%
and 53% were HCV-positive, negative and untested respectively.
After adjustment for known prognostic factors, previous ARVs
and baseline HIV viral load, a positive
HCV antibody was associated with a significantly
lower risk of death compared with the untested population
(RR=0.18; p<0.001).
2322
individuals subsequently commenced HAART of who 22%, 42% and
36% were HCV-positive, negative and untested. >90% of
IDUs were coinfected compared with <16% in other groups,
and after adjusting for IDU status there was no effect of
HCV on likelihood of achieving an undetectable viral load
(p=0.69).
The
authors conclude that HCV positivity may contribute to the
inferior virological responses seen in IDUs but the high prevalence
of HCV in this group makes it difficult to assess accurately.
In another
study Moore et al (abstract TuPe1.1C15) performed
a survival
analysis on 721 HIV monoinfected and 673 HIV/HCV
coinfected patients initiating HAART between 1999 and 2003.
Crude mortality rates were 8.6% and 18.1% in the mono and
coinfected groups respectively (p<0.001). After adjustment
for age, VL, IDU status and adherence
to HAART the baseline CD4 associated with increased
mortality were similar for HIV/HCV coinfected individuals
compared with those infected with HIV alone. This was interpreted
as suggesting no benefit to earlier HAART for HCV coinfected
subjects.
Impact of HCV on HIV
A number
of cohort analyses have suggested an increased risk of non-Hodgkins
lymphoma (NHL) in HCV moninfected populations. NHL is greatly
increased in HIV-infection and a UK cohort analysis examined
the relationship between HCV and NHL in HIV-infected individuals
(abstract TuPe1.1C09). 102 cases of NHL occurred in
5832 HIV-infected subjects but the incidence of NHL did not
differ between those with HIV/HCV coinfection and those with
HCV alone.
HAART Pharmacokinetics in Coinfected Patients
In the
cross-sectional HEPADOSE Study (abstract WePp0305)
the Cmin of various ARVs were compared between 66 HIV monoinfected
and 73 HIV/HCV coinfected patients. The coinfected group
had all undergone liver biopsy within the last 2 years and
the groups were matched for sex and antiretroviral agents.
The median
Cmin for protease
inhibitors were similar in the coinfected and
monoinfected individuals except for Lopinavir (LPV) which
was found to be significantly lower in the coinfected group
(p=0.04). For NNRTIs,
efavirenz/EFV
(Sustiva) and nevirapine/NVP
(Viramune) concentrations were both higher
in the presence of coinfection and these elevations correlated
significantly with hepatic fibrosis score; stage F4 fibrosis
was correlated with an 86% increase above the expected concentration
in NNRTI Cmin and stage F0-3 with a 56% elevation (p=0.01).
In
summary, lopinavir levels were unexpectedly decreased and
NNRTI levels increased in HIV/HCV coinfected patients; the
authors recommend the use of TDM
in this population.
However,
another analysis of lopinavir/ritonavir
(LPV/r; Kaletra) pharmacokinetics, presented
by Dickinson et al (WePe3.2C06) , quantified LPV concentrations
in 39 patients : 13 HIV monoinfected, 26 HBV or HCV coinfected
of whom 7 were cirrhotic. The area under the curve (AUC)
for both total and unbound LPV levels was unchanged in the
coinfected group.
Safety of ARVs in Coinfected Patients
Coinfection
with HIV and HBV or HCV may increase the risk of ARV-related
hepatotoxicity
and a number of studies addressed this issue.
The impact
of single PI, boosted PI and NNRTI based therapy on liver
enzymes in HIV/HCV coinfection was assessed Torti et al
(abstract TuPe1.1C14). Prospectively collected data from
an Italian cohort of 1038 HIV/HCV coinfected individuals was
used to construct a multivariate model including ARV history,
HBV status, CD4 and VL.
In
naïve patients (n=155) the risk of grade 3/4 transaminase
elevation was 17.1% per patient year; baseline ALT (HR=1.118;
p=0.029) and CD4 increment (HR=1.112; p=0.045) were the only
factors significantly associated with hepatotoxicity.
Hepatotoxicity
incidence and risk factors differed in experienced patients
(n=883). 8.22% per patient year developed grade 3/4 AST/ALT
rise; baseline ALT (HR=1.137 per 10 IU/l; p<0.001), previous
hepatotoxicity (HR=3.051; p<0.001) and NNRTI use (HR=2.752;
p<0.001) were significant risk factors; nevirapine was
associated with a greater risk of hepatotoxicity than efavirenz.
The
authors advised strict monitoring in ARV-experienced patients
with elevated ALT, previous hepatotoxicity or on NNRTI-containing
regimens.
In contrast,
Konopnicki et al (abstract TuPe2.1B03) found
that PI
and NRTI
agents but not NNRTIs were associated with hepatotoxicity
in HIV-infected individuals with chronic hepatitis. Of the
293, 770 and 488 subjects starting a triple NRTI, PI-based
or NNRTI-based regimen respectively, 13% were HCV and 5% HBV
coinfected. A >2 grade increase of at least one liver
enzyme was more frequent in the coinfected than monoinfected
group on a PI (24% vs 12%; p=0.0004) or triple-NRTI (14% vs
4%; p=0.02).
Multivariate
analysis of the PI group revealed chronic hepatitis to be
an independent risk factor for hepatotoxicity (OR 1.87; p=0.02)
while female sex (OR 0.42; p=0.002) and CD4 >250 cells/mm3
(OR0.47; p=0.004) were protective. Single or ritonavir-boosted
PI based therapies were not associated with
hepatotoxicity in naive or experienced coinfected subjects.
DeJesus et al presented
data confirming the safety of ritonavir-boosted fosamprenavir/
FPV/r (Lexiva) in therapy naïve individuals
coinfected with HBV or HCV (TuPe1.1C03). Subjects coinfected
with HBV or HCV could be enrolled into the SOLO
study if hepatic transaminase levels were not
in excess of 5 x ULN within 28 days of randomisation.
322 patients
enrolled in the SOLO study were randomised to receive fosamprenavir/r
and 211 continued into APV30005 (the SOLO rollover); a subanalysis
assessed liver enzymes and adverse events. 45/211 (21%) were
hepatitis coinfected at study entry, 20 (9%) with HBV (surface
antigen positive) and 26 (12%) with HCV (HCV antibody positive).
Median
baseline ALT and AST were higher in the coinfected patients
but there was a median decrease in liver transaminase levels
by week 120 in both patient groups; by week 120 5/164 (3%)
of moninfected and 13/45 (29%) had experienced a grade 3/4
ALT rise; however, only 3 new cases developed in each group
after week 48.
Of note,
there were 2 new cases of grade3/4 AST elevation in the monoinfected
subjects but none in the coinfected group Over 120 weeks
the numbers experiencing drug-related adverse events (AE)
overall were similar in the 2 groups. 44% of the coinfected
individuals experienced a grade2-4 drug-related AE compared
with 43% of those infected with HIV alone; the rates of serious
drug-related AEs were 11% and 10% respectively.
Overall
the authors concluded that ritonavir-boosted fosamprenavir
administered once daily had similar rates of AEs in HIV moninfected
and coinfected subjects; at 120 weeks there was a median decrease
in transaminase levels in both groups.
The safety
of abacavir(ABC)/lamivudine(3TC)
based HAART in naive subjects was assessed by Zhao et
al (abstract TuPe1.1C16) in an analysis of 4 randomised
trials using ABC/3TC once or twice daily in combination with
efavirenz (EFV) or a PI.
Safety
data were compared between individuals coinfected with HBV
(positive s-antigen) or HCV and those with HIV monoinfection.
20% of the 1985 subjects included were coinfected with HBV
and/or HCV. Baseline characteristics in the two groups (coinfected
vs monoinfected) were similar, as was the overall incidence
of adverse events (AEs) with 71% in each group reporting grade
2-4 AEs over 48 weeks. In addition the incidence of specific
AEs was also comparable.
Atazanavir
(Reyataz) safety was assessed by Perez-Elias
et al (abstract TuPe1.1C25) by comparing 180 coinfected
(‘Hep’) and 124 monoinfected (‘noHep’) prospectively recruited
into an early access study of ritonavir-boosted
atazanavir (ATV/r) based HAART. 67% Hep and
73% noHep individuals reached at least 6 months of follow-up.
Similar
rates of virological success (<500 copies/ml) were achieved
in both groups (approximately 75%) with 9.4% Hep and 5.6%
of noHep patients discontinuing treatment secondary to AEs.
Only 3 individuals (1.7%) were withdrawn for elevated liver
enzymes.
With
respect to scleral icterus and jaundice, 4.4% of the Hep
group and 3.2% the noHep group discontinued therapy for this
reason. Overall ATV/r-based HAART was concluded to be a safe
treatment option for those coinfected with HBV or HCV.
Ammassari et al (abstract
TuPe1.1C29) prospectively monitored transaminase and plasma
drug levels in 251 patients commencing HAART. Overall, liver
enzyme elevations were more frequent in patients reporting
poor adherence and those with suboptimal or undetectable drug
levels. No particular group of ARVs was associated with raised
ALT though in multivariate analysis, HCV coinfection and duration
of ARV exposure were (RR=2.71; p=0.04 for HCV, RR=1.44 per
year of ARV exposure; p=0.001).
The
same study showed no difference in hepatotoxicity in patients
receiving NNRTIs or lopinavir/r, there was also no relationship
between liver enzyme elevations and trough NNRTI levels (abstract
TuPe1.1C39).
To specifically
address the issue of HAART-related hepatotoxicity in HIV/HCV
coinfected individuals with advanced liver disease, Aranzabal
et al (abstract TuPe1.1C38) prospectively followed
195 individuals undergoing liver biopsy between 2000 and 2004.
They
found HAART-associated hepatotoxicity to be closely related
to HCV-related histological liver damage.
The presence
of HBV surface antigen (p=.01), increased baseline ALT (p=0.04)
and longer duration of HCV infection (p<0.01) were associated
with more advanced (grade 3-4) fibrosis. 47 patients developed
hepatotoxicity which, after adjusting for alcohol abuse, was
more frequent in those with grade 3-4 than 1-2 fibrosis (5
vs 2.3 cases/100 person years; p=0.02). HIV viral load, CD4,
HCV RNA and HCV
genotype were not associated with the risk
of hepatotoxicity.
In the
HEPATOX study presented by Aranzabal et al (TuPe2.3C25)
246 individuals who started HAART in 2004 were prospectively
monitored for hepatotoxicity. No associations with age, sex,
risk group, baseline CD4 or CD4 increment were detected and
only HCV was found to be independently associated with liver
enzyme elevations (RR=3.3; p<0.01). The overall rate of
hepatotoxicity was 4% over 100 days.
Finally,
in contrast to the above study, liver disease but not HCV
was shown to be predictive of HAART discontinuation by Uberti-Foppa
et al (TuPe2.1B04). A multivariate analysis of
526 patients commencing HAART found liver disease (low albumin),
but not HCV per se, to be associated with an increased risk
of stopping therapy.
Neuropsychological Function (NF) in HIV/HCV Coinfection
The suggestion
that HIV/HCV coinfection may be associated with greater impairment
in neurological
function (NF) than HIV alone was explored by
Munoz-Moreno et al (abstract TuPe1.1C35). In
a descriptive, observational study of 50 patients (10 coinfected)
NF, anxiety and depression scores, premorbid intelligence
and contributing HIV-related factors were assessed. A number
of differences were elicited between the two groups and HIV/HCV
coinfected subjects showed significant impairment in a number
of functions compared with their moninfected counterparts.
ARVs and HCV RNA
In order
to determine the effect of ARVs on HCV replication Braitstein
et al (abstract TuPe1.1C30) performed HCV RNA tests
on 118 HCV antibody-positive/RNA-negative individuals 6-12
months after commencing ARVs. 20% (24/118) became RNA-positive
suggesting that HIV therapy may affect HCV replication with
increased replication occurring as part of immune restoration
disease. This finding which is difficult to
explain needs to be assessed in other cohorts.
HBV Epidemiology
The afore-mentioned
study by Benea et al also calculated the prevalence
of HBV infection in their HIV cohort. Nearly 40% had at least
one marker of HBV infection and 13.53% were surface antigen
positive.
Similar
rates of active HBV infection (14.8%) were found in a Nigerian
clinic by Agbaji et al (abstract TuPe1.1C34).
This is an important issue in areas where agents active against
HBV may not be routinely available.
A
Brazilian HBV/HCV prevalence study (abstract TuPe1.1C36) found
that almost 28% of HIV-infected individuals had not been screened
for serological markers of HBV. 45.9% remained susceptible
to HBV emphasising the importance of screening for, and vaccinating
against, HBV.
Likewise,
a retrospective analysis in Venezuela found 70% of the 733
screened for HBV to be in need of vaccination.
HBV Prevention
Vaccination
against HBV is established as a safe and efficacious method
to protect against acquisition of HBV in high risk groups.
Health care workers are amongst those for whom routine vaccination
is usually recommended. A study of HCWs in Uganda found that
74% had not been tested for, or vaccinated against, HBV (abstract
MoPe11.10C28). A survey of HCWs in Pakistan reported that
60% had experienced one needle stick injury over an average
of 5 years but only 50% were HBV vaccinated.
Sud et al (abstract
TuPe1.1C41) confirmed previous analyses showing the success
of HBV vaccination in HIV-infected individuals depends on
CD4 cell count at time of vaccination. Subjects with a CD4
count <200 (n=13) produced lower titres of sAb than those
with a CD4 count >200 (n=27); p<0.05. However, even
those with a CD4 count >200 achieved lower titres than
HIV negative controls (n=20; p=0.05).
Impact of HAART on Liver-related Death
Liver
disease has emerged as the most frequent cause of mortality
in the HAART-era in a number of studies and a common cause
of morbidity in HIV-infected individuals.
Sanchez-Somolinos et al
(abstract TuPe1.1C32) performed a retrospective review of
hospital admissions in 2514 patients between 1996 and 2004,
the majority of whom were IDUs (82%). Decompensated chronic
viral liver disease (CVLD) was either the cause of or developed
during admission in 14% overall and increased significantly
between 1996 and 2001 (9.1% vs 15%) but decreased significantly
between 2001 and 2004 (11%). The same was found to be true
for liver-related deaths, accounting for 9%, 53% and 23% of
mortality in 1996, 2001 and 2004 respectively. Admissions
secondary to HAART-related hepatotoxicity increased after
2000.
Puoti et al (abstract
TuPe1.1C06) performed an analysis of 13 cohorts of HIV/HBV
coinfected patients who commenced HAART with liver
related death (LRD) as the study end-point.
The investigators defined LRD as death with concomitant decompensated
liver disease (DLD) or hepatocellular
carcinoma (HCC) in the absence of other causes
and calculated the impact of lamivudine (3TC) on LRD. 2041
individuals were included in the analysis amounting to 7648
patient years of follow-up on HAART, 5569 of those years 3TC-containing.
There
were 217 deaths during the study period and 57 of these were
defined as LRD; 38/57 had information available on previous
liver morbidity and 21 (55.3%) of these had experienced DLD
or HCC. A model was constructed including the 57 subjects
with LRD and the RR of LRD per year of 3TC use was calculated
to be 0.73 (95% CI 0.59-0.90; p=0.004).
Other
factors significantly associated with LRD were age with significantly
greater LRD per 10 years (p=0.003) and low CD4 cell count
(per 100 cell reduction; p=0.0001). The impacts of other
nucleoside
analogues (AZT, d4T, ddI and ddC) were analysed
and none were found to be associated with the rate of LRD
(p-values 0.1, 0.84, 0.97 and 0.28 respectively).
The
authors concluded that the use of 3TC within HAART is associated
with a reduction in LRD in HIV-infected subjects coinfected
with HBV or HCV over a 4 year period but acknowledge that
longer-term data are needed to verify this benefit despite
the development of the YMDD
mutation.
In another
presentation Puoti et al (TuPe2.3C26) prospectively
followed 812 individuals form 1997/1998 amounting to over
4000 patient years of follow-up. 46/129 deaths were liver
related and a number of factors were associated including
HCV infection (HR=9.2; p=00024), HBV infection (HR=2.7; p=0.0025),
alcohol abuse (HR=2.7; p=0.0017), occurrence of life-threatening
HAART-related hepatotoxicity (HR=5.8; p<0.0001) and HAART
initiation at a CD4 <350 cells/mm3.
Use
of HAART was found to be independently protective against
liver related death (HR=0.31; p<0.0001).
HBV Therapy
The use
of 3TC
(Epivir-HBV) monotherapy for the treatment
of HBV is associated with high rates of 3TC resistance, particularly
in HIV/HBV coinfected individuals. In contrast, HBV resistance
to the nucleotide analogue
tenofovir/ TDF) is uncommon. Whether initial
combination therapy with 3TC and TDF is superior to sequential
therapy with 3TC then TDF has not been determined.
Mauss et al (abstract
TuPe1.1C07) undertook a multicentre 1:2 matched pair study
comparing HIV/HBV coinfected subjects commencing TFV/3TC-containing
HAART with patients who had highly replicative, genotypic
3TC-resistant HBV who commenced TFV-based therapy
in the absence of other active anti-HBV agents.
Baseline
HBV-DNA was similar in the two groups, 56 million copies/ml
and 89 million copies/ml in the TFV/3TC (n=21) and TFV-only
(n=42) groups respectively (p=0.96). Both groups experienced
similar and strong HBV-DNA suppression at 3 and 12 months.
Sustained suppression of HBV-DNA (<1000 copies/ml) was
achieved in 18/21 (86%) on TFV/3TC and 33/42 (78%) on TFV
alone (p=0.74). HBV e-antigen seroconversion occurred in
6/19 on TFV/3TC and 12/38 on TFV (p=0.77) and loss of s-antigen
was seen in 1/21 and 4/42 patients respectively (p=0.66).
The investigators
concluded that in coinfected individuals the use of TFV after
the development of 3TC resistance was as effective as TFV/3TC
in terms of HBV-DNA suppression and e-antigen/s-antigen loss.
The durability of these responses will be assessed in continued
follow-up.
Occult HBV
10-18%
of individuals with HIV/HBV coinfection develop anti-core antibody (HBVcAb) in the absence
of neutralising surface
antibody (HBVsAb). 955 patients were screened
for HBV markers, including HBV DNA in cAb+/sAb- patients,
by Marino et al (abstract TuPe1.1C31). 19.9% tested
positive for cAb alone; 6.9% had detectable HBV DNA (between
102 and 103 copies/ml). Further follow-up
showed HBV DNA positivity to be intermittent and to occur
in 14.3% of cAb+/sAb- patients over a 6-12 month period.
These individuals did not demonstrate clinical or laboratory
abnormalities. The authors advise that longitudinal HBV DNA
detectability is required to form a diagnosis of occult
HBV infection.
Decompensated Liver Cirrhosis in HIV-infected Patients
A Spanish
cohort analysis studied 110 HIV-infected patients who developed
DLD between 1990 and 2003 (abstract TuPe1.1C08). Subjects
were sub-divided according to date of first decompensation;
group A (pre-HAART) 1990-1996 and group B (HAART) 1997-2003
contained 48 and 62 individuals respectively.
Of the
110, 81% were coinfected with HCV and 34.5% with active HBV.
The 4 commonest initial events were ascites
(89%), hepatic encephalopathy (19%), gastrointestinal bleeding
(7%) and spontaneous bacterial peritonitis (6%).
Comparison
between groups A and B revealed those in group A to be younger
(32 vs 38 years; p<0.01), less frequently on ARVs (29%
vs 56%; p=0.012) and with lower mean CD4 counts (134 vs 197;
p=0.09).
HIV risk
factor, cause of cirrhosis, Child-Pugh classification at first
decompensation and subsequent complications did not differ
significantly between group A and B. Median survival after
decompensation was 6 months and significantly associated with
Child-Pugh classification.
The cumulative
12 month survival after decompensation was the same for the
two time periods, 35% for group A and 34% for B (p=0.85).
However, death secondary to liver disease was commoner in
the HAART era (81.8% of deaths compared to 60% pre-HAART;
p=0.024).
This
study confirms the poor survival associated with decompensated liver cirrhosis and highlights
the need for rapid consideration of transplant
in these patients.
Cicconi et al (abstract
TuPe1.1C24) evaluated the incidence, risk factors and outcomes
for decompensated cirrhosis (DC) in the I.Co.N.A cohort.
The incidence of DC was 1.85/1000 person years in the 5138
individuals included and not influenced by calendar year after
adjustment for other variables.
Factors
associated with an increased risk of DC were IDU (RR=17.31
vs heterosexuals; p=0.0005) and increased age (RR=1.66 per
10 years; p=0.06); different ARVs were not found to influence
DC risk. DC was shown to be an independent risk factor for
death (RR=8.5; p=p<0.0001) with a median survival of 126
days after diagnosis of DC and a 2 year survival rate of 10.8%.
Hepatocellular Carcinoma in HIV/HCV Coinfection
Since
the huge reductions in HIV-related mortality in the HAART-era,
longer-term consequences of coinfection have emerged. HCV
is associated with a marked increase in the risk of developing
hepatocellular
carcinoma (HCC).
A European
study previously suggested shorter survival in HIV/HCV infection
than HCV alone leading Brau et al (abstract
TuPe1.1C17) to perform a retrospective chart review of HCV-infected
individuals with HCC with and without HIV co-infection. 41
coinfected HCC cases from 15 US and Canadian centres between
1992 and 2004 were identified and compared with 119 HCV-monoinfected
cases during the same time period.
Looking
at baseline demographics, 99% of the subjects were male.
The median CD4 cell count and HIV viral load at time of HCC
diagnosis were 273 cells/mm3 and 529 copies/ml
respectively.
The results
demonstrated a number of differences between the two groups.
Mean age at HCC diagnosis was significantly lower in coinfected
than monoinfected subjects (52.4 vs 61.1 years; p<0.001)
despite similar ages at HCV infection (25.5 and 23.9 years
respectively; p=0.46).
This
was mirrored by the duration of HCV infection prior to the
development of HCC, 26.4 years in the coinfected group and
35.2 years in monoinfected subjects (p<0.001).
In
addition, amongst coinfected individuals, median alpha-fetoprotein
(AFP) levels were significantly higher (1274ng/ml vs 192ng/ml;
p=0.02), rates of portal vein thrombosis were lower (10% vs
26%; p=0.03) and the incidence of multifocal HCC was higher
(58% vs 36%; p=0.011).
The study
also found that HIV-coinfected patients were more likely to
receive HCC treatment than those with HCV alone (56% vs 36%;
p=0.025).
In terms
of prognosis the presence of symptoms at diagnosis, HCC therapy
and AST/ALT ratio were all predictive of survival in a multivariate
analysis.
Elevated
AFP levels were only predictive in HCV-monoinfected patients
and CD4 cell count and HIV viral load were not associated
with survival rates in HIV-coinfected individuals. There
was no difference in survival between moninfected and coinfected
individuals (83.2% vs 80.5% mortality respectively).
Impact of HTLV-2 on HCV Replication
HTLV-2
is common in HCV patients. Toro et al (abstract
TuPe1.1C27) examined HCV RNA levels and rates of spontaneous
clearance in HIV/HCV coinfected subjects. 18.9% were also
infected with HTLV-2 but there was no impact on either of
the measured parameters.
Blood Transfusion
The risk
of viral blood-borne infections from transfusion of contaminated
blood are inarguable. Erhabot et al (WePe10.6P01)
tested 1500 blood donors in Nigeria for HIV, HBVsAg and HCV
antibody demonstrating prevalences of 1%, 1.1%
and 0.5% respectively; these were higher in remunerated donors
(1.45, 1.7 and 0.8%). The authors called for immediate implementation
of mandatory and universal donor screening.
Conclusions
Coinfection
with hepatitis viruses in the HIV-infected individual continue
to be of concern. Although there has been a rapid increase
in epidemiological
research on
this subject, the practicing physician is still hampered by
the lack of choice of agents to treat hepatitis infections
and whether the results of clinical trials on the monoinfected
patient can be translated into the dually infected population.
As
new drugs are developed it is important that they are studied
in the coinfected population.
09/09/05
Index
of HIV-HCV Coinfection Articles by Topic
Acute HCV in HIV Coinfection
Adherence
(HCV Drugs) / Adherence
Age
ALT
(alanine aminotransferase)
ALT
flares
AST
(aspartate aminotransferase)
Anemia
(ribavirin-related)
APRICOT
Trial (HAART plus Pegasys/Copegus)
Body
Mass Index
CD3+,
CD8+, CD4+ Cells/ Cell Count
Children and Infants
Cirrhosis / Cirrhotic
Patients
Clinical
Trials
Cognitive
Functioning
Combination
Therapy
Conferences/ Workshops
on HIV-HCV Coinfection
Depression
(HCV-related)
Developing
Countries
Discontinuation
of HAART or HCV Therapy in Coinfected Patients
Dosing
(standard interferons)
Dosing
(peginterferons: Pegasys or Peg Intron)
Dosing
(ribavirin)
Dosing
(HIV drugs)
Drug
Interactions
End-of-Treatment
Response (ETR)
Epidemiology
Erythropoietin
Experimental
Treatments
Extrahepatic
Complications
FDA-approved
Anti-HCV Treatments
FDA-approved
Anti-HIV Treatments
FDA-approved
HIV-HCV Coinfection Treatments
Fibrosis
/ Fibrosis progression
Filgrastim
DNA
Polymorphisms
Gay
Men
Genotypes
(general)
Genotypes
1 and 4
Genotypes
2 and 3
Genotypes
(multiple coinfection)
Genotypes
non 1,2,3,4
Growth
Factors
Guidelines
for Treatment of HCV
HAART
HAART
and Hepatotoxicity
HAART
(PI-based)
HCV
Clearance (eradication)
HCV
as Cofactor for HIV Disease Progression
HCV
Core Antigen
HCV
Disease Progression
HCV
Drug-related Toxicities/Side Effects
Pegasys/
Copegus
Peg
Intron / Rebetol
HCV
Mortality in HCV-HIV Coinfection
HCV
RNA (HCV Viral Load)
HCV-related
brain damage
HCV
Quantitative Assay (TRAK-C)
HCV
Viral Load
Hemophilia
Hepatic
Decompensation / Hepatic impairment
Hepatocellular
Carcinoma (HCC)
Hepatomegaly
Histological Response
(HR) Rate / Histologic Progression
HIV-HCV-HBV
triple coinfection
HIV
as Cofactor for HCV Disease Progression
HIV
Disease Progression
HIV
Drug-related Toxicities/Side Effects
HIV
RNA (HIV viral load)
Immune
Responses / Immune Restoration
Immune
Suppression
Injection
Drug Users (IDU)
Interferon
(IFN): standard interferon alfa-2a (Roferon A)
Interferon
(IFN): standard interferon alfa-2b (Intron A)
Interleukin-2 (IL-2)
Jaundice
Lipodystrophy
in HIV-HCV Coinfection
Liver
Biopsy
Liver
Disorders
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