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SPECIAL ARTICLE

Management and treatment of hepatitis C virus in

patients with HIV and hepatitis C virus coinfection:
A practical guide for health care professionals
Pierre Côté MD1,2*, Jean-Guy Baril MD1,2,3*, Marie-Nicole Hébert MUrb3*, Marina Klein MD FRCPC4,
Richard Lalonde MD FRCPC4*, Marc Poliquin MD FRCPC2, Danielle Rouleau MD MSc FRCPC2*,
Rachel Therrien MSc BPharm2*, Sylvie Vézina MD2,5, Bernard Willems MD FRCPC2, Harold Dion MD5,6*,
Patrice Junod MD2*, Normand Lapointe MD7*, Dominic Lévesque RN8*, Lyse Pinault9*,
Cécile Tremblay MD FRCPC2*, Benoît Trottier MD2,5*, Sylvie Trottier MD MSc FRCPC10*,
Chris Tsoukas CM MD FRCPC4*, Alain Piché MD11*

P Côté, J-G Baril, M-N Hébert, et al. Management and treatment La prise en charge et le traitement du virus de
of hepatitis C virus in patients with HIV and hepatitis C virus
coinfection: A practical guide for health care professionals. Can
l’hépatite C chez des patients co-infectés par le
J Infect Dis Med Microbiol 2007;18(5):293-303. VIH et le virus de l’hépatite C : Guide
pratique pour les professionnels de la santé
Concomitant HIV and hepatitis C virus (HCV) is a common yet
complex coinfection. The present document is a practical guide for La co-infection par le VIH et le virus de l’hépatite C (VHC) est courante,
treating HCV infection in people coinfected with HIV. Effective anti- mais complexe. Le présent document se veut un guide pratique pour le
retroviral therapies have prolonged survival rates for HIV-infected traitement de l’infection par le VHC chez les personnes co-infectées par le
people over the past decade, which have made latent complications of VIH. Des thérapies antirétrovirales efficaces ont prolongé les taux de
HCV major causes of morbidity and mortality in these patients. survie des personnes infectées par le VIH depuis dix ans, ce qui fait des
Advances in the treatment of HCV (eg, combined pegylated interferon complications latentes du VHC des causes importantes de morbidité et de
and ribavirin) offer the possibility of eradicating HCV infection in mortalité chez ces patients. Les progrès dans le traitement du VHC (p. ex.,
coinfected persons. The treatment of HCV must be considered in all PEG-interféron associé à la ribavirine) offrent la possibilité d’éradiquer
cases. Intensive management of the adverse effects of HCV treatment l’infection par le VHC chez les personnes co-infectées. Il faut envisager le
traitement du VHC dans tous les cas. La prise en charge intensive des
is one of the factors for the success of these therapies. HCV eradica-
effets indésirables du traitement du VHC fait partie des facteurs de réussite
tion is predicted to decrease the mortality associated with coinfection
de ces thérapies. L’éradication du VHC devrait réduire la mortalité
and reduce the toxicity of HIV treatment.
associée à la co-infection ainsi que la toxicité du traitement du VIH.

Key Words: Antiretrovirals; Coinfection; Hepatitis C virus; HIV;

Practical guide

oncomitant HIV and hepatitis C virus (HCV) infection is VIH (Consultant Committee). This Quebec-based panel
C a complex and frequent problem. The increased survival
rates since 1996 for HIV-infected people following highly
includes members with extensive experience in the care of
HIV patients. They are mandated by the Ministère de la Santé
active antiretroviral therapy have led to latent complications et des Services sociaux (Ministry of Health and Social
of HCV becoming major causes of morbidity and mortality in Services) to establish clinical guidelines on the management
people living with HIV. Interactions with respect to pathogen- and treatment of persons living with HIV. A subgroup of the
esis, complexity of clinical management and treatment of panel, in conjunction with HCV experts, was formed to
HCV and/or HIV are a challenge for clinicians and the health develop the present practical guide to provide guidance to
care system. The present document is a practical guide for health care providers on the treatment of HCV in the setting
treating HCV infection in people coinfected with HIV. It pro- of HIV-HCV coinfection. These recommendations are based
motes optimal follow-up and comprehensive case management on the current standard of care in treatment, published clinical
by multidisciplinary teams. guidelines, literature review and extensive clinical expertise by
The current practical guide was developed by the Comité the members of the panel. Recommendations were obtained by
consultatif sur la prise en charge des personnes vivant avec le consensus, and a medical writing subcommittee was established.
1Clinique médicale du Quartier Latin; 2Centre hospitalier de l’université de Montréal; 3Service de lutte contre les infections transmissibles sexuellement
et par le sang, Ministère de la Santé et des Services sociaux; 4Centre universitaire de santé McGill; 5Clinique médicale l’Actuel; 6Collège québécois
des médecins de famille (Quebec College of Family Physicians); 7Hôpital Sainte-Justine, Centre maternel et infantile sur le sida; 8Comité des
personnes atteintes du VIH du Québec (CPAVIH); 9Coalition des organismes communautaires québécois de lutte contre le sida (COCQ-sida),
Montreal; 10Centre hospitalier universitaire de Québec, Sainte-Foy; 11Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec
*Members of the Comité consultatif sur la prise en charge clinique des personnes vivant avec le VIH
Correspondence and reprints: Dr Pierre Côté, Clinique médicale du Quartier Latin, 905, boul René-Lévesque Est, Montréal, Québec H2L 5B1.
Telephone 514-285-5500, fax 514-285-2226, e-mail [email protected]
Received for publication August 2, 2006. Accepted June 11, 2007

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TABLE 1 associated with an increase in the HCV viral load (2), which
Risk of transmission in the absence of treatment or can result in a decreased response to eradication treatments (2).
postexposure prophylaxis HIV has been associated with a faster progression toward
Event HIV HCV (reference) cirrhosis (29), hepatic decompensation and, in some cases,
High-risk sexual exposure 0.5%–3% Rare; 3% if hepatocellular carcinoma (30). Median progression for the
coinfected (2) development of cirrhosis in people with HCV-HIV coinfection
Percutaneous exposure (small amounts) 0.3% 1.8% (3) can occur up to 10 years earlier than in those with HCV infec-
Vertical transmission 20%–30% 2% to 5%; up to 36% tion alone. A 1997 cross-sectional study (30) comparing the
if coinfected results of liver biopsies showed a median interval to cirrhosis of
(9,12,16)
6.9 years in coinfected people, compared with 23.2 years in
HCV Hepatitis C virus monoinfected people. A more severe immunodeficiency (CD4
count less than 200 cells/μL) (31), consumption of more than
50 g of alcohol per day (equivalent to 3.6 standard drinks
The document was then reviewed and endorsed by the [where one standard drink equals one beer, one glass of wine,
Consultant Committee. These recommendations are not one aperitif or one hard liquor]) (31,32) and being older than
intended to be a formal review of the published literature or to 20 years of age at the time of HCV infection are independent
supersede the judgment of clinicians who are knowledgeable in aggravating factors in coinfection. The effect of HIV antiretro-
the care of HIV-HCV coinfected persons. This is an evolving viral therapy on the evolution of HCV is not known (33), but
science; the availability of new clinical data with existing some cases of decreased inflammation and fibrosis have been
agents and the availability of new therapeutic options periodi- reported (31).
cally change treatment options and preferences. The influence of HCV infection on the natural history of
HIV infection is less significant. Different cohorts have pro-
EPIDEMIOLOGY duced discordant findings, which can be explained by the selec-
It is estimated that approximately 20% of HIV-infected people tion bias of populations with negative prognostic factors for HIV,
in Canada are coinfected by HCV (1). The two viruses have including alcohol and substance abuse, poor nutritional status
certain common modes of transmission. HCV is approximately and low adherence with antiretroviral treatment. Antiretroviral
10 times more transmissible than HIV by percutaneous expo- hepatotoxicity may be increased in the presence of HCV (34)
sure to contaminated needles (2). Transmission of one or the and has been reported to result in more frequent treatment
other is frequent in cases of transfusion or use of coagulation interruptions in coinfected patients (35). A recent Canadian
factors, as evidenced by the high rate of coinfection in hemo- study (36) has shown that HCV seropositivity is an independent
philiacs before the universal implementation of blood donor predictor of mortality, especially death related to HIV infection.
screening (3,4). The risk of HIV transmission following a sin-
gle, high-risk, unprotected incident of sexual contact has been LABORATORY TESTS AND THEIR
estimated to be 0.5% to 3% (5). HCV sexual transmission is INTERPRETATION
rare (6,7). Vertical transmission of HIV from mother to child in Diagnosis of coinfection
the absence of antiretroviral therapy has been found to occur in HCV infection is diagnosed using a serological test for anti-
approximately 20% to 30% of cases (2,8). Vertical HCV trans- HCV. However, a positive anti-HCV test does not distinguish
mission is rare (2% to 5%) in mothers with HCV alone (2), but between the majority of patients with chronic infection and a
has been found to occur in up to 36% of mothers with HIV- minority of those who have spontaneously cleared the virus.
HCV coinfection (9,10). HIV-HCV coinfection also increases Hence, a positive anti-HCV test should be confirmed by a qual-
the risk of sexual transmission of HCV (2,7,11), particularly in itative HCV RNA polymerase chain reaction test. All HIV-
homosexual men (10,12). Transmission rates are shown in infected people should be screened for HCV infection. At HIV
Table 1 (13). The number of HCV carriers in Canada has been diagnosis, HCV testing should be repeated for those who were
estimated to be 250,000 (1). In studies examining injection initially HCV seronegative based on risk factors and clinical
drug users (IDUs) in two Canadian cities before 1999, the manifestations.
annual incidence of HCV was reported to be 26% in Vancouver In immunocompromised people, HCV infection can be
and 27% in Montreal. The prevalence of HCV among IDUs in present despite a negative HCV antibody test (3% to 7% of
those two cities was 85% and 70%, respectively (14). In 2003, cases) (37,38). Qualitative HCV RNA testing is recommended
it was estimated that approximately 14.7% of Quebec IDUs in HIV-positive people, along with a negative HCV antibody
were infected by HIV (15) and other, American, data (7) test, to detect serologically negative HCV infections in people
showed that 85% of persons infected with HIV through injec- with a sustained increase in liver enzymes or with risk factors
tion drug use were also infected by HCV. for HCV (eg, IDUs and pre-1990 transfusion recipients).
HIV infection is diagnosed using a serological test for anti-
NATURAL HISTORY OF HIV. Note that HIV viral load is not a screening test for HIV
HIV-HCV COINFECTION infection. HCV-infected people should be screened for HIV
The independent natural histories of HIV and HCV has been infection, particularly when a treatment for HCV infection is
reported in detail elsewhere (2,16-27). These natural histories being considered.
can be significantly changed in the presence of coinfection.
HIV infection has a significant effect on the evolution of ASSESSMENT OF COINFECTED PATIENTS
HCV. HIV increases the frequency of persistence of HCV after The baseline assessment and follow-up for HIV includes CD4
infection (27,28). Spontaneous clearance of HCV only occurs lymphocyte quantitation and HIV viral load testing. HIV
in 5% to 10% of HIV-positive people. HIV infection can also be plasma viral load testing and CD4 lymphocyte quantitation

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Management of HCV in the setting of HIV-HCV coinfection

TABLE 2
The METAVIR scoring system taking into account inflammatory activity and fibrosis
Activity Grade Fibrosis Stage
No activity A0 No fibrosis F0
Minimal activity A1 Portal fibrosis without septa F1
Moderate activity A2 Portal fibrosis and some septa F2
Severe activity A3 Septal fibrosis without cirrhosis F3
Cirrhosis F4

Histology activity index – Knodell scoring system*

Periportal ± bridging Intralobular degeneration
necrosis Score and focal necrosis Score Portal inflammation Score Fibrosis Score
None 0 None 0 No portal inflammation 0 No fibrosis 0
Mild piecemeal necrosis 1 Mild (acidophilic bodies, 1 Mild (sprinkling of inflammatory Fibrous portal expansion 1
ballooning degeneration cells in <1/3 of portal tracts)
and/or scattered foci of
hepatocellular necrosis in 1/3
of lobules or nodules)
Moderate piecemeal necrosis 3 Moderate (involvement of 3 Moderate (increased 3 Bridging fibrosis (portal-portal 3
(involves <50% of the circumference 1/3–2/3 of lobules or nodules) inflammatory cells in 1/3–2/3 or portal-central linkage)
of most portal tracts of portal tracts)
Marked piecemeal necrosis 4 Marked (involvement of >2/3 of 4 Marked (dense packing of 4 Cirrhosis 4
(involves >50% of the circumference lobules or nodules) inflammatory cells in >2/3 of
of most portal tracts) portal tracts)
Moderate piecemeal necrosis 5
plus bridging necrosis
Marked piecemeal necrosis plus 6
bridging necrosis
Multilobular necrosis 10

*Total hepatic histology activity index (Knodell score) = ×/22. Data from references 44 and 45

should be performed at the time of HIV diagnosis and every There are at least four histological scores for inflammation
three to six months thereafter in untreated people. and fibrosis – the METAVIR, the Knodell, the Ishak and
Recommendations for HIV monitoring, treatment and patient the Scheuer scores are the most used (44,45). Table 2 shows
management are extensively covered in the literature (39-41). an example of the METAVIR and the Knodell scoring
In addition to HIV-specific biological parameters, monitoring systems. Interpretation of biopsy findings must be discussed
of a coinfected individual can include many other laboratory and with a HCV treatment specialist. Note that a liver biopsy is
imaging tests as determined on a case-by-case basis. useful but not essential to the decision of whether to treat;
Patients with clinical signs of liver failure or cirrhosis can its indication is controversial, particularly in the presence
be classified into stage A, B or C using the Child-Pugh scale, of a recent infection or an HCV genotype 2 or 3 infection.
which considers biochemical markers, as well as the presence The higher rate of efficacy in treating HCV of these two
or absence of ascites or encephalopathy. A score from 1 to 3 is genotypes makes the decision of whether to treat less
attributed to each of the parameters, and the total determines dependent on biopsy results.
the Child-Pugh stage (42). The stage determines the five-year
survival prognosis: 80% for stage A, 50% for stage B and 20% Warning signs of liver disease
for stage C. Clinicians should be aware that the Child-Pugh Assessment by an expert is recommended when the following
score may be artificially high in HIV-infected patients receiv- warning signs are present:
ing atazanavir- or indinavir-containing regimens. These • Persistent increase in aspartate aminotransferase levels or
patients may have increased total serum bilirubin levels on the alanine aminotransferase (ALT) levels to more than 10 times
basis of impaired glucuronidation, which is not indicative of the upper limit of normal;
liver disease.
If the coinfected patient can potentially be treated for HCV • Signs of liver failure (spider angioma in the cava territory,
(see indications and contraindications below), the assessment palmar erythema, jaundice, hepatic encephalopathy, white
should be more thorough and should include: nails, clubbing and ascites);
• HCV genotyping, which provides an indication of the • Signs of portal hypertension (gastrointestinal bleeding,
sensitivity to treatment. (There are at least six HCV splenomegaly, abdominal portal systemic collateral venous
genotypes [43]. Genotype 1 is the most frequent in circulation and ascites); and
Canada.) • Signs of cirrhosis decompensation (jaundice, ascites and
• Liver biopsy. The findings of a liver biopsy are interpreted hepatic encephalopathy).
based on semiquantitative criteria of the degree of Patients with biopsy-proven cirrhosis should be monitored
inflammatory activity, hepatocellular necrosis and fibrosis. more closely.

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TABLE 3 • Evaluating, informing and involving the support network

Monitoring tests with respect to side effects of medications;
Additional workup
in case of proven Additional • Promoting awareness of friends and family as to the impact
or suspected workup specific of treatment; and
Frequency Workup for HCV cirrhosis to HIV
• Assessing the patient’s motivation to follow the treatment
Baseline CBC, AST, ALT, Gastroscopy CD4 lymphocyte
program.
alkaline phosphatase quantitation, HIV
bilirubin, GGT, viral load, HIV
albumin, creatinine, genotyping testing Vaccination
INR, HCV RNA, for antiretroviral People with HCV-HIV coinfection should be protected
HBsAG, anti-HBs, resistance against other viral or bacterial infections. Of particular
anti-HBc, Igg, importance are hepatitis B virus, hepatitis A virus, influenza
liver biopsy, and pneumococcus (27,47-50). Clinicians should note that the
alpha-fetoprotein, immunogenicity of most vaccines is reduced in the HIV-
liver ultrasound
infected population. Serological testing should be performed
Every 3 to CBC, AST, ALT, Alpha-fetoprotein CD4 lymphocyte
first to identify the presence of pre-existing antibody and/or
6 months alkaline phosphatase, quantitation,
those who are susceptible. However, vaccination should not be
bilirubin, GGT, HIV viral load
albumin, creatinine,
delayed when exposure can be predicted, particularly in IDUs.
INR
Every 6 Alpha-fetoprotein, MONITORING OF COINFECTED PERSONS
months liver ultrasound In Canada, more than 70% of HCV-infected people have a
(can be performed history of injection drug use (14). Although it would be appro-
more often if priate to treat many of these patients for HIV and/or HCV, in
alpha-fetoproteins actual fact, only a few are treated particularly for HCV.
increase)
Active consumption of illicit psychotropic substances for
Every 2 to 5 years Liver biopsy Gastroscopy
recreational use can lower the chances of responding to
Repeat every month for the first three months after starting anti-HIV therapy treatment, because adherence is often reduced. Drug or alcohol
in coinfected patients. ALT Alanine aminotransferase; AST Aspartate consumption should not, however, be an absolute contraindi-
aminotransferase; CBC Complete blood count; GGT Gamma-glutamyl
transferase; HBc Hepatitis B core; HBsAg Hepatitis B surface antigen; Igg cation to treatment. The decision to initiate treatment should
Immunoglobulin G; INR International normalized ratio be made on an individual basis.
Adverse or toxic effects should be minimized, and drug inter-
actions should be avoided if possible. Physical, psychological and
Lifestyle recommendations social needs also have to be met, not only at the beginning, but
Screening for alcohol problems is extremely important, with throughout treatment.
the goal being complete abstinence. Alcohol consumption The monitoring of a coinfected person is complex. Several
should be minimized and should not exceed 50 g/day. Another tests are indicated for the optimal monitoring of patients with
lifestyle issue to consider is the degree of adherence to anti- HCV and those with HCV-HIV coinfection. Table 3 shows
retroviral treatment; steps should be taken to optimize adher- these tests and their optimal frequency.
ence. Steps should also be taken to prevent HCV reinfections Optimal monitoring is achieved when there is access to a
because prior infection does not confer protective immunity. multidisciplinary health team with experience in considering
Finally, it is imperative to provide weight maintenance coun- HIV, HCV, addiction, mental health, nutrition, and psycho-
selling, because weight gain can lead to faster development of logical and social aspects.
fibrosis in the presence of fatty liver (46).
WHICH INFECTION TO TREAT FIRST
Assessment of psychological and social stability It is not recommended to begin HIV and HCV treatments
The psychological and social assessment and case management simultaneously due to their complexity and overlapping drug
of coinfected patients involves several important aspects. First, toxicities. Clinical experience has shown that adherence is
these patients should all undergo screening for mental health better when treatments are introduced separately. The efficacy
problems, because untreated psychosis and depression with of and tolerance to a single treatment should be determined
suicidal ideation are contraindications to interferon (IFN) before beginning another.
treatment, and a history of severe depression can sometimes be Ideally, treatment of HCV should be initiated before anti-
a relative contraindication for treatment. HIV treatment to decrease the risk of hepatotoxicity of anti-
Addictions are also a key consideration; one should aim for HIV medication, to decrease the potential risks of hepatic
psychological and social stabilization, which, in cases of active decompensation during immune reconstitution syndrome, and
addiction, can be assessed via the following elements: to avoid overlapping drug toxicity between anti-HIV and
• Having stable lodging; HCV treatments.
• Being able to cooperate in a context of care; HCV treatment should be initiated before HIV therapy
when the HIV infection is stable and does not require immedi-
• Keeping appointments and taking medication as ate therapeutic intervention. This is usually the case when the
prescribed; CD4 cell count is higher than 350 cells/μL.
• Having access to drug insurance and providing for essential Treating HIV first is clearly indicated when the CD4
needs – food, hygiene and transportation; lymphocyte count is very low (less than 200 cells/μL). In some

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Management of HCV in the setting of HIV-HCV coinfection

cases, however, when CD4 counts are between 200 cells/μL TABLE 4
and 350 cells/μL, antiretroviral treatment can be delayed, par- Pegasys RBV* (pegylated interferon alpha-2a) and
ticularly in the absence of opportunistic infections or markers COPEGUS† (ribavirin) doses
of rapid progression (elevated viral load or clinical symptoms). Genotype Pegasys dose weekly Ribavirin dose daily
The caregiving team needs to evaluate the risks and benefits of 1 or 4 180 μg Weight <75 kg = 1000 mg/day
treating HIV or HCV first on a case-by-case basis. Weight ≥75 kg = 1200 mg/day
2 or 3 180 μg 800 mg (regardless of weight)
TREATMENT OF HCV *Hoffmann-La Roche Ltd, Canada; †Hoffmann-La Roche Inc, USA
The relevance of treating HCV should be considered for each
coinfected patient. The decision of whether to treat must be Pegetron* (pegylated interferon-alpha-2b) and ribavirin
made on an individual basis, considering the risk of progression doses
of liver disease, the possibility of response to treatment, the Pegetron Amount of Volume
risk of side effects, and the patient’s condition and motivation RediPen* or Pegetron of Pegetron Ribavirin dose
(51). Weight vial strength to administer to administer to administer
(kg) to use weekly (μg) weekly (mL) daily (mg)
When the decision to treat is taken, additional tests are
called for to assess response to treatment and side effects, <40 50 μg/0.5 mL 50 0.5 800
including quantitative HCV RNA and HCV genotype. 40–<50 80 μg/0.5 mL 64 0.4 800
HCV treatment is contraindicated in certain cases. 50–<64 80 μg/0.5 mL 80 0.5 800
Absolute contraindications include (52,53): 64–<75 120 μg/0.5 mL 96 0.4 1000
75–<85 120 μg/0.5 mL 120 0.5 1000
• Pregnancy, breastfeeding or the inability to use an effective
≥85 150 μg/0.5 mL 150 0.5 1200
means of contraception;
*Schering-Plough Canada Inc
• Hypersensitivity to IFNs, ribavirin (RBV) or excipients in
the medication;
• Active autoimmune disease, such as uncontrolled thyroid
diseases or autoimmune hepatitis; even truer for patients with a genotype 2 or 3 HCV infection
because of the good response rate in these cases.
• Kidney failure with a creatinine clearance of less than
In cases of acute HCV infection (less than six months),
50 mL/min (in these cases, pegylated [PEG] IFN-α-2a-based
studies (56) have reported very high response rates for
treatment without RBV can be considered with dose
monoinfection (98%). There are little similar published data
reduction if the creatinine clearance is less than
for coinfection (57,58). However, in the presence of acute
20 mL/min); and
HCV infection and when not contraindicated, treatment
• Decompensated liver disease. should be initiated quickly, without a liver biopsy, as soon as
possible following the 12-week postdiagnosis period (symp-
Relative contraindications include:
toms or viremia outbreak). Chances of spontaneous disappear-
• Problems with taking medication and keeping medical ance of HCV infection are low after 12 weeks.
appointments;
Treatment of HCV infection
• Major uncontrolled depression and repeated suicide attempts The most effective known treatment for HCV is PEG IFN
– a psychological evaluation is necessary to assess suicide risk; with RBV. There are two formulations marketed in Canada.
• An uncontrolled psychotic state – if the psychosis is stable, 1) Pegasys RBV (Hoffmann-La Roche Ltd, Canada): It consists
HCV treatment may be undertaken if there is appropriate of PEG IFN-α-2a at a fixed dose of 180 μg, once a week,
follow-up; associated with RBV. For genotype 1 or 4, RBV is given at a
• Severe coronary and valvular heart disease; daily weight-adapted dose of 1000 mg for people weighing
less than 75 kg and 1200 mg for people weighing 75 kg or
• Uncontrolled epilepsy; more. For genotype 2 or 3, the dose of RBV is 800 mg
• Retinopathy; (regardless of weight) (Table 4) (52).
• Platelet count less than 50,000×109/L; 2) Pegetron (Schering-Plough Canada Inc): It consists of
• Neutropenia less than 750×109/L; PEG IFN α-2b administered in variable doses based on
weight 1.5 μg/kg (as a subcutaneous injection once a
• Severe anemia – hemoglobin (Hb) level lower than week), with a variable oral dose of between 800 mg/day
100 g/L; and and 1200 mg/day of RBV based on weight (Table 4) (53).
• CD4 count less than 200 cells/μL. There are no comparative studies showing whether one of
To consider a treatment for HCV, liver biopsy is highly the PEG IFN/RBV formulations available is more effective
desirable (2). It should show significant damage – for example, than the other for coinfection. In December 2005, Health
a METAVIR score of F2 or higher, or equivalent (Table 2). Canada approved Pegasys RBV formulation for use in HIV-
Studies have shown that anti-HCV therapy treatment HCV coinfected patients with a RBV dose of 800 mg (52).
response is reduced in the presence of hepatic cirrhosis (54). However, clinical studies following pivotal trials have
Some authors believe that due to the prognosis of HCV in demonstrated superior results with increased doses of RBV. RBV
coinfection, treatment can be justified even in patients with doses of between 1000 mg/day and 1200 mg/day (based on
little histological damage (55). The patient’s refusal to undergo weight) as used in monotherapy are, therefore, recommended
a biopsy is not in itself a contraindication to treatment. This is when tolerated (51,59,60).

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TABLE 5 RNA must be performed. After 12 weeks of treatment, HCV

Summary of sustained virological response in arms RNA qualitative and quantitative testing must be repeated.
treated with pegylated interferon-alpha (PEG IFN-α α) +
ribavirin (RBV) in HIV-hepatitis C virus (HCV) coinfected
Quantitative RNA testing is only to be perfomed if qualitative
patients compared with HCV monoinfected patients RNA is positive.
A negative qualitative HCV RNA at week 12 or a minimal
Length Genotype Genotype two-log decrease in HCV RNA from initiation of anti-HCV
RBV of 1 2+3 therapy is required to continue treatment (54). If qualitative
Study Treatment dose treatment response response
(reference) population n (mg) PEG IFN (weeks) (%) (%) polymerase chain reaction is still positive at week 12, a quanti-
CLINIVIC, Coinfected 52 800/1200 α-2b 48 38* 53
tative HCV RNA viral load test should be performed. If the
Laguno et al
quantitative viral load shows a two-log decrease (100 times)
(60)† compared with baseline, treatment should be continued and a
RIBAVIC- Coinfected 412 800 α-2b 48 17 44 qualitative HCV RNA test should be performed at week 24 to
ANRS (61) ensure that results are negative (54). If the quantitative HCV
APRICOT Coinfected 289 800 α-2a 48 29 62 RNA viral load has not decreased by more than two-log, treat-
(54) ment should be discontinued. The probability of virological
ACTGA5071 Coinfected 67 600/1000 α-2a 48 14 73 response in these cases is less than 2% (54).
(62) HCV relapse is defined by a repositivation of qualitative
Hadziyannis Monoinfected 361 800 α-2a 48 41 79 HCV RNA at week 72 in the absence of clinical factors
et al (63) indicative of possible reinfection.
Monoinfected 436 1000/1200 α-2a 48 52 80

PROPOSED MONITORING AT THE BEGINNING

Fried et al Monoinfected 1121 1000/1200 α-2a 48 46 76
(87)
OF AND DURING TREATMENT
Manns et al Monoinfected 1530 1000/1200 α-2b 48 42 82
An electrocardiogram should be performed in patients older
(88) than 50 years of age or in those with risk factors for arterioscle-
rotic heart disease. A chest x-ray and a tuberculin skin test
*Genotype 1 and genotype 4 patients combined. ACTG AIDS Clinical Trial
Group; APRICOT AIDS Pegasys Ribavirin International Co-infection Trial;
(baseline purified protein derivative) should be performed in all
ANRS Agence nationale de recherches sur le sida patients who have not previously had these tests completed as
part of their baseline HIV assessment. In general, medical visits
should be scheduled for every 15 days for the first two months
Studies (54,60-62) have shown that response to HCV and every month thereafter. Frequency and monitoring are sug-
treatment is reduced in coinfected patients. HCV is treated for gestions and can be adapted on a case-by-case basis. At the first
48 weeks, regardless of genotype, in the setting of coinfection. For visit, the patient should undergo a CD4/CD8 profile and HIV
monoinfection, the duration of treatment depends on the geno- viral load test. At each visit, a complete blood count (CBC)
type. Genotype 2 or 3 is treated for 24 weeks and genotype 1 or 4 should be performed, and electrolyte, glucose, creatinine, bicar-
is treated for 48 weeks. bonate, aspartate aminotransferase, ALT, alkaline phosphatase,
gamma-glutamyl transferase, bilirubin, albumin, amylase and
HOW TO EVALUATE THE uric acid levels should be measured. Once a month, a CD4/CD8
RESPONSE TO TREATMENT profile and a urinalysis should be performed. Also, venous lactic
Response to treatment is evaluated at different follow-up stages: acid should be measured in the presence of symptoms of lactic
acidosis or lowered bicarbonates. Once every three months,
• Early virological response (EVR) – negative qualitative
HCV RNA test or two-log10 decrease at 12 weeks in thyroid-stimulating hormone, HIV viral load and amylase should
quantitative HCV RNA, followed by a negative be measured and a fasting lipid profile should be obtained. Table 6
qualitative HCV RNA test at week 24 (54); shows a representation of an optimal monitoring regimen.

• End-of-treatment virological response (ETR) – negative Adverse effects of PEG IFN and RBV treatment
qualitative HCV RNA test at 48 weeks; and There are many common side effects of PEG IFN and RBV
• Sustained virological response (SVR) – negative qualitative treatment. General symptoms include flu-like symptoms
HCV RNA test 24 weeks after the end of treatment (week characterized by discomfort, joint pain, headaches, fever,
72) and sustained normal liver enzyme values. weight loss and alopecia. Psychiatric and neurological symp-
HCV treatment efficacy is reduced in the presence of toms can include irritability, anxiety, insomnia, depression and
coinfection. Recent studies (54,60-62) have compared coin- psychosis; there can also be convulsions, ototoxicity, neuropa-
fected patient treatment efficacy with that of monoinfected thy and altered vision (for symptoms that suggest retinal alter-
patients (Table 5) (54,62,63). In coinfected patients, HCV ation, refer for urgent ophthalmology consultation).
treatment efficacy varies between 14% and 38% for genotype 1, Cutaneous symptoms are also common, such as eruptions,
compared with between 41% and 52% in monoinfections. For pruritus, dryness and local inflammation at the injection site.
genotypes 2 and 3, efficacy is between 44% and 73%, com- Many patients experience gastrointestinal symptoms such as
pared with approximately 80% in monoinfected patients. anorexia, nausea, diarrhea, abdominal cramps and pancreatitis.
Treatment efficacy and indication to continue treatment for Hematological effects include neutropenia, thrombocytopenia
48 weeks with PEG IFN plus RBV are evaluated as a function of and anemia. Cardiovascular or pulmonary complications may
kinetic viral response (HCV viral clearance) at 12 weeks. Before also arise such as hypotension, arrhythmia, myocardial
starting treatment, quantitative (viral load) testing of HCV infarction, cardiomyopathy or pulmonary edema. Finally, there

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Management of HCV in the setting of HIV-HCV coinfection

are several autoimmune or renal adverse effects associated with TABLE 6

PEG IFN and RBV treatment, such as thyroid dysfunction, Monitoring of coinfected patients before and during
treatment of hepatitis C virus (HCV) infection
vasculitis, arthritis, proteinuria and electrolyte imbalance.
Test Start 2 4 6 8 10 12 16 20 24 28 32 34 36 40 44 48 60 72
ECG •
Complications associated with treatment of HCV in Chest x-ray •
coinfection and their management Qualitative • • •* • •†
1. Flu-like symptoms: Acetaminophen can be used up to a HCV RNA
maximum dose of 1000 mg orally, four times a day, as Quantitative • •‡
needed. Other options include hydration and nonsteroidal HCV RNA
anti-inflammatory drugs. CD4/CD8 • • • • • • • • • • • • • • • •
HIV RNA • • • • • • •
2. Insomnia: Oxazepam, temazepam or lorazepam can be used
CBC • • • • • • • • • • • • • • • • • • •
as needed. Other benzodiazepines are metabolized in the
Electrolytes • • • • • • • • • • • • • • • • • • •
liver and can have interactions with HIV protease inhibitors.
Glucose • • • • • • • • • • • • • • • • • • •
3. Rash: 10 mg to 25 mg of hydroxyzine taken orally, three Creatinine • • • • • • • • • • • • • • • • • • •
times daily, can be used as needed. This medication also Bicarbonates • • • • • • • • • • • • • • • • •
has a sedating effect that can be helpful at bedtime. AST/ALT • • • • • • • • • • • • • • • • • • •
ALKP/GGT • • • • • • • • • • • • • • • • • • •
4. Depression: If depression develops during PEG IFN plus
Bilirubin • • • • • • • • • • • • • • • • • • •
RBV treatment, the usual therapeutic options can be used. Albumin • • • • • • • • • • • • • • • • • • •
A psychiatric assessment is always preferable, with a joint Amylase • • • • • • •
follow-up during treatment if possible. HCV treatment Chol/TGs • • • • • • •
should be discontinued in cases of de novo psychosis, Lactic acid Do this test if bicarbonates are low or in presence of symptoms
hallucinations, significant paranoia, suicide attempts or TSH • • • •
ideation, and an emergency psychiatric opinion should be Urinalysis • • • • • • • • • • • • • •
obtained. Antidepressants are often helpful or necessary. It Pregnancy •
is best to avoid bupropion. test§
5. Hematological impact: Interventions should be based on *Must be performed if qualitative HCV RNA is positive at week 12 and if there
individual product monographs with respect to was a two-log10 drop in quantitative HCV RNA at week 12 to determine
whether treatment must be continued; †Must be performed if qualitative HCV
hematological complications and dose adjustments. RNA is negative at week 48 to confirm sustained response; ‡Must be per-
In general, the following interventions are recommended. formed if qualitative HCV RNA is positive at week 12; §Ensure proper contra-
ception is used while under treatment. ALKP Alkaline phosphatase; ALT
Furthermore, adjustments may vary on a case-by-case basis, Alanine aminotransferase; AST Aspartate aminotransferase; CBC Complete
based on the individual treating physician’s experience: blood count; Chol/TG Cholesterol/triglycerides; ECG Electrocardiogram; GGT
Gamma-glutamyl transferase; TSH Thyroid-stimulating hormone
5a. Thrombocytopenia (less than 50,000×109/L): This
mainly appears at the beginning of treatment. PEG IFN
taking into consideration the baseline Hb level, the rate
dosage may be reduced by 25% to 50%, and a CBC
of fall, and the presence or absence of symptoms:
should be performed every 15 days. Treatment should be
discontinued if thrombocytopenia does not improve • Switch AZT for another NRTI.
despite reduced doses, if there are hemorrhagic complica- • In patients with stable cardiac disease or chronic
tions or if the platelet count is less than 20,000×109/L. obstructive pulmonary disease, if the drop in Hb level is
5b. Neutropenia: If the neutrophil count drops to less than greater than 20 g/L or if the Hb level drops below
750×109/L, PEG IFN dosage may be reduced by 25% to 100 g/L in any patient, the RBV dose should be reduced
50% and the neutrophil count should be retested every in 200 mg increments (one capsule) and CBC should be
seven to 15 days. If the neutrophil count is less than monitored every seven to 14 days. RBV dose can be
500×109/L, options are to reduce the dose of PEG, reduced in this way, to a minimum of 600 mg/day.
discontinue treatment or administer granulocyte-colony • If the Hb level falls below 85 g/L despite AZT
stimulating factor – filgrastim (Neupogen, Amgen Canada discontinuation, RBV dose reduction, and/or use of
Inc), 5 μg/kg, subcutaneously, two or three times per week. recombinant erythropoietin (Eprex, Janssen-Ortho
5c. Anemia: The combination of azidothymidine (AZT) Inc, Canada) or darbepoetin (Aranesp, Amgen
(64) and RBV increases the risk of developing anemia. Canada Inc), RBV should be discontinued.
RBV in association with tenofovir or abacavir is better • In the absence of response or if the anemia gets
tolerated. These latter options reduce hematological worse, other causes of anemia must be investigated
toxicity caused by RBV and allow for optimal dosing for (bleeding or bone marrow involvement), and
successful therapy. If anemia is present from the start, recombinant erythropoetin can be administered
AZT can be replaced with another nucleoside reverse subcutaneously two to three times a week (50 U/kg to
transcriptase inhibitor (NRTI) such as abacavir or 100 U/kg) to a maximum of 40,000 U/kg per week.
tenofovir when possible (absence of resistance or Some authors recommend usage of recombinant
intolerance), before the start of HCV treatment. erythropoietin before reducing the RBV dose to
In patients who develop anemia during treatment, the increase the chance of successful HCV treatment
following can be considered on a case-by-case basis, (64,65).

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Côté et al

the presence of metabolic acidosis and an increase in blood

Symptomatic lactic acid levels to more than 5 mmol/L. In the presence of
symptoms, an increase in lactic acidemia to between
YES NO 2 mmol/L and 5 mmol/L points to the possibility of this
Test for blood lactate Do not test for lactate diagnosis in certain cases (Figure 1) (66). It should be noted
that increases in blood lactic acid levels are common.
Between 15% and 35% of patients treated with NRTIs may
<2 mmol/L ≥2 mmol/L–≤5 mmol/L >5 mmol/L present asymptomatic hyperlactatemia (66), which is not
predictive of lactic acidosis arising later (69). When
interpreting an elevated lactic acid level, the patient’s
Normal OBSERVE: ACIDOSIS?
If bicarbonates <20 mmol/L - Discontinue NRTIs symptoms, blood bicarbonate levels and, if required, arterial
If symptoms increase - Supportive treatment gas analysis results must be taken into account. Blood for
CONSIDER:
Discontinuation or
lactic acid testing is drawn without a tourniquet and sent
modification of NRTIs immediately to the laboratory on ice. Unless the diagnosis is
Supportive treatment probable or certain, and discontinuation of treatment is an
emergency, an HIV expert should be consulted before
Figure 1) Investigation and treatment of hyperlactatemia. Adapted modifying or stopping antiretroviral therapy. It is believed
from reference 66. NRTIs Nucleoside reverse transcriptase inhibitors that RBV may potentiate the mitochondrial toxicity of
certain NRTIs (65,70), which is why the concomitant
6. If the CD4 count decreases to less than 200 cells/μL, administration of ddI is avoided and stavudine-based (d4T)
prophylactic anti-Pneumocystis jiroveci (carinii) treatment therapies are used with caution. Routine lactate testing is
must be initiated. The relative percentage of CD4 cells is not recommended because of complexities associated with
not impacted much by HCV treatment, and the risk of specimen collection, as well as the sensitivity and specificity
developing an opportunistic infection is low. It is not clear limits of this marker.
whether IFN-driven decreases in CD4 count below 10. Acute pancreatitis: There is an increased risk of pancreatitis
200 cells/mm3, unassociated with a fall in CD4 percentage, in patients receiving ddI and the combination of PEG IFN
are associated with any increase in opportunistic infections with RBV. Some hepatic decompensation episodes have
in general or in P jiroveci pneumonia in particular. Hence, occurred in cirrhotic patients receiving RBV and ddI (71);
it is not clear whether instituting P jiroveci pneumonia concomitant use of ddI was identified as a strong
prophylaxis for such patients is essential. HCV treatment independent risk factor for hepatic decompensation in
can be discontinued if opportunistic infections arise. patients with HIV-HCV coinfection receiving anti-HCV
7. If the HIV viral load increases (rare occurrence), the treatment (71).
patient’s adherence to treatment must be checked and the 11. Hepatic decompensation: In case of evidence of hepatic
merits of the following discussed with an HIV expert: decompensation, HCV treatment should be discontinued
• Observe only; (52,53).
• Introduce an antiretroviral treatment; and
• Modify an antiretroviral treatment, if applicable. Hepatotoxicity, HCV and HIV antiretroviral agents
8. Hypo- or hyperthyroidism: This complication does not Most coinfected patients present elevated ALT levels to a cer-
usually require HCV treatment to be discontinued. tain degree after starting anti-HIV treatment. As many as 12%
Thyroxin substitution treatment is indicated in the of patients develop severe hepatotoxicity (ALT levels greater
presence of hypothyroidism. If hyperthyroidism is present, than 10 times the upper limit of normal) (34,72-74). Table 7
subacute thyroiditis, or more rarely, Graves disease, may be shows recommendations for the use of antiretrovirals in cases
the cause. Diagnosis is made using a radioactive iodine of hepatotoxicity.
scan and a thyroid-stimulating hormone receptor antibody
Intervention in cases of hepatotoxicity
test. Follow-up with an endocrinologist is recommended if
It is essential, particularly in coinfected patients, to carefully mon-
required.
itor liver function after introducing a new HIV antiretroviral
9. Lactic acidosis: Lactic acidosis is a rare complication of HIV agent (see complications below). Transaminases should be tested
treatments attributable to NRTI mitochondrial toxicity, every month for the first three months and every three months
resulting in depletion of mitochondrial DNA. Of thereafter. If ALT levels increase, other potential causes should be
1000 people taking NRTIs, the frequency is approximately investigated, such as alcohol or cocaine use, acute or chronic hep-
four to five people per year (66). Symptoms are nonspecific. atitis B, hepatitis A, opportunistic diseases or the hepatotoxicity
Patients consult for significant general malaise, with lack of of a concomitant medication. Interruption of HIV antiretroviral
appetite, nausea, vomiting, weight loss, severe asthenia, treatment may be required if there are symptoms or in cases of
dyspnea, cardiac arrhythmia and abdominal pain. These severe hepatitis. Reintroduction should be performed with cau-
manifestations have been described mainly in women with tion due to the risk of hepatotoxicity recurring. Eradicating HCV
fatty liver on stavudine, didanosine (ddI) or both (67,68). virus before initiating HIV treatment can improve tolerance to
They result from the toxicity of medication on the antiretrovirals and should be considered in coinfected people with
mitochondria, which prevent these organelles from breaking a CD4 count higher than 350 cells/μL (2).
down glucose via the usual metabolic pathways, resulting in An algorithm for the management of hepatotoxicity is pre-
excess production of lactic acid. The diagnosis is made in sented in Figure 2 (75).

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TABLE 7 ALT/AST ≥5x ULN

Antiretroviral dose adjustment in patients with hepatic (upper limit of normal range)

insufficiency
Dose adjustment required in liver Exclude other causes: acute hepatitis Examine for signs of drug hypersensitivity
(HAV, HBV, alcohol, others) Check serum lactate serum with symptoms
Medication Hepatic metabolism failure
Nucleoside/Nucleotide reverse transcriptase inhibitors
ALT/AST ALT/AST
Abacavir Yes No recommended in patients with ≥10x ULN or <10x ULN +
symptoms of acute absence of
moderate to severe impairment hepatitis symptoms

Child-Pugh score (dose):

Stop antiretroviral ALT/AST >10x ULN - Monitor liver function tests
therapy or symptoms every 3-4 weeks.
5–6 (200 mg twice a day) - Continue antiretroviral therapy
Zidovudine Yes No dosage adjustment
Lamivudine No No dosage adjustment Restart antiretroviral therapy when Perform additional investigation and possible liver
ALT/AST <2-3x ULN biopsy if:
Didanosine No No dosage adjustment - lack of resolution of elevated ALT/AST within
3-6 months
Stavudine No No dosage adjustment - underlying chronic viral hepatitis (HBV, HCV)

Emtricitabine No No dosage adjustment

Tenofovir No No dosage adjustment
Figure 2) Clinical management of severe hepatotoxicity. Adapted
from reference 75. ALT Alanine aminotransferase; AST Aspartate
Non-nucleoside reverse transcriptase inhibitors
aminotransferase; HAV Hepatitis A virus; HBV Hepatitis B virus;
Delavirdine Yes No dosage adjustment; use with HCV Hepatitis C virus; ULN Upper limit of normal
caution in patients with hepatic
impairment
Efavirenz Yes No dosage adjustment; use with Antiretroviral metabolism
caution in patients with hepatic It has been shown that chronic liver disease can affect the
impairment pharmacokinetics of some anti-HIV agents. Increases in the
Nevirapine* Yes Avoid initiation in women with a CD4 plasma concentrations of most non-NRTIs and protease
count >250 cells/μL or in men with inhibitors have been reported with varying degrees of liver
a CD4 count >400 cells/μL; if dysfunction (40,80-84). In some cases, these increases have
initiated, close monitoring is been linked to toxicity (83). Therapeutic drug monitoring can
recommended (every 2 weeks for possibly be helpful when available.
the first month, then monthly for
for 3 months, then every 3 months)
HIV medication to avoid while treating HCV
Protease inhibitors ddI is the only antiretroviral contraindicated during HCV
Atazanavir† Yes Child-Pugh score (dose): treatment due to its increased toxicity in the presence of RBV.
7–9 (300 mg every day) RBV has potentiated the antiretroviral effect of ddI in vitro
>9 (not recommended) and in animals by increasing the formation of the active
Fosamprenavir Yes Child-Pugh score (dose): triphosphate anabolite (ddATP). This observation raised the
5–8 (700 mg twice a day) possibility that concomitant administration of RBV and ddI
9–12 (not recommended) could increase the risk of adverse reactions to ddI (eg, periph-
Indinavir† Yes Mild to moderate hepatic insufficiency eral neuropathy, pancreatitis and fatty liver accompanied by
because of cirrhosis: 600 mg q8h lactic acidosis). Increased frequency of pancreatitis and lactic
Nelfinavir Yes No dosage adjustment; use with acidosis has been observed with the coadministration of ddI
caution in patients with hepatic and RBV (51,54,85,86).
impairment The coadministration of zidovudine (AZT) and RBV has
Saquinavir Yes No dosage adjustment; use with been associated with a greater risk of anemia (86). AZT is rel-
caution in patients with hepatic atively contraindicated during the treatment of HCV; when
impairment used, it must be closely monitored. It is recommended that
Lopinavir/ritonavir Yes No dosage adjustment; use with patients be switched to a nonzidovudine-containing regimen if
caution in patients with hepatic at all possible.
impairment The use of d4T with RBV increases the risk of lactic acido-
Tipranavir Yes No dosage adjustment; use with sis; particular attention should be paid to symptoms of hyper-
caution in patients with hepatic lactatemia or lactic acidosis (51,54).
impairment. TPV/RTV is
contraindicated in patients with
CONCLUSIONS
moderate to severe hepatic impair-
Advances in the treatment of HCV using combined PEG IFN
ment (Child-Pugh classes B and C)
and RBV offer the possibility of eradicating HCV infection in
Darunavir Yes No data with patients with hepatic
coinfected people. Due to the risk for hepatic morbidity associ-
impairment; use with caution in
this population
ated with HCV infection in HIV-positive people, HCV eradi-
cation treatment must be considered in all cases in which there
Fusion inhibitors
is no contraindication. Intensive management of the side
Enfuvirtide (T-20) No No dosage adjustment
effects of HCV treatment is one of the factors for the success of
*Reported cases of severe fulminant hepatitis and death – use not recom- these therapies. HCV eradication is predicted to decrease the
mended in cases of liver failure; †Associated with unconjugated hyperbiliru-
binemia – refer to product monograph. q8h Every 8 h; TPV/RTV mortality associated with coinfection and reduce the toxicity
Tipranavir/ritonavir. Data from reference 79 of HIV treatment.

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