Hepatitis B Virus and Hepatitis C Virus

Co-infection with HIV

Dr. Shree Narayan Yadav

Internal Medicine
NAMS
 Introduction
HBV is an enveloped, double-stranded DNA virus of the
Hepadnaviridae family that may cause an acute self-limited infection,
fulminant hepatic failure, or may develop into a chronic disease.(I.P.-2-3
months )

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family

with 6 primary genotypes(I.P.-5-6 weeks)

Incubation period Prodromal stage Icteric stage(ALF)

Resolution stage Chronic phase
 Introduction
HBV with HIV Co-infection
Coinfection with HIV has a major impact on the natural history,
diagnosis, progression, and morbidity and mortality related to hepatitis
B virus (HBV) infection

The presence of chronic hepatitis B can also lead to an increased risk

of hepatotoxicity related to the administration of potent antiretroviral
therapy (ART).
• In patients infected with HIV, chronic hepatitis B infection (CHB) has
emerged as a major cause accounting for substantial rises in cirrhosis,
hepatocellular carcinoma (HCC), and end-stage liver disease

• Recent data also suggest that CHB might also alter the course of HIV
disease by inducing a more profound immunosuppression in non-
treated patients and by increasing the risk of all-cause mortality.
 Epidemiology
Because of shared routes of transmission and infected with human
immunodeficiency virus (HIV), the prevalence of HIV/HBV coinfection
ranges from 5 to 15%.

The rates of HIV/HBV coinfection vary according to geographic

region and are highest in sub-Saharan Africa and Asia, where most
transmission occurs perinatally and horizontally.
 Epidemiology

• In countries where HBV prevalence is low (<2%, i.e.Europe, USA,

Australia), HBV infection is acquired during adulthood mainly
through sexual intercourse, intravenous drug use and nosocomial
exposure.
• It affects 5–8% of HIV-infected patients, in whom HBV immunization is not
performing well
• Conversely, in countries where HBV prevalence is high (>8%, Africa
and Asia), CHB is usually acquired perinatally or during early
childhood.
• The prevalence of CHB in HIV infected patients is, ranging from 10 to15%
 Pathogenesis and Pathology
• These phenomena may explain some of the effects of HIV coinfection and cART on
CHB:

Higher risk of chronicity after acute HBV infection (increased HBV replication and lower rates of
HBeAg seroconversion in patients with HIV/HBV coinfection,)

Higher level of HBV replication and a higher rate of reactivation compared with persons without
HIV coinfection

 Increased liver injury (either due to immune-reconstitution hepatitis or direct hepatotoxicity) and
liver disease progression in case of ART.

• However, optimal control of HBV replication is more beneficial than deleterious in the
long term.
• It induces a regression of liver fibrosis and may lead to a reduction in mortality rates
DIAGNOSIS OF CHRONIC HBV INFECTION
 Evaluation
• All patients newly diagnosed with HIV should undergo hepatitis B screening.

• HBV markers such as HBs antigen, anti-HBc and anti-HBs antibodies will help
identify those with CHB and those in need of immunization.

• The determination of HBe status and quantification of HBV-DNA will help in

providing the best therapeutic guidance.

• Initial liver evaluation should also contain an assessment of liver fibrosis.

• Complete liver assessment should be performed annually in patients with F0–F2 fibrosis
level
• Special attention should begiven to patients with isolated HBc antibody and quantification
of HBV-DNA will help determine the presence of occult CHB.
 EVALUATION
Detailed history and physical examination to assess for hepatotoxic
medications and evidence of advanced liver disease;
Laboratory testing to evaluate markers of HBV activity, kidney
function, liver function, and coexisting causes of liver disease;
 Ultrasound imaging to screen for evidence of hepatocellular
carcinoma.
 Serum Fibrosis marker
• Fibrometer is an algorithm combining a number of parameters
including
• number of platelets, prothrombin time, AST, α2-macroglobulin, hyaluronate,
urea and age
• The fibrotest is a composite of five serum biochemical markers
• alpha-2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl
transpeptidase, and bilirubin
• The Enhanced Liver Fibrosis (ELF) algorithm includes
• hyaluronic acid, the N-terminal pro-peptide of type III collagen, and tissue
inhibitors of matrix metalloproteinase
• Liver biopsy is currently the ‘gold standard’ for assessing liver
disease and fibrosis.
 Fibrosis Marker

APRI score greater than 1.0 had a sensitivity of 76% and specificity of 72% for predicting cirrhosis .

APRI cutoff score of 2.0 was more specific (91%) but less sensitive (46%).

APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis)
higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis);
 FIB-4 score <1.45 had a negative predictive value of 90% for advanced fibrosis
fibrosis score 4-6 which includes early bridging fibrosis to cirrhosis
In contrast, a FIB-4 >3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis .
RATIONALE FOR TREATMENT
• Patients with HIV and chronic HBV infection should receive treatment
to suppress both viruses regardless of HBV DNA level or degree of
liver damage 
 Difference in treatment of chronic HBV in persons with HIV is as
follows:
Prevent HIV and HBV drug resistance –

Certain antiretroviral agents used to treat HIV are also used to treat HBV.

Coinfected patients may be initiated on medications for their HIV that have
activity against HBV.
CONTD
Slow progression of HBV infection which has an accelerated course
in coinfected patients
Reduce the incidence of immune reconstitution inflammatory
syndrome (IRIS) – By treating both HIV and HBV concurrently
Patients with occult hepatitis B should also receive treatment to
suppress both viruses. 
ANTIVIRAL MEDICATIONS FOR HBV
Tenofovir, 
Entecavir, 
Lamivudine ,
Emtricitabine, 
Telbivudine, And 
Adefovir 
• These NRTIs can suppress hepatitis B virus (HBV) DNA
• All are renally metabolized.
• The doses of these agents should be reduced for patients with reduced
kidney function
 Tenofovir
• First line for patients with chronic HBV

• High virologic efficacy

• Low risk of HBV resistance

• Effective in both treatment-naïve and treatment-experienced patients

• Also active against lamivudine-resistant HBV

• Worsening kidney function in some patients

• More likely to occur in patients receiving tenofovir disoproxil

fumarate(TDF) compared with tenofovir alafenamide(TAF)

• For patients who were initially receiving TDF, switch TDF to TAF eGFR<60
mL/min/1.73 m2

• Discontinue and start entecavir who develop acute kidney injury or a

Fanconi-like syndrome, regardless of the eGFR and baseline HBV status
 Entecavir
• Potent inhibitor of Hep B polymerase

• Greater HBV suppression compared with lamivudine

• Risk of resistant develops in cases of suspected lamivudine resistance

• Suitable alternative for HBV treatment-naïve patients in the setting

of severly reduced kidney function
 Lamivudine/emtricitabine
•  Demonstrated efficacy against HBV infection in both hepatitis B e antigen
(HBeAg)-positive and HBeAg-negative patients

• Avoid an HIV ART regimen that uses lamivudine monotherapy.

• Rapid emergence of lamivudine-resistant HBV due to a mutation

within the YMDD motif of HBV reverse transcriptase
 Adefovir

• Weaker antiviral activity than tenofovir

• Safe in patients with HIV

• Associated with lower rates of resistance mutations compared with

lamivudine
 Management

• The principal goals of anti-HBV treatment are

to stop or decrease liver disease progression,
 prevent cirrhosis and hepatocellular carcinoma.

• Following the publication -analysis of the SMART which proved that

HIV-HBV coinfected patients were more at risk of liver-related events
when treatment was initiated late,
• It is now recommended to treat all patients with dual HIV-HBV infection,
regardless of the level of HBV replication or CD4 count
Management cont.
• The only recommended drug is tenofovir because of its dual and very
potent activity against HBV and HIV.

• After 7 years of treatment, more than 90% of patients do not exhibit

HBV replication anymore.

• In the remaining 10%, persistence of viral replication is mainly due to

non-adherence.

• To date, no viral resistance to tenofovir in vivo has been described,

although resistant strains have been identified in vitro.
Management cont.
• The addition of lamivudine or emtricitabine is dictated by the need of
also controlling HIV within an optimal antiretroviral combination.

• There is presently no place for pegylated-interferon because recent

trials have not been able to demonstrate an impact of peg-interferon in
HBe, HBs seroconversion or control of HBV-DNA in the long term,
compared to nucleotide analogs, and tenofovir in particular.
Management cont.
• Issues raised by the long-term treatment with tenofovir are threefold.
First, long-term tolerance of tenofovir is questionable because of its
impact on renal and bone metabolism.

• In that perspective, the development of tenofovir alafenamide, which has the

ability to reach a higher cell but lower plasma concentration, may lead to a
better renal and bone profile with an equivalent antiviral efficacy.
Second, although patients are virologically suppressed in the long
term, they very seldom seroconvert and the risk of hepatocellular
carcinoma (HCC) is low but not eliminated.
• Patients should therefore be screened annually (or biannually if cirrhotic) for
HCC.
Finally, around 10% of patients still exhibit a low level of HBV-DNA
replication (ranging from 10 to 2000 IU/mL), although in most cases
adherence is good.
• Reasons for persistent low-level replication are not clear and may be host-
(immune profile) more than virus- (resistance) related.
• Tenofovir-containing ART regimen for the treatment of HIV/HBV
coinfection. (C/I only if patients with a history of a severe adverse
reaction to TDF, those with an estimated glomerular filtration rate
[eGFR] <15 mL/min/1.73 m2 who are not receiving dialysis, and those
with severe osteoporosis).
• Dolutegravir plus tenofovir alafenamide-emtricitabine (TAF/FTC)
• Bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF)
Duration of therapy 
• Patients with HIV and hepatitis B virus (HBV) coinfection will receive
indefinite treatment for HIV and HBV, typically with a regimen
containing tenofovir.
• Based upon the chronic nature of HBV infection and the fact that
patients with HIV require life-long ART.
Hepatitis C Virus Co-infection with HIV
 Hepatitis C virus (HCV) coinfection
• Hepatitis C virus (HCV) coinfection can be found in 25% of all
human immunodeficiency virus (HIV) patients in Europe and North
America.

• High rates of HCV liver disease morbidity and mortality occur when
accompanied by HIV coinfection;
• In particular, in countries where intravenous drug use is the main
driver of the HIV epidemic, such as in Ukraine or Russia, up to 70%
of HIV patients are dually infected with HCV.

• More recently, there also have been reports of an outbreak of acute

HCV among HIV-seropositive men who have sex with men from
Europe, Australia, Taiwan and the USA.
 VIROLOGY OF HCV

Viral kinetics — HIV (a retrovirus) and HCV (a flavivirus) are RNA viruses.

• HIV viral production rates approximate 10 virions a day with a half-life of less than
six hours.
• Virion production rates are even greater with HCV, approaching 12 virions a day with
a virion half-life of 2.7 hours
Viral load —HCV RNA levels increase after HIV seroconversion and
continue to increase over time compared with patients with HCV alone.

Viral reservoirs —  HCV RNA replication in PBMCs (peripheral blood

mononuclear cells (PBMCs) may occur in patients with HIV/HCV
coinfection, but not in those with HCV alone.
 Pathogenesis

• In the natural course of hepatitis C in HIV, in the absence of

antiretroviral therapy, a faster progression of hepatic fibrosis has been
observed.
• This enhanced fibrosis progression may be a result of the direct
fibrogenic effect of HIV in the liver and a likely consequence of
• HIV-induced impairment of the innate and adaptive immune system leading to
more inflammation, apoptosis and fibrosis.
• Importantly, successful anti-HIV therapy can slow down the
accelerated cause of fibrosis progression in HIV/HCV coinfected
patients.
• The levels of HCV viremia which represent a hallmark of HIV/HCV
coinfection have been found to decrease in a significant amount of
patients in whom successful combined antiretroviral therapy has been
started
 Effects of HIV in the natural history of HCV

• They are less likely to clear viral infection.

• Have more rapid rates of fibrosis.

• Higher risk of hepatic decompensating compared with HCV monoinfected patients.

• HIV-infected patients have lower rates of spontaneous virologic clearance during

acute infection, especially in the setting of lower CD4 cell counts.
GOALS OF THERAPY
• Sustained virologic response as cure — Successful antiviral therapy is
characterized by achievement of a sustained virologic response (SVR), defined as
an undetectable HCV RNA 12 to 24 weeks after the end of treatment

• Clinical benefits of cure

• Improvement and/or delayed progression of fibrosis and necroinflammation
• Reduction of morbidity and mortality secondary to liver disease
• Reduced incidence of hepatocellular carcinoma
Screening for HCV infection

Step 1. All HIV-infected persons should be screened for HCV infection

• Acute HCV infection, antibodies may not be detectable for three to eight weeks following
initial HCV infection

•Antibodies persist indefinitely, in chronically infected patients but the antibody titres may
decrease (and even disappear)in patients who clear HCV (either spontaneously or after
antiviral treatment).

•HIV can impair antibody responses to HCV infection , so a second- or third- generation
enzyme immunoassay for HCV antibodies should be used in coinfected individuals.

•<5% pt’s with severe immunosuppression (eg, CD4 cell counts <100 cells/mm3) may have
a false negative serology due to impaired antibody formation.
Step 2. When testing for HCV antibodies is positive, detection of HCV RNA
should be performed to confirm or exclude active replication

• HCV RNA can be detected as soon as a few days after infection.

• HCV RNA can be detected by PCR (polymerase chain reaction) or by TMA

(transcription-mediated amplification).

• High pretreatment HCV RNA levels are associated with lower rates of sustained
virological response .the cut-off is generally 800 000 copies/ml (IU/ml).

• It is important to consider that viral load is higher (0.5–1 log on average) This
may also account for higher HCV transmission to children born to coinfected
mothers.
Step 3. Use HCV genotype determination in predicting
treatment response.
• Infections with more than one HCV genotype appear to be more often (>5%) in
patients coinfected with HCV and HIV, particularly IDUs and haemophiliacs.

• For genotypes other than 1 or 4, SVR rates are generally high ranging from 73%
in the ACTG 5071 study , to 62% in the APRICOT study , 53% in the Barcelona
study and 44% in the RIBAVIC study.

• For genotype 1, SVR rates lower range from 29% in APRICOT to 17% in
RIBAVIC and 14% in ACTG 5071 , while Barcelona reported a 38% SVR rate for
those with genotype 1 or 4 .
Evaluation of HCV disease severity

• Clinical evaluation of liver disease( stigmata of CLD)

• Biochemical parameters(AST/ALT, GGT, bilirubin, PT/INR, Albumin)
• CTP score
• USG.
• Non-invasive markers of liver fibrosis( fibroscan)
Extrahepatic Manifestations of Hepatitis C
• Hematologic:
• Cryoglobulinemia
• lymphoma
• Rheumatologic: rheumatoid arthritis
• Renal: Glomerulonephritis
• Dermatologic:
• Porphyria cutanea tarda
• Cutaneous necrotizing vasculitis
• Lichen planus
• CNS: depression
• Systemic: fatigue
GOALS OF THERAPY
• Sustained virologic response as cure — Successful antiviral therapy is
characterized by achievement of a sustained virologic response (SVR), defined as
an undetectable HCV RNA 12 to 24 weeks after the end of treatment

• Clinical benefits of cure

• Improvement and/or delayed progression of fibrosis and necroinflammation
• Reduction of morbidity and mortality secondary to liver disease
• Reduced incidence of hepatocellular carcinoma
 ANTIRETROVIRAL MANAGEMENT

ART-naïve patients
• Initiation of ART prior to HCV antiviral therapy allows assessment of
tolerability and adverse effects of ART alone.

ART-experienced patients
• HIV/HCV-coinfected patients who have achieved HIV viral suppression on an
ART regimen that they tolerate can continue the regimen if it does not have
any expected significant drug interactions with the selected HCV treatment
regimen.
• In contrast, a regimen switch may be indicated if components of the ART
regimen cannot be used with the HCV antiviral agents.
Considerations When Starting Antiretroviral Therapy
• When both HIV and HCV treatments are indicated, the ARV regimen should be
selected with careful consideration of potential drug-drug interactions with the HCV
treatment regimen
• Before starting HCV therapy, the ART regimen may need to be modified to reduce the
drug-drug interaction potential.
• HIV RNA should be measured within 2 to 8 weeks after changing HIV therapy to
confirm the effectiveness of the new regimen

• In persons with HCV/HBV coinfection, HBV reactivation has been observed during
HCV treatment with DAAs.
• Therefore, before initiating HCV therapy, persons with HCV/HIV coinfection and active HBV
infection (HBsAg positive) should receive ART that includes agents with anti-HBV activity
(such as tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide plus emtricitabine or
lamivudine).
• Patients with cirrhosis should be evaluated for signs of liver
decompensation according to the Child Turcotte-Pugh classification
system.
• All patients with Child-Pugh class B or C disease should be evaluated
by an expert in advanced liver disease and considered for liver
transplantation.
• Hepatically metabolized ARV and HCV DAA drugs may be
contraindicated or require dose modification in patients with Child-
Pugh class B and C disease
Hepatotoxicity
• Drug-induced liver injury (DILI) following the initiation of ART is
more common in patients with HCV/HIV coinfection than in those
with HIV mono-infection
• Significant elevations in ALT and/or AST levels( >5 times ULN),
concomitant increase in total bilirubin, and/or concomitant symptoms
(weakness, nausea, vomiting) should be carefully evaluated for signs
and symptoms of liver insufficiency .
• If these signs and symptoms do not resolve, ART should be
discontinued
• An interferon-free regimen of sofosbuvir and ribavirin in HIV/HCV dually infected
individuals for 12–24 weeks have been presented from the PHOTON study
demonstrating very high cure rates for genotype 2 (88% after 12 weeks of therapy)
and high cure rates with genotype 1 patients after 24 weeks of treatment (76%).

• The following regimen options with direct-acting antivirals such as 

sofosbuvir, ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-
voxilaprevir, glecaprevir-pibrentasvir, elbasvir-grazoprevir, ombitasvir-
paritaprevir-ritonavir  with or without dasabuvir, daclatasvir, and simeprevir  are
currently or imminently available.
Highly effective Interferon- free options
• Genotype 1 infection — Ledipasvir-sofosbuvir, sofosbuvir-velpatasvir.
• Genotype 2 infection — Sofosbuvir-velpatasvir for 12 weeks is the preferred
regimen.
• Genotype 3 infection —Sofosbuvir-velpatasvir for 12 weeks is the preferred
regimen.
• Genotype 4 — Several interferon-free regimens have high expected efficacy
against genotype 4 infection. Eg.: ledipasvir-sofosbuvir, sofosbuvir-velpatasvir for
12 weeks duration
• Genotype 5 — Data on treatment of genotype 5 infection are limited. The
interferon-free options are the fixed-dose combination of ledipasvir-sofosbuvir or
sofosbuvir-velpatasvir for 12 weeks
• Genotype 6 --- same as genotype 5
Regimens Not Recommended
 References
• UPTODATE 21TH EDITION
• Infectious Diseases by Jonathan Cohen
• Harrison 20th edition
THANK YOU