HIV/AIDS BY SYSTEM

HIV and the liver

Whats new?

Gary Brook
C

Abstract
There are different ways that HIV-related liver disease can be categorized.
Clinically, it can be split into: disease that relates to the immunocompromised state; disease that involves co-infection with hepatitis viruses; and
drug-related adverse events. In the immunocompromised patient with a
low CD4+ lymphocyte count, biliary tract disease caused by cytomegalovirus and cryptosporidia, granulomatous hepatitis with infections such
as tuberculosis and leishmaniasis, and malignant hepatic infiltration
including lymphoma, Kaposis sarcoma and hepatoma have to be considered. HIV patients are more likely to develop chronic hepatitis B virus
(HBV) or hepatitis C virus (HCV) infection in which the prognosis is
worse and treatment less effective than in HIV-uninfected individuals.
Drug-related liver dysfunction is also common in HIV infection and includes hepatocellular dysfunction with antiretrovirals such as nevirapine,
hyperbilirubinaemia due to atazanavir, portal hypertension due to didanosine and hepatic steatosis due to stavudine. These conditions can be
treated and combination antiretroviral therapy (cART) has made HIVrelated liver disease of all types more amenable to therapy. Chronic
HBV infection responds to a range of drugs including pegylated interferon, adefovir, telbivudine and the antiretrovirals tenofovir, lamivudine
and emtricitabine. Acute and chronic hepatitis C will respond to pegylated
interferon and ribavirin. More recently, the direct-acting antivirals for
hepatitis C (boceprevir and telaprevir) have greatly increased treatment
response rates in HIV co-infected patients to levels similar to those
seen in HCV mono-infected patients. Liver transplantation can be also
offered when appropriate.

Liver disease in immunocompromised HIV-positive patients

Cholestatic liver disease1
Causes: chronic cholangitis simulating sclerosing cholangitis is
seen mostly when the CD4 lymphocyte count is less than 200
cells/ml. The two pathogens most commonly associated with this
are Cryptosporidium parvum and cytomegalovirus (CMV). In a
proportion of patients, a pathogen cannot be identified (HIVrelated cholangiopathy).
Presentation: right hypochondrial pain or painless jaundice with
low-grade fever. C. parvum will also cause watery diarrhoea and
CMV can present with systemic illness and retinitis.

Keywords antiretrovirals; cholangitis; chronic liver disease; drug-related

hepatitis; hepatitis B; hepatitis C; liver transplantation

Diagnosis: typically serum alkaline phosphatase (ALP) and total

bilirubin are raised with normal alanine aminotransferase (ALT).
Imaging techniques such as magnetic resonance imaging (MRI)
or endoscopic retrograde cholangiopancreatography (ERCP) will
reveal changes suggestive of cholangitis. C. parvum can be seen
in the stool (auramine staining) and CMV is detected in blood by
polymerase chain reaction (PCR). Both pathogens may be identified from biliary samples taken at ERCP. Idiopathic HIV-related
cholangiopathy is a diagnosis of exclusion.

Introduction
Liver disease in HIV-positive patients can be categorized in
several ways. One way is to look at patterns of liver enzyme
abnormality (Table 1). An alternative and clinically useful categorization is to divide the causes into three types:

diseases seen in immunocompromised patients

viral hepatitis co-infection

drug-related hepatic dysfunction
In order to understand the differential diagnosis of liver
dysfunction, the history should include the CD4 lymphocyte
count, any history of potential exposure to pathogens or bloodborne viruses, treatment history, including antiretrovirals and
other potentially hepatotoxic drugs (e.g. tuberculosis (TB) therapy), and the duration of symptoms.

Management: it may be necessary to improve biliary drainage

using a stent or sphincterotomy. Management focuses on combination antiretroviral therapy (cART); improved host immunity
facilitates recovery. CMV will respond to ganciclovir, foscarnet or
cidofovir. Cryptosporidiosis is less amenable to therapy,
although paromomycin, nitazoxanide or atovaquone may have
some benefit.
Infiltrative and mass lesions of the liver2
Causes: some infections and malignancies affecting the liver
present as infiltrative or mass lesions. The most common cause
of diffuse granulomatous hepatitis is mycobacterial infection (TB
or atypical), but less commonly other infections such as syphilis

Gary Brook MD FRCP BSc DTM&H DipGUM is Consultant Physician at the

North West London Hospitals NHS Trust, London, UK. Competing
interests: none declared.

MEDICINE 41:8

Portal hypertension and nodular regenerative hyperplasia of the

liver is being increasingly recognized in HIV-positive patients
previously treated with the antiretroviral didanosine
Syphilis is common, especially amongst men who have sex with
men, and should be considered as a cause of abnormal liver
function tests and granulomatous hepatitis
All patients with HIV and hepatitis B co-infection should be
considered for therapy and this would often be with triple antiretroviral therapy that includes tenofovir plus lamivudine or
emtricitabine
All patients with chronic hepatitis C should be considered for
therapy with pegylated interferon, ribavirin and boceprevir or
telaprevir and a treatment response rate of >50% is likely
Newer, direct-acting antivirals for hepatitis C are likely to be
licensed soon, further increasing response rates and possibly
leading to non-interferon regimens

446

2013 Elsevier Ltd. All rights reserved.

HIV/AIDS BY SYSTEM

Patterns of liver enzyme abnormality seen in HIV-related pathology

Liver enzyme abnormality

Mechanisms

Examples

Raised bilirubin, normal ALT/ALP/GGT

Inhibition of bilirubin conjugation

Haemolysis
Space-occupying lesions in the
liver parenchyma

Antiretrovirals such as atazanavir (common)

Dapsone for PCP prophylaxis in G6PD deficiency
C
Granulomatous infiltration (e.g. TB, syphilis,
visceral leishmaniasis)
C
Malignancy (e.g. lymphoma)
C
Chronic hepatitis B or C
C
Drug-related hepatitis (e.g. nevirapine, anti-TB drugs)
C
Acute viral hepatitis (A, B, C, etc.)
C
Drug toxicity (e.g. nevirapine or anti-TB drugs)
C
Hepatic steatosis
HIV-related idiopathic cholangiopathy
Cryptosporidiosis, CMV infection
Past or current didanosine treatment, possibly
with other co-factors

Raised ALP and GGT, normal bilirubin/ALT

Raised ALT alone

Chronic hepatocellular damage

Acutely raised ALT, bilirubin and ALP

Acute hepatocellular damage

Raised bilirubin/ALP with normal

or modestly raised ALT
Normal LFT or modest rise in ALT
or ALP in the presence of portal hypertension

Biliary dysfunction
Cholangitis
Atrophy of the portal venules,
sometimes with hepatic nodular
regenerative hyperplasia

ALP, alkaline phosphatase; ALT, alanine aminotransferase; CMV, cytomegalovirus; G6PD, glucose-6-phosphate dehydrogenase; GGT, gamma glutamyl transferase;
HIV, human immunodeficiency virus; LFT, liver function test; PCP, Pneumocystis carinii (jirovecii) pneumonitis; TB, tuberculosis.

Table 1

(secondary or tertiary), disseminated fungal infections (e.g. histoplasmosis) or visceral leishmaniasis (VL) will present similarly.
Lymphomas (typically non-Hodgkins type) and solid malignancies, such as hepatocellular carcinoma or Kaposis sarcoma,
can also present in this way.

seropositive patients with a very low CD4 count (<50 cells/ml),

relapse of chronic hepatitis B or C may not be associated with
positive serological markers other than HBV DNA or HCV RNA,
respectively.
Management: patients with acute hepatitis C should be
considered for treatment with weekly pegylated interferon a
injections and ribavirin for 3e6 months. Otherwise treat
symptomatically.

Presentation: right hypochondrial discomfort and/or hepatomegaly and fever.

Diagnosis: ALP and g-glutamyl transferase (GGT) will be raised
with little or no abnormality of the ALT or bilirubin. Ultrasound,
CT or MRI scanning of the liver will reveal infiltrative or mass
lesions. TB or lymphoma may be suspected from other systemic
features such as lymphadenopathy or lung disease. Ultrasoundguided liver biopsy usually provides the diagnosis.

Chronic viral hepatitis3e8

Causes: viral hepatitis types B (D) or C. Drug-related hepatitis
or hepatic steatosis can present in a similar way.
Presentation: most patients are asymptomatic, apart from some
lethargy, unless cirrhosis and hepatic decompensation ensue.
Progression to cirrhosis and liver cancer is two to five times
higher in HIV-seropositive patients compared to those who are
hepatitis mono-infected.

Management: therapy is directed at the underlying cause. Antiretroviral therapy also improves the prognosis.
Acute viral hepatitis3
Causes: viral hepatitis types A, B, C, D and E. Consider CMV,
EpsteinBarr virus and drug-related hepatitis. Acute relapse of
chronic viral hepatitis due to falling immunity may also present
in this way.

Diagnosis: chronic viral hepatitis should be considered if

serum ALT is raised with normal ALP and bilirubin. ALT is
frequently normal; so all HIV-seropositive patients should be
screened for hepatitis B and C annually and more often if the
patient is at particular risk. Screening should involve testing for
anti-HBc or HBsAg for hepatitis B and anti-HCV antibodies for
hepatitis C. A small number (1e2%) will be negative on serological testing, but will have detectable serum HBV DNA or
HCV RNA. Therefore, patients with raised ALT of unknown
cause should be tested for HBV DNA or HCV RNA. A liver scan
is mandatory. Liver biopsy or hepatic elastography should be
considered for any patient with suspected cirrhosis. It will
also help the decision as to when to treat chronic hepatitis C
(Table 2).

Presentation: the symptoms of acute viral hepatitis are as seen in

the immunocompetent host. The rate of progression to chronic
infection in hepatitis B is much higher in HIV-seropositive patients and is in the order of 20%. All patients known to be HIVpositive with no immunity to hepatitis B or C should be vaccinated accordingly.
Diagnosis: the virological diagnosis and liver function test (LFT)
abnormalities are as seen in the immunocompetent host. In HIV-

MEDICINE 41:8

447

2013 Elsevier Ltd. All rights reserved.

HIV/AIDS BY SYSTEM

Antiviral therapy for chronic viral hepatitis in HIV-positive patients

Type of hepatitis
Hepatitis B
HBV-DNA >2  103 IU/ml
or HBeAg ve, fibrosis
excluded

Hepatitis B with HBV DNA

>2  103 IU/ml (>2  102
IU/ml in cirrhosis)
Hepatitis B and D
Hepatitis B and D
Hepatitis C
Genotypes 1 and 4

Genotypes 1 and 4
Genotypes 2 and 3

Factors influencing treatment

Treatment

CD4 count >350 cells/ml

Pegylated interferon a weekly for 4e6 months

(only if HBeAg ve, CD4 >500)
or
Start antiretroviral therapy with HBV-active agents (see below)
or
Adefovir and/or telbivudine until CD4 falls enough for
antiretroviral therapy to be started
cART to include tenofovir plus either emtricitabine
or lamivudine
Continue these drugs, even if the HIV becomes resistant,
if they show continuing anti-HBV activity

CD4 count <350 cells/mm3 or cirrhosis

Any CD4 count

cART as above
Pegylated interferon may be considered

Liver biopsy shows significant fibrosis12

(METAVIR stages F 2e4)

Pegylated interferon ab weekly plus ribavirin for

48e72 weeks
For genotype 1 add boceprevir or telaprevir
If CD4 count <350 cells/ml stabilize on cART firsta
Defer interferon/ribavirin and monitor liver fibrosis status
If CD4 count <350 cells/ml start on cARTa
Pegylated interferon ab weekly intramuscular/subcutaneous
plus ribavirin for 24 weeks
If CD4 count <350 cells/ml stabilize on cART firsta

Liver biopsy does not show significant

fibrosis12 (METAVIR stages F 0e1)
No evidence of decompensated cirrhosis
(liver biopsy not mandatory)

cART, combined antiretroviral therapy; HBV, hepatitis B virus; HIV, human immunodeficiency virus.
a
Avoid zidovudine, stavudine, abacavir, didanosine and nevirapine because of liver toxicity and drug interactions.
b
Patients with cirrhosis tolerate interferon poorly and may decompensate.

Table 2

Management: the decision process for specific treatment of

chronic viral hepatitis is quite complex (Table 2).
Hepatitis B e pegylated interferon is reserved for HBeAgpositive patients. Entecavir should not be used, unless given
alongside cART, as it induces the M184V mutation (conferring
resistance of HIV to lamivudine/emtricitabine). Adefovir, telbivudine, tenofovir, lamivudine and emtricitabine suppress HBV
DNA with improvement in the LFT but need to be given in the
long term. Tenofovir, lamivudine and emtricitabine should be
given only as part of cART to avoid HIV-resistance mutations
developing. Tenofovir is normally given with one of the other
two drugs, for example as Truvada (tenofovir plus emtricitabine), as the combination is more effective and reduces the risk
of HBV-resistance mutations. Lamivudine and emtricitabine are
not given together as they have an identical mode of action and
without additional tenofovir can induce HBV-resistance mutations in the YMDD area of the polymerase gene.
Hepatitis D e this is very difficult to treat. Interferon and
antiviral therapy may have some benefit, but patients with this
infection inevitably progress to cirrhosis.
Hepatitis C e pegylated interferon plus ribavirin is effective in
inducing a sustained virological response in about 50% of patients with HCV genotypes 2 and 3 and about 30% of those with

MEDICINE 41:8

types 1 and 4. However adding the anti-HCV protease inhibitors,

boceprevir and telaprevir, will increase treatment response by a
further 20% in those with genotype 1. Numerous other directacting antivirals for HCV are also under trial and should be
considered when available, Response is best when the CD4 is
high, and this may mean starting cART first (CD4 <350 cells/ml).
Ideally, anti-HCV therapy would be started before cART is
needed. As the response rate for genotypes 1 and 4 is quite low,
treatment is usually reserved for those patients with a high
fibrosis score on biopsy (METAVIR score F2e4). In contrast,
treatment is recommended for all suitable patients with genotypes 2 and 3 because of the high response rate. Treatment for
hepatitis C is now rules-based, depending on the virological
response in the first 3 months, which means that treatment
should be stopped if no evidence of early response is seen.
Screening for hepatocellular carcinoma (HCC) by 6-monthly
liver ultrasound scans plus serum a-fetoprotein should be performed on all patients with cirrhosis and in those patients
with chronic hepatitis B with a viral load of greater than
200,000 IU/ml or if they are Asian and aged over 40 years or African
and aged over 20 years.5 Liver transplantation should be considered
for all suitable patients with cirrhosis or HCC although the outcomes
for patients with HCV are less good than for patients with HBV.5

448

2013 Elsevier Ltd. All rights reserved.

HIV/AIDS BY SYSTEM

Drug-related hepatitis9e13
LFT abnormalities in HIV-positive patients are often drug related
and physicians should be aware of the many possible drugs that
can be responsible.

8 FriedricheRust M, Ong M. Performance of transient elastography for

the staging of liver fibrosis: a meta-analysis. Gastroenterol 2008;
134: 960e74.
9 Petersen K, Riddle MS, Jones LE, et al. Use of bilirubin as a markerof adher
ence to atazanavir-based antiretroviral therapy. AIDS 2005; 19: 1700e2.
10 Macias J, Neukam K, Mallolas J, et al. Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one
non-nucleoside analog or one ritonavir-boosted protease inhibitor in
HIV/HCV-coinfected patients. HIV Clin Trial 2012; 13: 61e9.
11 Ristig M, Drechsler H, Powderly WG. Hepatic steatosis and HIV
infection. AIDS Patient Care STDS 2005; 19: 356e65.
12 Velayudham LS, Farrell GC. Drug-induced cholestasis. Expert OpinDrug Saf 2003; 2: 287e304.
13 Scourfield A, Waters L, Holmes P, et al. Non-cirrhotic portal hypertension in HIV-infected individuals. IntJ STD AIDS 2011; 22: 324e8.

Solitary unconjugated bilirubinaemia: the antiretroviral, atazanavir, invariably causes a benign rise in serum bilirubin in all treated
patients. Other protease inhibitors may also have this effect.
Hepatocellular dysfunction: LFT abnormalities indistinguishable from acute or chronic hepatitis can be caused by drugs
commonly used in HIV. Most antiretrovirals can do this,
although the non-nucleoside reverse transcriptase inhibitors,
nevirapine and efavirenz, and protease inhibitors such as lopinavir have been most frequently linked. Other drugs to consider
include isoniazid, rifampicin and pyrazinamide, when used to
treat concurrent TB.

Practice points
Cholestatic liver disease: this is less common but may be
associated with stavudine as part of a disease spectrum that includes hepatic steatosis and lactic acidosis. Anabolic steroids
used to treat HIV-related weight loss can cause cholestasis.

Non-cirrhotic portal hypertension: this problem has been

increasingly recognized in recent years and is strongly linked to
the current or past use of the anti-retroviral didanosine (DDI). In
some cases the liver histology shows nodular-regenerative hyperplasia related to severe atrophy of the portal venules.
A

REFERENCES
1 Bilgin M, Balci NC, Erdogan A, et al. Hepatobiliary and pancreatic MRI and
MRCP findings in patients with HIV infection. Am J Roentgenol 2008; 191:
228e32.
2 Lizardi CJ, Soto RLE, Poo JL, Uribe M. Hepatobiliary diseases in patients with human immunodeficiency virus (HIV) treated with non
highly active anti-retroviral therapy: frequency and clinical manifestations. Ann Hepatol 2005; 4: 188e91.
3 Lacombe K, Rockstroh J. HIV and viral hepatitis coinfections: advances and challenges. Gut 2012; 61(suppl 1): i47e58.
4 Williams I, Churchill D, Anderson J, et al. HIV and viral hepatitis coinfection. In: British HIV association guidelines for the treatment of
HIV-1-positive adults with antiretroviral therapy, 2012. http://www.
bhiva.org/documents/Guidelines/Treatment/2012/hiv1029_2.pdf
(accessed November 2012).
5 Rockstroh JK, Bhagani S, Bruno R, et al. Clinical management and
treatment of chronic hepatitis B and C coinfection in HIV-infected
Adults. In: European AIDS Clinical Society (EACS) guidelines version
6.1, November 2012. http://www.europeanaidsclinicalsociety.org/
images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf (accessed
February 2013).
6 Chun HM, Roediger MP, Hullsiek KH, et al. Infectious Disease Clinical
Research Program HIV Working Group. Hepatitis B virus coinfection
negatively impacts HIV outcomes in HIV seroconverters. J Infect Dis
2012; 205: 185e93.
7 Weber R, Sabin CA, Friis-Mller N, et al. Liver-related deaths inpersons infected with the human immunodeficiency virus: the D:A:D
study. Arch Intern Med 2006; 166: 1632e41.

MEDICINE 41:8

In HIV-positive patients with a low CD4+ lymphocyte count

(<200 cells/ml) and hepatic dysfunction, consider secondary
infection or malignancy as a cause
Biliary disease in the immunocompromised patient may be due to
cytomegalovirus, cryptosporidia or HIV-related cholangiopathy
Mycobacterial disease, syphilis, leishmaniasis and disseminated fungal infection cause granulomatous hepatitis
Mass lesions of the liver are commonly due to lymphoma,
Kaposis sarcoma and hepatoma
Consider drugs, especially antiretrovirals as a cause of liver
function test abnormalities
Non-cirrhotic portal hypertension related to current or past
didanosine use has been increasingly recognized recently
Refer patients with acute or chronic liver failure at an early
stage to a liver transplant surgeon

Viral hepatitis e practice points

C

Screen all HIV-positive patients for hepatitis B (HBV) and C (HCV)

 annually e more frequently if high risk
 include anti-HBc/HBsAg and anti-HCV

Vaccinate if no immunity to hepatitis B

Test patients with raised alanine transaminase of unknown
cause for HBV DNA and HCV RNA
 antibody tests may give false-negative results

449

Screen for hepatocellular carcinoma 6-monthly by ultrasound

scans and serum a-fetoprotein in:
 all patients with cirrhosis
 chronic hepatitis B with HBV DNA >200,000 IU/ml
 Asian aged >40 or African aged >20
Treat patients with chronic hepatitis B and HBV-DNA >2  103
IU/ml with pegylated interferon or antivirals
Consider all patients with chronic hepatitis C co-infection for
treatment with pegylated interferon, ribavirin, and boceprevir
or telaprevir

2013 Elsevier Ltd. All rights reserved.