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Chapter
10
Abnormal Laboratory Values In HIV Disease
David H.
Spach, MD
John G. Bartlett, MD
Common
Abnormalities
TOP
What are
some common abnormalities found when screening asymptomatic patients?
Some disease
processes associated with HIV can be first identified in laboratory
screening tests while patients are still asymptomatic. The primary
care provider plays an essential role in monitoring for laboratory
abnormalities, whether these abnormalities result from diseases
or from antiretroviral therapy (ART). Table 10-1 lists screening
tests that assist in promptly identifying and managing medical problems
in asymptomatic patients. Abnormal laboratory tests occur more frequently
in HIV-infected persons because 1) HIV is a multi-system disease,
2) HIV causes immune suppression that may result in opportunistic
infections and tumors that involve multiple systems, 3) the drugs
used routinely in management can cause adverse reactions that affect
multiple systems, and 4) patients at high risk for HIV are often
at high risk for other medical conditions.
Table
10-1. Abnormalities Identified in Screening Tests
CBC |
- Anemia
- usually due to HIV or zidovudine.
- Neutropenia
- usually due to HIV or drugs, especially ganciclovir
and zidovudine.
- Thrombocytopenia
- usually due to HIV.
|
Alanine
aminotransferase (ALT) |
Usual
causes of elevated levels are chronic hepatitis (HBV, HCV),
alcoholic liver disease, or adverse drug reactions. |
Creatinine |
Usual
causes of renal failure are common medical conditions in this
population (hypertension, heroin use, diabetes, IgA nepropathy,
etc), adverse reactions to drugs (including indinavir), or
HIV nephropathy. |
Toxoplasma
titer |
Positive
results in 10% of adults in US, higher in other countries.
This indicates latent disease with possible activation if
CD4 count <100/mm3. |
VDRL
or RPR |
If
positive, need confirmatory
FTA-ABS. |
Screen
for N. gonorrhoeae and C. trachomatis |
Positive
results indicate high-risk behavior and need for treatment. |
PPD |
Induration
5mm indicates need for evaluation for active TB and, if negative,
INH treatment. |
Chest
x-ray |
Ghon
complex, adenopathy, or evidence of chronic lung disease. |
CD4
count |
Barometer
of immune function. |
Viral
load |
Indicates
rate of progression of untreated HIV and response to HAART. |
Hepatitis
Panel
|
Anti-HCV |
Positive
results ± confirmatory HCV RNA usually indicates chronic
HCV infection. |
Anti-HBc
or
Anti-HBs serology
|
Positive
results indicate prior antigenic experience with HBV. |
HBsAg |
Indicates
HBV; if positive >6 months indicates chronic HBV. |
Anti-HAV |
Positive
test indicates prior antigenic experience due to HAV infection
or vaccination. |
What constitutes
a positive PPD in HIV disease?
Induration
of 5mm or more at 48-72 hours constitutes a positive PPD test for
tuberculosis in a person with HIV. A PPD should be done at baseline
and repeated annually if the initial test was negative and the patient
is in a high-risk category for tuberculosis. The test has a relatively
high rate of false-negative results in patients with a CD4 cell
count of <200/mm3. Therefore, if the initial test was done when
the CD4 cell count was low, it should be repeated when the CD4 cell
count increases to >200/mm3 following ART. Patients with a positive
PPD test need a chest x-ray and evaluation for active disease before
isoniazid (INH) prophylaxis is initiated.
What is
the role of a baseline chest x-ray?
A chest x-ray
is recommended for detection of latent or active tuberculosis and
other lung diseases and as a baseline for patients who are at high
risk for pulmonary disease, especially bacterial pneumonia, Pneumocystis
pneumonia, and tuberculosis. The x-ray is particularly important
for any patients with a positive PPD skin test.
What do
you do when a patient has a positive VDRL or RPR?
The standard
screening tests for syphilis in sexually active patients are the
nontreponemal tests, the VDRL or RPR. Any positive screening test
should be confirmed with a fluorescent treponemal antibody absorbed
test (FTA-ABS). Confirmation is particularly important because for
biologic false-positive tests are more common with injection drug
use, pregnancy and HIV infection. With a positive test, primary,
secondary, and early latent syphilis (less than 1 year) should be
treated with a single injection of benzathine penicillin (2.4 million
units IM) once, late latent syphilis (more than 1 year or of unknown
duration) should be treated with 3 doses at 1-week intervals of
benzathine penicillin (2.4 million units IM with each dose), and
neurosyphilis should be treated with aqueous penicillin G, 18-24
million units/day IV for 10-14 days. Patients who are not pregnant
and do not have neurosyphilis who cannot receive penicillin may
be treated with doxycycline (100 mg po bid) given for 14 days for
primary, secondary, and early latent syphilis and for 28 days for
late latent syphilis. Because the efficacy of doxycycline is not
well established, patients who received doxycycline need extra followup.
With penicillin allergy and neurosyphilis or pregnancy, there should
be penicillin skin testing; if negative, penicillin is given, and
if positive the patient should undergo penicillin desensitization
followed by penicillin treatment. A lumbar puncture is recommended
for any patient with neurologic signs or symptoms, patients with
therapeutic failure (persistent clinical evidence of syphilis or
a sustained 4-fold increase in titer), and all patients with latent
syphilis, which includes latent syphilis of unknown duration. Some
experts have recommended performing lumbar puncture for all HIV-infected
persons with syphilis, regardless of the stage of syphilis. With
respect to followup, the nontreponemal test should be done at 3,
6, 9, 12, and 24 months.
Hematologic
Complications
TOP
What are
the common causes of anemia?
Anemia, which
is common in HIV disease, is usually caused by 1) late-stage HIV,
presumably due to viral infection of progenitor cells, 2) associated
complications that infiltrate the marrow, 3) nutritional deficiency,
4) adverse drug reactions, or 5) iron deficiency. The findings and
management are summarized in
Table 10-2.
What causes
thrombocytopenia?
Most cases
are attributed to HIV infection of the multi-lineage hematopoietic
progenitor cells in the marrow. This HIV-associated thrombyocytopenia
can occur in relatively early HIV, but is more common with late-stage
disease. Although zidovudine (AZT) may cause anemia or neutropenia,
early studies showed that it reverses thrombocytopenia. For patients
not receiving ART, the preferred treatment for HIV-associated thrombocytopenia
is to promptly initiate ART. The decision to intervene with intravenous
immune globulin (IVIG) or corticosteroids is driven by signs or
symptoms of active bleeding, the need to do an invasive procedure,
or a lack of response to ART.
What causes
neutropenia?
Neutropenia
is most commonly related to drug therapy, especially with zidovudine
(AZT), ganciclovir, or valganciclovir, but it can also be caused
by late-stage HIV or marrow-infiltrate disease. With absolute neutrophil
counts of <500/mm3 it is important to monitor for infection and
intervene with empiric antibiotics rapidly when appropriate. Address
neutropenia by discontinuing the implicated agent or by providing
cytokine therapy using G-CSF or GM-CSF.
Table
10-2. Causes of Anemia in HIV
HIV
disease |
Normal
|
Low
|
Low
erythropoietin level |
ART
Recombinant human erythropoietin (rHU EPO) |
Tumors
and infectious diseases |
Normal
|
Low
|
Positive
identification of underlying disease (eg, lymphoma, KS, MAC,
TB, CMV, histoplasmosis) |
Treatment
of underlying disease |
Parvovirus |
Normal
|
0
|
Positive
serology & PCR for parvovirus |
IVIG |
Nutritional
deficiency |
MCV
> 100 (but not with AZT or d4T)
|
Low
|
Low
B12/folate level |
Folic
acid or cobalamin |
Iron
deficiency |
MCV
low
|
Low
|
Blood
loss, low Fe, transferrin |
Treatment
of cause
Iron therapy
|
Drug
(toxicity) |
Normal
|
Normal
|
Identify
offending drug (zidovudine, ganciclovir, TMP-SMX, etc.) |
Stop
implicated agent |
Drug
(hemolysis) |
Normal
|
Increased
|
Identify
offending drug (dapsone, ribavirin); increased LDH, indirect
bilirubin/low haptoglobin |
RBC
therapy
Stop drug
|
Liver
Disease
TOP
What are
the common causes of abnormal liver function tests?
Abnormal screening
liver function tests reflect associated conditions (hepatitis B
or C viral infection as discussed below), adverse drug reactions,
alcoholic hepatitis, and HIV-related complications, including Kaposi
sarcoma, lymphoma, Mycobacterium avium complex (MAC), tuberculosis,
cytomegalovirus (CMV), or histoplasmosis. Start by defining the
process as cholangiopathic or hepatocellular based on results of
liver function tests (LFTs).
- AIDS cholangiopathy
typically presents with right upper quadrant pain, high alkaline
phosphatase, characteristic duct dilatation on ultrasound, and
a CD4 cell count of <100/mm3. The usual causes are infection
(microsporidia, cytomegalovirus, or cryptosporidia) or idiopathic.
Most cases respond temporarily to endoscopic biliary sphincterotomy.
- Hepatocellular
injury is much more common and is caused by diverse conditions,
including 1) hepatitis viruses, 2) alcoholic hepatitis, 3) cirrhosis,
and 4) adverse drug reactions. All antiretroviral drugs are potentially
hepatotoxic, but the indications for intervention vary depending
on the mechanism and severity (see Table 10-3).
When should
you stop antiretroviral drugs because of hepatotoxicity?
There are 3
situations in which antiretroviral drugs should be stopped because
of hepatotoxicity (see Table 10-3):
- Hypersensitivity
syndrome (drug rash with eosinophilia and systemic symptoms [DRESS]).
The hypersensitivity reaction seen with abacavir (ABC) and nevirapine
(NVP) is characterized by fever, eosinophilia, rash, and GI complaints,
and usually occurs during the first 6 weeks of therapy. This situation
should be urgently managed, and deaths have been reported.
- Symptomatic
lactic acidosis. This is ascribed to drugs in the NRTI class,
which should be stopped.
- Increased
transaminase levels. This is ascribed to the PIs and the NNRTIs
nevirapine (NVP) and efavirenz (EFV). The most serious reactions
have occurred with nevirapine-associated hepatoxicity.
The mechanism is unclear, and treatment interruption is often
considered necessary only when clinical hepatitis occurs.
Table
10-3. Antiretroviral Drugs That Cause Abnormal Liver Function
NRTIs |
stavudine (d4T)
didanosine (ddI)
zidovudine (AZT)
|
8%-16%
|
Mitochondrial
toxicity; risk highest with stavudine and didanosine together;
risk with zidovudine lower than stavudine. |
lamivudine
(3TC)
emtricitabine (FTC)
abacavir (ABC)
tenofovir (TDF) |
|
Rare
cause of mitochondrial toxicity. |
abacavir
(ABC) |
4%-6%
|
Hypersensitivity-DRESS
syndrome. |
lamivudine
(3TC)
emtricitabine (FTC)
tenofovir (TDF)
|
|
Withdrawal
of these drugs may cause HBV exacerbation. |
NNRTIs |
nevirapine
(NVP)
efavirenz (EFV)
|
8%-16%
|
Mechanism
not known. |
nevirapine
(NVP) |
Rare
|
Hypersensitivity
- DRESS syndrome. |
PIs |
All
PIs |
4%-6%
|
Mechanism
unknown. |
indinavir
(IDV)
atazanavir (ATV)
|
10%-20%
30%-50%
|
Elevated
indirect bilirubin; usually asyptomatic. |
Do patients
infected with HIV have increased rates of hepatitis B virus (HBV)
and hepatitis C virus (HCV) infection, and does coinfection affect
the natural progression of HIV?
HIV-infected
patients have higher rates of chronic HBV infection after exposure
to HBV. With HBV coinfection, there is a higher frequency of evidence
for HBV replication (higher frequency of HBeAg and higher levels
of HBV DNA) and higher rates of HBV-associated liver disease. It
is not known if HBV alters the natural history of HIV, but coinfection
is associated with increased frequency of hepatotoxicity with ART.
The relationship with HCV is similar. HIV coinfection is relatively
common, a frequency of about 30% in all HIV-infected patients and
as many as 85% in those with injection drug use as the risk factor.
HIV has an important effect on promoting more rapid progression
of HCV, but it is not clear whether HCV adversely affects the rate
of HIV progression. Many studies have shown that HCV coinfection
is a poor prognostic factor in the ART era, but this may well reflect
the influence of injection drug use rather than HCV-associated liver
disease.
Who should
you test for HBV and HCV, and what tests should you perform?
At entry into
health care, all patients with HIV should be screened for antibodies
to HBV and HCV, as well as HBV antigen (see Table 3-1 in Chapter
3). Knowledge of the HBV and HCV status can provide valuable information
for those persons with abnormal LFTs. In addition, testing can identify
patients who are seronegative for HBV who can receive HBV vaccination.
Some patients with HIV have negative HBV surface antibody titers,
negative HBV antigen, but positive core HBV antibody. If they have
not recently acquired HBV, this serologic pattern suggests a low-level
persistent immune response to HBV; these individuals probably have
adequate protection to prevent reinfection, but no studies have
been done to accurately evaluate their risk. Moreover, no formal
recommendation exists to provide a booster HBV vaccine to those
persons with negative HBV surface antibody titers but positive HBV
core antibody. Serologic testing using an enzyme immunoassay for
HCV is the preferred screening test for HCV, and those with positive
tests should have a confirmatory test with either the RIBA assay
or a test that detects HCV RNA. Several studies have shown that
some persons coinfected with HIV and HCV, particularly those with
severe advanced HIV disease, can have a negative HCV antibody test
on the enzyme immunoassay, but a repeatable positive HCV RNA test.
Thus, some experts would recommend doing an HCV RNA assay on a person
with a negative HCV enzyme immunoassay if HCV infection is suspected
(usually because of abnormal LFTs).
How should
you treat HBV in persons coinfected with HIV?
All coinfected
patients should be considered for HBV therapy. Recommendations are
somewhat arbitrary, but most recommend therapy with an alanine aminotransferase
(ALT) at least 2 times the upper limit of normal (ULN), evidence
of active HBV replication (e antigen or HBV DNA level of >105c/mL),
and preferably with histologic evidence of moderate disease activity
or fibrosis. There are 2 major forms of treatment and neither is
"preferred." One form is interferon-alfa-2a or alfa-2b
given subcutaneously 3 times a week or once a day for 24-48 weeks.
Many authorities now recommend pegylated interferon with subcutaneous
injections once a week, although there are few published studies
with this formulation for treatment of HBV. The second form of therapy
is nucleosides and nucleotides with activity against HBV. This gets
tricky because many of these agents are active against HIV as well,
and there are variable rates of HBV resistance. Lamivudine (3TC)
is highly active against HBV but is associated with high rates of
HBV resistance, up to 90% at 4 years. The same applies to emtricitabine
(FTC). Alternatives are adefovir
dipivoxil (trade name Hepsera), which is used in a dose that is
probably not active against HIV but is highly active against HBV,
has good activity against lamivudine-resistant strains, and has
low rates of resistance by HBV during treatment. Tenofovir (TDF)
has the same attributes as adefovir but is also highly active against
HIV. It should be emphasized that the rationale for treating HBV
is to reduce viral replication and hepatic disease progression but
that cure is rarely achieved. Other standard components of therapy
in patients coinfected with HBV are 1) advising them to avoid or
limit alcohol consumption, 2) teaching them appropriate precautions
to prevent transmission of both viruses, and 3) administering hepatitis
A vaccine if they are susceptible.
Who should
receive HBV vaccine?
All HIV-infected
persons with no evidence of HBV infection should receive this vaccine,
although the response rates are related to age (decreased with increasing
age) and with CD4 cell counts (responses decrease with lower counts).
The standard is 3 doses followed by a measurement of HBs antibody
levels about 1 month after the third dose. If the level is <10
IU/mL the 3-dose series should be repeated. If the patient does
not respond to the second series, no further vaccinations are currently
recommended and the patient is considered a "non-responder."
How do you
treat patients with HCV coinfection?
Patients coinfected
with HIV and HCV should be 1) advised to avoid or limit alcohol
consumption, 2) counseled to use appropriate precautions to prevent
transmission of both viruses, and 3) given hepatitis A and B vaccine
if they are susceptible. The prevention message should emphasize
that the major route of transmission is by shared needles; the risk
of transmission of HCV perinatally or with sexual contact is substantially
less than that for HIV or HBV.
With regard
to treatment of HCV, the goal is for cure, something that cannot
be achieved with HIV or, to a large extent, with HBV. All patients
with HCV should be evaluated for HCV therapy. Standard indications
in the absence of HIV infection are chronic HCV, detectable HCV-RNA,
and a liver biopsy showing bridging or portal fibrosis. The ALT
levels may be elevated, but this finding is variable and does not
indicate the severity of HCV-associated liver disease and is considered
nonspecific. The liver biopsy is important for HCV therapeutic decisionmaking,
but it is indicated only if the patient is considered a candidate
for treatment based on multiple variables including the severity
and stability of HIV, other comorbidities, probability of adherence,
and contraindications for interferon. The standard treatment is
pegylated interferon plus ribavirin for 48 weeks, regardless of
the genotype. There is limited long-term experience with this treatment
in patients with HIV coinfection, but it appears that the rate of
a sustained virologic response as indicated by negative HCV DNA
levels at 6 months post-therapy are significantly lower compared
to those who are seronegative for HIV. This particularly applies
to genotype 1, which accounts for the majority of cases. It also
appears that the optimal response occurs when patients have relatively
high CD4 cell counts, so this treatment is often preferred for those
in early stage disease and for those who have responded to ART.
What HCV
therapy should you use for persons coinfected with HIV and HCV?
Currently,
there are limited published data regarding various HCV treatment
regimens for persons coinfected with HIV. Trials have generally
shown relatively poor responses to interferon monotherapy. Based
on rapidly accumulating data from trials that have not included
HIV-infected persons, pegylated interferon (pegylated interferon-alpha-2a
or pegylated interferon-alpha-2b) plus ribavirin is now the standard
of care. (For treatment guidelines, refer to Suggested Resources.)
In addition, several series involving persons coinfected with HIV
and HCV have suggested better sustained viral response rates with
pegylated interferon plus ribavirin than with older regimens. For
persons not infected with HIV, recent guidelines have recommended
that those with genotypes 2 or 3 receive 24 weeks of therapy and
those with genotypes 1 and 4 receive 48 weeks of therapy. The optimal
duration of therapy for persons coinfected with HIV and HCV remains
unknown, but most trials have used 48 weeks, regardless of genotype.
Are there
special considerations regarding adverse effects of HCV therapy
in persons coinfected with HIV?
Treatment with
interferon (or pegylated interferon) and ribavirin has significant
possible adverse effects, including reactions at injection sites,
bone marrow suppression, thyroid dysfunction, neuropsychiatric symptoms,
and birth defects. Because interferon may cause significant leukopenia,
CD4 cell counts should be monitored, and patients should be warned
that CD4 counts might transiently decline while they are receiving
interferon. Persons coinfected with HCV and HIV may suffer drug
interactions and toxicities. Ribavirin causes anemia; because this
complication occurs more frequently when ribavirin is combined with
AZT, either this combination should be avoided or more frequent
use of erythtopoetin should be anticipated. Ribavirin may enhance
intracellular didanosine (ddI) levels and augment toxicity of the
drug resulting with higher rates of pancreatitis and lactic acidosis;
didanosine should not be given with ribavirin.
Is liver
transplantation an option for HIV-infected persons?
Liver transplantation
is an option in some transplant centers that combine expertise in
HIV management with the transplant service. In a study at 5 institutions
of 24 HIV-infected patients survival rates were similar to rates
in patients without HIV infection (Ragni et al, 2003). Nevertheless,
management is complicated by problems of drug interactions between
ART and the standard immunosuppressive agents, poor tolerance of
ART after liver transplantation, and relatively high frequency of
acute graft rejection. As in patients without HIV infection, the
prognosis with liver transplantion is poorer when liver disease
is caused by HCV. The recommendation at present is to give
the highest priority in patients with HIV infection to those without
HCV and to those receiving and tolerating ART who have achieved
HIV virologic control and immune reconstitution.
Renal
Disease
TOP
What are
the possible causes of abnormal renal function tests?
Renal function
is important to monitor because abnormal renal function may require
altering drug dosage regimens, and it is important to know the cause
of the abnormality. In general, renal dysfunction in patients with
HIV infection can be caused by adverse drug reactions, HIV-associated
nephropathy, and non-HIV-related conditions. The multitude of conditions
that are not necessarily complications of HIV infection or its treatment
include hypertension, glomerulonephritis, and heroin use.
For the
patient on ART, what drugs are most likely to cause renal disease?
Adverse drug
reactions that cause renal disease are most commonly associated
with aminoglycosides, amphotericin, foscarnet, and cidofovir. The
antiretroviral agent that is most frequently implicated is indinavir
(IDV), which may cause indinavir crystals in the collection system,
resulting in nephrolithiasis. The presentation may be renal colic,
or it may be asymptomatic with evidence of crystals on urinalysis.
In addition, indinavir can cause a crystal-induced nephropathy.
On rare occasions, tenofovir (TDF) may cause renal insufficiency.
What are
the cause and implications of HIV-associated nephropathy?
HIV-associated
nephropathy, which is apparently the result of HIV infection of
the kidney, presents as large, echogenic kidneys on ultrasound,
nephrotic-range proteinuria, and rapidly progressing renal failure.
This may occur at any stage of HIV but is most common as a late
complication. Pre-ART studies show benefit from treatment with ACE
inhibitors and possibly with corticosteroids; more recent studies
show anecdotal evidence of a sometimes dramatic response to ART,
but data from controlled trials are not available. Renal biopsy
is necessary to establish the diagnosis. For patients with end-stage
renal disease, there is increasing interest in and experience with
renal transplantation. The usual criteria are irreversible renal
failure combined with HIV response to ART resulting in virologic
control and a CD4 cell count of >200mm3.
- Laboratory
tests are frequently abnormal in HIV disease because 1) HIV is
a multi-system disease, 2) HIV causes immune suppression that
may result in opportunistic infections and tumors, 3) treatment
has many potential adverse reactions affecting multiple systems,
and 4) patients with HIV are often at high risk for other medical
conditions.
- Hematologic
complications include anemia, neutropenia, and thrombocytopenia.
The most common causes of anemia and neutropenia are either drug
toxicity or the direct effect of HIV on progenitor cells; the
cause of thrombocytopenia is most commonly a direct effect of
HIV.
- Liver disease
is common because of high rates of concurrent viral hepatitis,
especially HCV, and because all antiretrovirals are potentially
hepatotoxic.
Abnormal renal function is usually a direct effect of HIV infection
of the kidneys resulting in a rapid progression with nephrosis
and end-stage renal disease; abnormal renal function from any
cause is important to know about because it requires altering
dose regimens for nucleosides.
Suggested
Resources
TOP
Kimmel PL,
Barisoni L, Kopp JB. "Pathogenesis and treatment of HIV-associated
renal diseases." Ann Intern Med. 2003;139:214-226.
Lok ASF, McMahon
BJ. "AASLD
Practice Guidelines" Hepatology 2001;34:1225-1241.
Accessed 1/04.
"Management
of Hepatitis C: 2002." NIH
Consensus and State-of-the-Science Statements. 2002 Jun
10-12;19:1-46. Accessed 12/03.
Ogedegbe AO,
Sulkowski MS. "Antiretroviral-associated liver injury".
Clin Liver Dis. 2003;7:475-499.
Orenstein R.
"Presenting syndromes of human immunodeficiency virus."
Mayo Clin Proc. 2002; 77:1093-1102.
Rockstroh JK.
"Management of hepatitis B and C in HIV co-infected patients."
J Acquir Immune Defic Syndr. 2003;34 Suppl 1:S59-65.
Sulkowski MS,
Thomas DL. "Hepatitis C in the HIV-infected person." Ann
Intern Med 2003;138:197-207.
Volberding
P. "Consensus statement: anemia in HIV infection--current trends,
treatment options, and practice strategies." Anemia in HIV
Working Group. Clin Ther. 2000;22:1004-1020.
WEBSITES
CDC
National Center for Infectious Diseases. Accessed 2/04.
Hepatitis
B Foundation. Accessed 2/04.
HIV
and Hepatitis. Accessed 2/04.
References
TOP
Ragni MV, Belle
SH, Im K, et al. "Survival of human immunodeficiency virus-infected
liver transplant recipients." J Infect Dis. 2003;188:1412-20.
|