Limiting Liver Toxicity In The
HIV-Positive Patient With Latent
Tuberculosis Infection

HIV/TB Collaborative Care

Consultation with a physician with expertise
in the management of both TB and HIV
should be sought. HIV and TB providers
should work closely together to ensure that
all management decisions avoid serious
drug-drug interactions, minimize toxicity, and
provide good patient outcomes.

Matec, Midwest AIDS Training and Education Center.

The University of Texas Health Science Center at Tyler, Heartland National TB Center. A partnership of UT Health Science Center and TCID.

GENERAL SCREENING GUIDELINES IN
HIV/TB COINFECTION

The CDC recommends routine and opt-out HIV testing for
all individualsaged 13-64 in all healthcare settings.

At the time of HIV diagnosis, all patients should be
screened for TB witha risk assessment and a TB skin test
(TST) or Interferon Gamma Release Assay (IGRA).

TB screening guidelines in HIV positive individuals include:

CDC recommends testing in HIV-infected patients
without previously positive Tuberculine Skin Test.

Tuberculine Skin Test should be repeated annually if initial test
negative and the patient is at high risk for TB.

Tuberculine Skin Test should be repeated upon immune reconstitution
or when CD4 count reaches 200.

All patients diagnosed with Latent TB Infection or TB disease should be
tested for HIV.

A Tuberculine Skin Test with 5mm induration is positive in an HIV-infected
individual.

A diagnosis of Latent TB Infection can be made with Positive Tuberculine Skin Test or
IGRA, NO signs or symptoms of active TB disease,and a
normal chest x-ray.

Active TB must be excluded prior to starting treatment for
Latent TB Infection. If the chest x-ray is abnormal or the patient is symptomatic,
sputum smears and cultures should be obtained. Consult
your local health department for assistance in sputum
testing.

INTERFERON GAMMA RELEASE ASSAYS
(IGRA's) AND HIV/TB COINFECTION

IGRA's function througha lymphocytic recognition of
protein antigens specific to MTB, not other strains of
mycobacterium or BCG. The recognition process involves
the generation and secretion of interferon gamma, which
can be quantified.

It is suspected that these assays in general may be less
sensitive in HIV positive patients, but are as sensitive
as or slightly better than a Tuberculine Skin Test. A higher number of
indeterminate or negative IGRA reactions are likely in
those with lower CD4 cell just as the Tuberculine Skin Test is less likely to
be positive with declining CD4 counts. The IGRA tests are
more specific for MTB.

Early studies suggest that the T-spot may be more
sensitive than the Tuberculine Skin Test or QuantiFeron Gold tests in
detection of MTB in HIV positive patients.

STRATEGIES TO LIMIT TOxICITY

Recognize the potential for hepatotoxicity specific to
medications prescribed.

Identify patient risk factors thatmight predispose
the individual to develop hepatotoxicity.

Identify drug-drug interactions and needed dose
adjustments

Screen for viral hepatitis and HIV.

Provide ongoing assessment for hepatotoxicity
through patient report, physical exam findings, and
laboratoryresults.

Rapid response and evaluation in response to
possible toxicity. Where applicable include:

Temporaryor permanent discontinuation of
medication

Laboratory evaluation

Clinical evaluation

Alteration in therapeutic regimen

Comprehensive and ongoing patient education

PATIENT EDUCATION

Printed instructions should include:

Clinic telephone numbers.

Instructions for after-hours care.

Appropriate language/translation.

Explicitly tell patients to immediately stop
medications and call the clinic for further
instruction if they experience:

Nausea

Vomiting

Abdominal discomfort

Unexplained fatigue

Discuss the potential for hepatotoxicity with
the use of concomitant alcohol and over-thecounter
medications such as acetaminophen.
All alternative and prescription medications
should be reported to both primary and
infectious disease providers.

Document all patient education.

LATENT TUBERCULOSIS INFECTION (LTBI) IN THE CONTExT OF HIV

The risk of developing active TB from Latent TB Infection is increased 100-fold in the setting of HIV infection. Patients with HIV and latent tuberculosis infection have a 7-10% risk per year of progressing from latent to active TB disease. This is in contrast to a 10% risk over a lifetime in a non-HIV
infected individual. Active TB must be excluded prior to treatment of Latent TB Infection. This is especially important, however more difficult, in the context of HIV infection. Treatment of active TB with a single drug leads to drug resistance. If a rifampin-based Latent TB Infection treatment regimen is used in a person
with active TB, rifampin resistance may develop, markedly compromising a good treatment outcome.

POTENTIAL FOR HEPATOTOxICITY IN THE SETTING OF ANTI-TB TREATMENT & HIV

The risk of developing hepatotoxicity depends on the individual treatment regimens for both TB and HIV. Common culprits in hepatotoxicity for antiretroviral medications include the classes NRTI's, NNRTI's, and PI's.
The HIV virus itself may increase the risk of developing drug induced hepatotoxicity in the setting of TB treatment. Additional overlapping risk factors such as Hepatitis B or Coinfection, presence of chronic liver disease, alcohol use, pregnancy, age, and concomitant use of fluconozole,
acetaminophen, or other offending OTC agents may further compound the risk.

TOxICITY MONITORING CONSIDERATIONS FOR THE HIV POSITIVE PATIENT TREATED FOR Latent TB Infection

Baseline: CBC with platelets (rifamycins), Liver Function Tests, total bilirubin, hepatitis panel for everyone. Monthly (at minimum) or as appropriate: Toxicity
assessment, clinical evaluation, and laboratory assessment (with INH include liver enzymes; with Rifamycins include CBC, platelets, liver enzymes, total bilirubin). At first sign of toxicity: Laboratory assessment and
provider visit within 24 hours. **Patient education on clinical signs and symptoms of hepatotoxicity should be documented at baseline and monthly.

IDENTIFICATION AND MANAGEMENT OF HEPATOTOXICITY IN HIV/TB COINFECTED PATIENTS BEING TREATED FOR Latent TB Infection

Identification:

Early symptoms of hepatotoxicity can be subtle and mimic nonspecific drug effects, indigestion, or other infectious process. When a new or different complaint develops, evaluate liver enzymes to exclude hepatotoxicity.
Symptoms may include:

Decreased energy

Decreased appetite

Fatigue

Indigestion

Abdominal discomfort

Nausea

Vomiting

Myalgia

Rash*

Late symptoms of hepatotoxicity include:

Dark urine

Light stool

Jaundice

Mental status change

Abdominal swelling

Ascites

*Evaluating a Rash:

An early finding with hepatotoxicity can be a maculopapular rash. If the rash does not resolve within 24 hours or have another likely cause, liver enzymes should be evaluated, particularly if associated with
fatigue or GI upset. The antiretroviral Abacavir (ABC)/Ziagen can be implicated in the development of a life-threatening hypersensitivity reaction often manifested by a rash. Additional HIV medications may also result in the development of severe rash and/or hypersensitivity
reactions. In the case of a rash, medications warrant a thorough and prompt evaluation.

Differentiating toxicity from drug reactions:

In manycases, symptoms of a drug reaction develop shortly after taking the medication and resolve within several hours. Even if this appears to be the pattern, checking liver enzymes once to rule out hepatotoxicity
may still be reasonable.

Management:

If liver enzymes are elevated and/or the patient is symptomatic, refer to the toxicity algorithm for recommended action.

Drug,Isoniazid (INH)

Dose,300 mg daily

Treatment Duration,9 months

Frequency of Hepatotoxicity, 0.1 to 1.86 percent Mild transaminitis occurs initially in greater than 10 percent, most asymptomatic, resolves with continued therapy.

HIV-Specific Considerations, Can be administered to HIV infected patients on HAART without risk of drug-drug interactions

Drug, Rifampin

Dose, Dose based on ARV regimen.

Treatment Duration, 4 months.

Frequency of Hepatotoxicity, 0.0 to 0.8 percent.

Drug, Rifabutin.

Dose, Dose based on ARV regimen.

Treatment Duration, 4 months.

Frequency of Hepatotoxicity, No data, generally felt to be less hepatotoxic than rifampin.

HIV-Specific Considerations, Key interactions occur between rifamycin antibiotics and a wide variety of medications including 4 classes of HIV
medications: Protease Inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, CCR5-Receptor Antagonists, and Integrase Inhibitors. A common source of rifamycin interaction is the Cytochrome P450 system. Rifampin interacts with manydrugs used in HAART. Rifabutin can be substituted for rifampin to lessen the intensity of drug-drug interactions with HAART.
Prior to prescribing a rifamycin-based regimen, drug interactions and dose adjustments should be checked: http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm,
http://AIDSinfo.nih.gov

RIFAMPIN/PZA SHOULD NOT BE USED IN THIS PATIENT POPULATION

Check Baseline evaluation for Alanine Aminotransferase, Aspartate Amino Transferase, Bilirubin, Tepatitis panel, (rifamycins - CBC and plts).

Are signs and symptoms present c/w TB? If yes, exclude TB disease. If no, is chest x-ray normal? If no, exclude TB disease. If yes, check if Alanine Aminotransferase greater than 3 times the upper normal limit. If no, Evaluate risks and benefits of Latent TB Infection therapy consultation.

Consider the following options, Stop when risk is greater than benefits, If Liver Function Tests stay 3 to 4 times the upper normal limit ULN, stop INH. Also consider an INH rechallenge and when Alanine Aminotransferase less than 2 times the upper normal limit consider risks and benefits of Rifamycins esp with HAART.
If Alanine Aminotransferase less than 3 times the upper normal limit then Treat INH monthly while monitoring. Is patient symptomatic? If no, Alanine
Aminotransferase greater than equal to 5 times the upper normal limit or 2 to 3 times baseline. Hold treatment and repeat Liver Function Tests, and Consider the following options, Stop when risk is greater than benefits, If Liver Function Tests stay 3 to 4 times the upper normal limit ULN, stop INH. Also consider an INH rechallenge and when Alanine Aminotransferase less than 2 times the upper normal limit consider risks and benefits of Rifamycins esp with HAART. If patient is symtomatic, are Alanine Aminotransferase greather than equal to 3 times the upper normal limit? if no, manage Symtoms, continue INH, reevaluate as needed, monitor monthly. If Alanine Aminotransferase is greater than 3x ULN then Hold treatment and repeat Liver Function Tests and consider the following options, INH rechallenge and when Alanine Aminotransferase less than 2 times the upper normal limit consider risks and benefits of Rifamycins esp with HAART. Liver Function Tests stay greater than 3 times the upper normal limit, stop INH or also consider the option to Stop when risk is greater than benefits.

REPORTING OF SERIOUS ADVERSE EVENTS

Health care providers should report serious adverse effects, including hepatotoxicity, to the U.S. FDA's Med-Watch program. Reporting may be by mail, telephone 1 800 FDA 1088, fax 1 800 FDA 0178, or the Internet website www.fda.gov/medwatch.

Adverse effects of treating Latent TB Infection that are serious
enough to entail hospital admission or death
should be reported to the CDC through local
public health authorities or by calling 404 639 8401.

These surveillance systems capture different
data, and reporting to both is necessary.

FOR CASE CONSULTATION

Heartland National TB Center

1 800 839 5864

http://www.heartlandntbc.org/

National HIV/AIDS Clinicians' Consultation
Center (NCCC)

http://www.nccc.ucsf.edu/

1 800 933 3413

For Additional Information:

Heartland National TB Center

1-800-839-5864

http://www.heartlandntbc.org/

MATEC

1-312-996-1373

http://www.matec.info

Revised 12/01/10