Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 2: Health Maintenance and Disease Prevention

Latent Tuberculosis

July 2006

Background

Latent (or inactive) tuberculosis (TB) infection occurs when an individual has dormant Mycobacterium tuberculosis organisms and no active disease, and can be diagnosed by a tuberculin skin test (TST). Persons with HIV or AIDS and latent TB infection (LTBI) have a much higher risk of developing active TB (estimated at 10% per year) than does the general population (estimated at 10% in a lifetime). The risk of developing active TB can be reduced dramatically with treatment of LTBI. Hence, identifying and treating HIV-infected persons for LTBI is a high priority. Treatment of LTBI not only reduces the risk of disease for the individual, but also reduces the risk of further TB transmission should the HIV/TB-coinfected person develop active pulmonary TB. Standard treatment with isoniazid (INH) is effective and safe.

Issues of concern regarding the treatment of LTBI among HIV-infected persons include the following:

• Excluding active pulmonary or extrapulmonary TB disease before treatment with INH alone
• Assessing the risk of latent infection with drug-resistant TB
• Avoiding or managing drug interactions if rifampin or rifabutin regimens are used
• Exercising great caution in the use of rifampin/rifabutin and pyrazinamide combinations for LTBI treatment

S: Subjective

HIV-infected persons who have no symptoms of active TB (ie, afebrile, stable weight, no cough) and who have not been treated previously for active or latent TB are eligible for LTBI treatment. When patients do have symptoms that could represent active TB, active TB must be evaluated and ruled out by appropriate diagnostic methods before initiating treatment (see "Assessment" below).

Persons who have had bacillus Calmette-Guérin (BCG) vaccine should be evaluated in the same way as those who have never had BCG. Immigrants from many countries will have had childhood vaccination.

History

Health care providers should ask about a history of potential exposure to TB, because this might indicate infection with drug-resistant TB. Such risk might occur when there is knowledge of a source patient or when the exposure occurred in a setting with known drug resistance or a location with ongoing TB transmission where others remain at risk for exposure.

O: Objective

Diagnostic Evaluation

Current U.S. guidelines strongly recommend performing a TST in newly diagnosed HIV-infected persons. Repeat testing is recommended for those whose CD4 lymphocyte count increases from low numbers to counts of >200 cells/µL, and annual testing is suggested for those who initially test negative. The TST is administered as an intradermal injection of 0.1 mL (5 tuberculin units TUs) of purified protein derivative (PPD), which raises a wheal in the skin. This also is known as the Mantoux test. Multiple-puncture tests such as tine tests and the use of other strengths of PPD are considered unreliable. Anergy testing is not recommended routinely because a randomized controlled study in HIV-positive patients in the United States failed to show an advantage to treating anergic, tuberculin-negative persons.

PPD tests are not designed for reading by the patient; a trained health care worker must measure the area of induration (not erythema) 48-72 hours after the test is placed. Induration of 5 mm or more is a positive result in HIV-infected persons, other immunosuppressed persons, anyone with recent TB exposure, and anyone with fibrosis on chest x-ray consistent with previous TB. For HIV-uninfected health care workers, 10 mm of induration is positive; in various other populations, either 10 mm or 15 mm of induration may be considered positive. Many large HIV clinics find it challenging to get their patients to return for the PPD reading. One randomized study found that offering incentives (eg, a fast-food coupon) plus counseling was more effective than counseling alone in obtaining return visits for PPD readings.

Recently licensed tests for gamma-interferon, which is produced by peripheral blood T cells in response to TB antigens, have not been not validated for use in HIV-infected persons and currently are not recommended for this population.

A: Assessment

TST-positive, HIV-infected persons without cough or other symptoms should have a chest x-ray. If the chest x-ray in an asymptomatic patient is negative, the patient should be offered treatment for LTBI. Persons with symptoms consistent with pulmonary or extrapulmonary TB, and those with abnormal findings on chest radiography, require further assessment. This assessment may include sending 3 sputum specimens on 3 separate mornings (using saline mist to induce cough for those not coughing spontaneously) for acid-fast bacilli stain and culture or obtaining other specimens, depending on the suspected site of extrapulmonary TB. If suspicion of TB is low, then those with negative sputum smears (or other biopsy or tissue samples) can begin LTBI treatment. If suspicion of active disease is high, treatment for active disease should be started while the culture results are pending (see chapter Mycobacterium tuberculosis: Treatment in the United States and Other High-Income Nations).

HIV-infected close contacts of patients with active pulmonary TB should receive preventive therapy regardless of PPD results or previous courses of preventive treatment, after active TB has been excluded. Such contacts should be tested with 5 TUs of PPD if previously negative and then started on preventive therapy. If the initial TST result is negative, the individual should be evaluated again 3 months after discontinuation of contact with the infectious source. If the contact is severely immunosuppressed, a full course of preventive treatment usually is provided even if that individual remains PPD negative. Contacts who are not immunosuppressed and who remain PPD negative may discontinue preventive treatment.

P: Plan

As with any treatment of TB, adherence with the regimen is required for success. Treatment regimens for LTBI are presented in Table 1.

Table 1. Treatment Regimens for Latent Tuberculosis

Drug Dose (taken orally) Frequency Duration (minimum number of doses for completion) Recommended Isoniazid* Adults: 300 mg Children: 5 mg/kg Daily 9 months OR 270 doses in 12 months Alternative Isoniazid* Adults: 900 mg Children: 15 mg/kg Twice-weekly DOT** 9 months OR 76 supervised doses in 12 months Exposure to isoniazid-resistant TB or intolerance to isoniazid Rifampin*** Adults: 600 mg Children: 10-20 mg/kg Daily 4 months OR 120 doses in 6 months Use only in special situations Rifampin*** and pyrazinamide Highly toxic; to be used only by persons experienced in LTBI treatment in special situations Exposure to multidrug-resistant (MDR) TB Consider pyrazinamide with either ethambutol or a fluoroquinolone Seek expert advice from public health authorities and those experienced in treatment of MDR TB. May be postponed or may be based on resistance pattern of index case, if known.

*10-25 mg of pyridoxine (vitamin B6) should be given with each isoniazid dose to reduce the risk of isoniazid-induced peripheral neuropathy. ** DOT = directly observed treatment *** Rifampin has significant interactions with antiretroviral drugs in the nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) classes and with other medications. See text about contraindicated combinations, dosage adjustments, and substitution of rifabutin for rifampin.

INH may cause liver toxicity and its use should be monitored carefully in patients with active alcohol use, liver disease, or chronic hepatitis B or C. INH is contraindicated in patients with acute hepatitis or decompensated liver disease. Before INH use, baseline liver and renal function tests should be checked. Routine monthly clinical monitoring for fever, fatigue, anorexia, nausea, vomiting, abdominal pain, jaundice, peripheral neuropathy, and rash should be performed. Alanine aminotransferase (ALT) should be monitored monthly in HIV-infected patients and others at risk for hepatitis. If patients develop abnormalities in liver transaminases while taking INH (ALT or aspartate aminotransferase >3 times the upper limit of normal with symptoms, or >5 times the upper limit of normal in the absence of symptoms), INH should be withheld. Obtain expert consultation before treating patients with abnormal liver function tests or advanced liver disease.

Before rifampin use, baseline liver and renal function tests and a complete blood count are suggested. Follow-up is the same as for INH use.

Drug Interactions with Antiretroviral Therapy

Rifampin and rifabutin have significant interactions with certain antiretroviral drugs, including nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Rifampin can be used in persons taking efavirenz, although some experts recommend increasing the efavirenz dosage to 800 mg daily. Rifampin decreases the blood concentrations of nevirapine and all unboosted PIs (except ritonavir) and should not be used with these drugs. Standard ritonavir boosting of PIs fails to overcome the drug interaction, causes additional toxicity, or both. Although recommended in the past, rifampin should not be used in combination with ritonavir-boosted saquinavir because of high rates of hepatic toxicity. Adding more ritonavir to the fixed-dose combination of lopinavir/ritonavir (Kaletra) may overcome the pharmacokinetic effects of concurrent rifampin, but the regimen is poorly tolerated. Use of ritonavir-boosted PI regimens in combination with rifampin is best avoided and should be done only in consultation with an expert.

No data are available on the use of rifabutin for the treatment of LTBI. Nevertheless, rifabutin may be considered in place of rifampin for patients taking antiretroviral combinations that include NNRTIs (other than efavirenz) or PIs (other than ritonavir alone). In these cases, the dosages of both rifabutin and the antiretroviral agent usually require adjustment.

Table 2 presents information on combining antiretroviral agents with rifampin or rifabutin.

Other Drug Interactions

Rifampin decreases the blood concentrations of estrogens, anticonvulsants, hypoglycemic agents, and many other drugs. Review all medications a patient is taking before initiating rifampin and make adjustments as necessary. (See Table 12: Clinically significant drug-drug interactions involving rifamycins at www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#tab12.)

Pregnancy

HIV-infected pregnant women with a positive TST and no evidence of active TB should receive standard prophylaxis as soon as possible, even during the first trimester. The preferred prophylaxis in pregnancy is a 9-month INH regimen (with pyridoxine, as above). Alternative regimens, such as rifampin or rifabutin, should be used with caution because of limited experience. Neonates born to women who received rifampin during pregnancy should be given vitamin K (10 mg) to reduce the risk of hemorrhagic disease. Pyrazinamide generally is avoided during pregnancy because of lack of information about fetal effects.

Table 2. Combinations of Antiretroviral Medications with Rifampin or Rifabutin: Contraindicated Combinations and Dose Adjustments

Rifampin Rifabutin* Nonnucleoside Reverse Transcriptase Inhibitors Efavirenz** Rifampin dose unchanged, efavirenz dose 600-800 mg daily No change in efavirenz dose Increase rifabutin to 450 mg/day or 600 mg 3 times weekly Nevirapine Generally not recommended; despite 25-50% reduction in nevirapine levels, 2 small studies claim standard doses are effective Use standard dose of nevirapine Rifabutin 300 mg daily or 3 times weekly Delavirdine Never combine Never combine Protease Inhibitors (Nonboosted) Ritonavir May be used at standard doses; limited clinical experience Ritonavir at standard dose Rifabutin 150 mg alternate days or 3 times weekly Amprenavir/fosamprenavir Never combine PIs at standard dose Rifabutin 150 mg/day or 300 mg 3 times weekly Atazanavir Never combine Atazanavir at standard dose Rifabutin 150 mg alternate days or 3 times weekly Indinavir Never combine Increase indinavir to 1,000 mg every 8 hours Rifabutin 150 mg/day or 300 mg 3 times weekly Nelfinavir Never combine Increase nelfinavir to 1,000 mg every 8 hours Rifabutin 150 mg/day or 300 mg 3 times weekly Saquinavir Never combine Never combine Ritonavir-Boosted Protease Inhibitors Lopinavir/ritonavir (Kaletra) Lopinavir/ritonavir (3 capsules twice daily) must be supplemented with additional ritonavir 300 mg twice daily; limited experience, not well tolerated Standard dose of lopinavir/ritonavir Decrease rifabutin to 150 mg alternate days or 3 times weekly Saquinavir/ritonavir Due to high rates of hepatotoxicity this combination should not be used Standard dose of lopinavir/ritonavir Decrease rifabutin to 150 mg alternate days or 3 times weekly All other ritonavir-boosted PIs Should not be used (adequate dosing regimens not defined) Standard dose of PI/ritonavir Decrease rifabutin to 150 mg alternate days or 3 times weekly

U.S. Centers for Disease Control and Prevention. Updated Guidelines for the Use of Rifamycins for the Treatment of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors. 1/20/2004. Available online at www.cdc.gov/nchstp/tb/tb_hiv_drugs/TOC.htm. (Nucleoside and nucleotide analogues are given in standard doses with either rifampin or rifabutin.) * If available, rifabutin may be substituted for rifampin when TB treatment and antiretroviral therapy is combined. ** Avoid efavirenz during pregnancy or in women who may become pregnant during therapy. Both rifampin and rifabutin significantly reduce estrogen and progestin levels for women on hormonal contraceptives; efavirenz raises estrogen levels moderately. Two forms of birth control including one barrier method and either a mid- to high-dose hormonal contraceptive or intrauterine device are most often recommended. Barrier methods are also recommended for reducing HIV transmission in women who are infertile.

Patient Education

• Patients should know that although they have the TB germ in their bodies, they cannot pass the germ to others while TB is latent. However, because they have HIV infection, the TB germ is more likely to make them sick at some point in the future.
• The medicine patients are starting will help kill the TB germ and reduce their chances of getting sick with active TB.
• Patients must take all of their medicine, every day, to prevent the TB germ from spreading and making them sick.
• If patients have adverse effects, such as rash or itching, tell them to contact their health care providers immediately. Occasionally, INH can cause tingling or numbness in the hands or feet. The pyridoxine (vitamin B6) they are taking should help prevent that, but they should let their providers know if it occurs.
• Patients should avoid alcohol while taking these medications. The medicines for TB are processed by the liver and, when combined with alcohol, they easily can overload the liver. Acetaminophen (Tylenol) also is processed by the liver, so patients should keep their intake to a minimum. (Patients with hepatitis C, liver disease, or chronic alcohol use should not take more than 3.5 grams per day.)
• Blood tests will be done regularly to make sure the liver is working well, so it is important for patients to keep their follow-up appointments. They should take all their medications, vitamins, and supplements with them to the clinic so that their health care providers can review them and make sure there are no drug interactions.
• If patients experience nausea, vomiting, poor appetite, or abdominal pain, if they notice their urine darkening or becoming cola-colored, or if they notice their eyes or skin yellowing, they should return to the clinic immediately. These problems may indicate that the liver is being overwhelmed, and it is important to find out before permanent damage is done.
• Rifampin will cause sweat, tears, urine, and plastic contact lenses to turn orange.
• Rifampin will make birth control pills ineffective. Patients should use a backup method of contraception until treatment is complete. Condoms can help prevent HIV transmission and reduce the risk of pregnancy.

References

• American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000 Jun 9;49(RR-6):1-51.
• Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA. 2005 Jun 8;293(22):2776-84.
• Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials. AIDS. 1999 Mar 11;13(4):501-7.
• Centers for Disease Control and Prevention, American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep. 2003 Aug 8;52(31):735-9.
• Leinhardt C, Fielding K, Sillah J, et al. Risk factors for tuberculosis infection in sub-Saharan Africa: a contact study in The Gambia. Am J Respir Crit Care Med. 2003 Aug 15;168(4):448-55.
• Quigley MA, Mwinga A, Hosp M, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS. 2001 Jan 26;15(2):215-22.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. MMWR Recomm Rep. 2002 Jun 14;51(RR08);1-46. Available online at aidsinfo.nih.gov/Guidelines/.