Management Of Tuberculosis In HIV Infected Patients

Zaw Htay, M.D.
Zaw Htay, M.D. is Chief of the Tuberculosis Section and a Clinical Assistant Professor
of Medicine with the University of Florida Health Science Center / Jacksonville.

The number of TB cases increased in the United States in the late 1980's and early 1990's. One reason for this increase was clearly due to HIV. Overlap between AIDS and TB epidemics continues to result in increased TB morbidity.

According to surveys in 1993-1994, at least 14% of persons with active TB in the U.S. were co-infected with HIV. In Duval County the rate of co-infection was 20% in 1998. Because of the diminished cell mediated immune response seen with HIV infection, the risk of TB reactivation is significantly higher in HIV infected patients. The rate of TB disease among HIV infected, tuberculin skin test (TST) positive patients is approximately 4-26 times higher than the rate among comparable HIV infected TST negative patients; and it is 200-800 times higher than the rate of TB among populations overall (0.01%). Therefore, to control and eliminate TB in HIV infected patients with latent TB infection, they need to be identified and provided with preventive therapy to prevent progression to active TB disease.

There are also significant interactions between the two pathogens, HIV and TB. As HIV infection can accelerate the natural progression of TB by diminishing cell mediated immune response; host immune reaction to TB can also enhance HIV replication and accelerate HIV disease progression. The mycobacterial antigens activate antigen specific CD4+ T cells releaseing interferon gamma, which then activates host macrophages and enhances their ability to contain mycobacterial infection. The activated macrophages release proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. These cytokines enhance HIV replication in monocyte cell lines in vitro. Therefore, patients who are co-infected with HIV and TB should be evaluated and be treated for both diseases to improve their clinical outcomes.

Due to recent advances in antiretoviral therapy, anti-TB therapy has become more complicated. This is because of significant drug-drug interactions between anti-TB drugs, mainly rifamycins, and anti-HIV drugs, especially protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Rifamycins are the most important drugs among anti-TB medications. Anti-TB regimens which do not contain rifamycins require longer duration of treatment, 12 to 15 months, and also are associated with higher rates of treatment failure and relapse. Rifamycins, which include rifampin, rifabutin and rifapentine, are inducers of the hepatic cytochrome CYP450 enzyme system. They accelerate the metabolism of drugs that are metabolized through this enzyme system e.g. protease inhibitors (PI's) and non-nucleoside reverse transcriptase inhibitors (NNRTI's), decreasing their serum concentration, which could diminish the efficacy of anti-retroviral therapy. Among the rifamycins, rifampin is the most potent and rifabutin is the least potent inducer. Conversely, PI's are inhibitors of hepatic cytochrome CYP450 enzyme system and increase the serum concentration of rifamycins and their toxicities. The rank order of agents in terms of potency in inhibiting CYP450 enzyme system is retronavir (most potent), amprenavir, indinivir, nelfinivir and saquinavir (least potent). There are three approved NNRTI's which have diverse effects on the CYP450 enzyme system. Nevirapine is an inducer, delavirdine is an inhibitor and efavirenze is both an inducer and inhibitor.

Because rifampin markedly lowers the blood levels of many PI's and NNRTI's and is likely to result in suboptimal antiretroviral therapy, the use of rifampin to treat active TB in a patient who is taking a PI or NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CYP450 cytochrome enzymes than rifampin and when used in appropriately modified dose, might not be associated with a clinically significant reduction of PI's or NNRTI's. Thus rifabutin can be substituted for rifampin in TB treatment regimen for patients who are undergoing therapy with PI's (with the exception of ritonavir or hard gel capsule saquinavir) or with the NNRTI's nevirapine or efavirenze (but not delavirdine). Rifapentine is not recommended as a substitute for rifampin because it's safety and effectives have not been established for the treatment of patients with HIV related TB. As an alternative to the use of rifamycins for the treatment of TB, the use of streptomycin based regimens that do not contain rifamycins can be considered for the treatment of TB in patients undergoing antiretroviral therapy with PI's or NNRTI's.

The following are updated recommendations by the CDC for the diagnosis, treatment, and prevention of TB among persons co-infected with HIV, while concurrently promoting optimal antiretroviral care for these patients. As new antiretoviral agents and new data regarding existing agents alter therapeutic options and preferences for antiretroviral therapy, these changes might affect future recommendations for the treatment of TB infection and disease among patients co-infected with HIV and the treatment of HIV infections among persons with TB.

The typical signs and symptoms of pulmonary TB are cough with or without fever, night sweats, weight loss and upper lobe infiltrates with or without cavitation on chest X-rays. The diagnosis of TB in some HIV infected patients might be difficult because of atypical clinical presentations and paucity of findings on chest X-rays. It could also be complicated by the presence of other pulmonary infections such as Pneumocystis carinii pneumonia and Mycobacterium avian complex disease and the occurrence of extrapulmonary TB.

Every person suspected of having TB should undergo thorough medical evaluation including HIV counseling and testing, unless the person has a documented positive HIV test or negative test within the past six months. All HIV infected patients who have active TB should be treated by DOT (directly observed therapy). One of the following treatment options can be used to treat pansensitive TB in the HIV infected patient who is being treated or will be treated concurrently with an antiretroviral regimen containing PI's or NNRTI's.

• Option I
  6 months of a TB regimen consisting of isoniazid, rifabutin, pyrazinamide, and ethambutol for the initial 2 months of induction phase, given daily for the first 2 months or daily for the first 2 weeks followed by 6 weeks of biweekly treatment. The second phase of treatment consists of isoniazid and rifabutin, given either daily or biweekly for the remaining 4 months of treatment.
• Option II
  For patients for whom the use of a rifamycins is limited or contraindicated for any reasons (e.g. intolerance, allergic reaction), the initial phase of a 9 months regimen consists of isoniazid, streptomycin, pyrazinamide and ethambutol, administered either daily for the whole 8 weeks or daily for the first 2 weeks and then biweekly for 6 weeks to complete initial 2 months of treatment. The second phase of treatment consists of isoniazid, streptomycin and pyrazinamide administered 2-3 times a week for 7 months.
• Option III
  For those who are not a candidate for antiretroviral or for those patients for whom a decision is made not to combine the initiation of antiretroviral therapy with TB therapy, a 6 months regimen that consists of isoniazid, rifampin, pyrazinamide and ethambutol (or streptomycin) can be used. These drugs are administered daily for 8 weeks or daily for the first 2 weeks followed by 2-3 times per week dosing for 6 weeks to complete a 2 months induction phase. The second phase of treatment consists of isoniazid and rifampin administered daily or 2-3 times a week for 4 months.

TB regimens consisting of isoniazid, pyrazinamide and ethambutol (e.g. 3 drug regimens that do not contain rifamycins or injectable aminoglycosides or capreomycin) should generally not be used for the treatment of patients with HIV-related TB. If these regimens are used for the treatment of TB, the minimum duration of treatment should be 18 months or 12 months after culture conversion. Pyridoxine (Vitamin B6), 25-50 mg daily or 50-100 mg biweekly, should be given to all HIV infected patients who are undergoing TB treatment with isoniazid to reduce the occurrence of isoniazid induced side effects in the central and peripheral nervous system. Because the CDC's most recent recommendations for the use of antiretroviral therapy advise against interruptions of therapy, and because alternative TB treatment that do not contain rifampin are available, previous anti-TB therapy option that involved stopping PI therapy to allow the use of rifampin are no longer recommended.

Medication and dose adjustments of PI's, NNRTI's and rifabutin are required when used concurrently in HIV infected patients with TB. When rifabutin is used concurrently with indinavir, nelfinavir or amprenavir, the daily dose of rifabutin should be decreased from 300 mg to 150 mg. The recommended dose of rifabutin for biweekly therapy is 300 mg. Conversely, indinavir dose should be increased from 800 mg TID to 1200 mg TID and nelfinavir dose should be increased from 750 mg TID to 1000 mg TID, when used concurrently with rifabutin. When rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and biweekly administration should be increased from 300 mg to 450 mg. It is uncertain whether the dose of rifabutin should be decreased when used concurrently with either saquinavir soft gel capsules or nevirapine. Whether dose modifications are needed for saquinavir soft gel capsule, amprenavir, nevirapine and efavirenze when used concurrently with rifabutin is also unknown. No modifications in the usually recommended doses of isoniazid, pyrazinamide, ethambutol or streptomycin are necessary if these drugs are used concurrently with PI's, NNRTI's or NRTI's.

The duration of treatment should be prolonged for patients with delayed response to treatment, from 6 months to 9 months with rifamycin-based regimens (or 4 months after culture conversion is documented) and from 9 months to 12 months for streptomycin-based regimen (or 6 months after culture conversion is documented). Each patient should be evaluated at least monthly to monitor response to anti TB therapy, drug toxicities and drug interactions.

Routine use of pyrazinamide is not recommended in pregnant woman with TB due to inadequate teratogenicity data. However, for HIV infected pregnant women, the benefits of a TB treatment regimen that includes pyrazinamide outweighs potential pyrazinamide related risk to the fetus. Aminoglycosides are contraindicated in pregnant women because of potential adverse effects on the fetus.

For HIV infected children, even though who are too young to be evaluated for visual acuity and red green perception, ethambutol at a dosage of 15mg/kg should generally be included as part of the initial regimen, unless the infecting strain of MTB is known or suspected of being susceptible to isoniazid and rifampin. If drug susceptibility results are not available, a four-drug regimen (e.g., isoniazid, rifamycin, pyrazinamide and ethambutol) for 2 months followed by intermittent administration of isoniazid and rifamycin for 4 months, is recommended.

The same principles of treatment for pulmonary TB also apply to extrapulmonary TB. The drug regimens and treatment durations that are recommended for treating pulmonary TB in HIV infected adults and children are also recommended for treating most patients with extrapulmo-nary TB. However, for certain forms of extrapulmonary diseases, such as meningitis, bone, or joint TB, using rifamycin-based regimens for at least 9 months is generally recommended.

Identification and Treatment of Latent Mycobacterial
Tuberculosis Infection in HIV-Infected Patients

The presence of M.TB infection can be identified by TST (tuberculin skin testing) by the mantoux-method, where 5TU of purified protein derivative is administered intradermally and the reaction is read 48 to 72 hours later. The reliability of TST can diminish as CD4+ T cells counts decline in HIV-infected patients. Therefore, the result of the TST may not be accurate in HIV-infected patients who are anergic, i.e. they may be infected with latent Mycobacterium tuberculosis even though their TST are negative. TST reaction size of greater than or equal to 5 mm induration is considered positive in HIV-infected patients. The following are the indications for tuberculin skin testing in HIV-infected patients:

1. As soon as possible after HIV infection is diagnosed, all persons should receive a TST, unless previously tested and found to be positive.
2. As soon as possible after being exposed to a patient with infectious TB, all HIV-infected patients should be evaluated for TB and receive TST, regardless of any previous TST results.
3. TST should be conducted periodically for HIV-infected patients who are TST negative on initial evaluation and who belong to populations with a substantial risk of exposure to Mycobacterial tuberculosis (e.g., residents of prisons, jails or homeless shelters).
4. Repeat TST should also be considered in HIV-infected patients who are TST negative on initial evaluation and whose immune function is restored because of effective antiretroviral therapy.

Candidates for TB Preventive Therapy Among HIV-Infected Patients Include:

1. All HIV-infected persons with positive TST reactions (equal or greater than 5 mm induration), who have not previously received treatment for M. tuberculosis infection should receive TB preventive therapy regardless of age.
2. HIV-infected persons who have had recent contact with infectious TB patients should receive TB preventive treatment, regardless of age, results of TSTs, or history of previous TB preventive treatment.
3. HIV-infected persons with a history of prior untreated or inadequately treated past TB that healed and no history of adequate treatment for TB should receive TB preventive treatment regardless of their age or results of TSTs.
4. Primary prophylaxis for TST-negative, HIV-infected patients with an ongoing and unavoidable high risk of exposure to M. tuberculosis for the duration of the exposure time (residents of prisons, jails or homeless shelters in which the current prevalence of TB is high) should be considered in some situations.

The following are the preventive TB treatment options for HIV-infected persons who have positive TST reaction, presumed to be infected with M. tb sensitive to INH and Rifampin:

• Option I -- 9 months regimen of isoniazid administered daily or biweekly, preferably by DOPT (directly observed preventive therapy)
• Option II -- Two months regimen of rifampin (10 mg/kg/day, max. 600 mg) plus pyrazinamide (20 mg/kg/day, max. 1250 mg), by DOPT, for persons who are not receiving PI's or NNRTI's.
• Option III -- Two months regimen of rifabutin (150 mg/day) plus pyrazinamide (20 mg/kg/day, max. 1250 mg) for those who are taking PI's or NNRTI's. Rifabutin dose should be increased to 450 mg/day for those who are taking efavirenz.

If the person exposed to M. TB. is known to be resistant to isoniazid and susceptible to rifamycins, a 2 month preventive treatment regimen of a rifamycin (rifampin or rifabutin) and pyrazinamide is recommended. For persons with intolerance to pyrazinamide, a 4-6 month regimen of rifamycin (rifampin or rifabutin) alone is recommended.

If the person exposed to M. TB. is known to be resistant to both isoniazid and rifampin (MDR TB), preventive therapy regimen should be based on the susceptibility pattern of the M. TB strain, and should include at least 2 anti-TB drugs to which the infecting strain is believed to be susceptible (e.g., ethambutol and pyrazinamide, levofloxacin and ethambutol).

For HIV-infected pregnant women who have positive TST reaction, a 9 months regimen of isoniazid administered daily or biweekly is the only preventive treatment option. It should be initiated even during the first trimester.

For HIV-infected children with positive TST reaction, a 12 months regimen of isoniazid administered daily is recommended by the American Academy of Pediatrics.

In conclusion, implementing TB prevention and control strategies for persons infected with HIV has always been important and is even more critical now that a larger selection of new, more potent antiretroviral drugs has enabled clinicians to implement therapies that improve the health and prolong the lives of HIV-infected persons. These antiretroviral therapeutic strategies often include the use of drugs such as PI's and NNRTI's, which because of drug-drug interactions cannot be used concurrently with rifampin, the most important anti-TB drug. All health care providers who take care of HIV-infected persons with TB should be aware of these strategies. Therapy of TB in the HIV infected patient is sufficiently complicated that all cases should be referred to an expert for management.

Reference

1. CDC. Prevention and Treatment of Tuberculosis Among Patients Infected With Human Immunodeficiency Virus: Principles of Therapy and Revised Recommendations. MMWR. 1998; 47 (RR-20), 1-58.

Jacksonville Medicine / August, 1999