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Management Recommendations > TB Treatment

Ward 86 Management Recommendations

Treatment of Tuberculosis and Latent Mycobacterium tuberculosis Infection in HIV-Infected Patients

updated July 2016

Contributors: Gabriel Chamie, MD
Annie Luetkemeyer, MD
Diane Havlir, MD

  1. We concur with the treatment recommendations published by the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (CDC/NIH/HIVMA Guidelines) for drug-susceptible tuberculosis (see Tables 2-3 below).(1) However, we also recommend that a local tuberculosis expert always be consulted for advice regarding which agents to use and whether dosing modifications are indicated owing to drug-drug interactions in the following situations: (In the United States, all local health departments either have staff members who can answer these questions or they can refer providers to the appropriate state or CDC tuberculosis expert.)

    1. Patients known or suspected to have drug-resistant tuberculosis.

    2. Patients with central nervous system tuberculosis (in which concomitant corticosteroid therapy is indicated) or pericardial tuberculosis (in which concomitant corticosteroid therapy may be indicated, particularly for patients at high risk of serious complications, ie, those with large effusions, significant inflammation in the pericardial fluid, or early signs of constriction).

    3. Patients for whom antiretroviral agents they are currently receiving are contraindicated with concomitant rifampin or rifabutin.

    4. Patients receiving concomitant medications for hepatitis C infection.

  2. Timing of initiating antiretroviral therapy (ART) in patients with tuberculosis: There are competing risks in the timing of initiating ART in HIV patients with tuberculosis. Earlier ART initiation increases the risks of adherence difficulties and immune reconstitution inflammatory syndrome (IRIS), and later initiation increases the risks of AIDS-related opportunistic infections and mortality. A series of randomized trials have clarified optimal timing of initiating ART as follows.(2,3,4)

    1. ART should be started within 2 weeks of initiating antimycobacterial therapy for tuberculosis in patients who have an absolute CD4 count of <50 cells/µL, except for those with tuberculous meningitis in whom a full 2 weeks of antimycobacterial therapy should be administered before ART is initiated.

    2. ART should be started between 2 weeks and 2 months of initiating antimycobacterial therapy for tuberculosis in all other patients, even those whose CD4 cell counts are in the normal range.

  3. We concur with the treatment recommendations published in the CDC/NIH/HIVMA Guidelines (last updated in 2013) for latent Mycobacterium tuberculosis infection (see Table 1 below), with one exception. A recently published trial demonstrated that a 3-month course of once-weekly, directly observed rifapentine and isoniazid is a reasonable alternative to 9 months of INH monotherapy for HIV patients.(5) A South African study also indicated that 3 months of once-weekly rifapentine and isoniazid had reductions in tuberculosis similar to 9 months of INH in HIV-infected patients not taking ART.(6) The regimen is administered as: once-weekly rifapentine 600-900 mg (adjusted by weight above or below 50 kg) and isoniazid 15 mg/kg (25 mg/kg in children; rounded up to nearest 50 mg; 900 mg maximum) given under direct observation. Of note, in a recent study, self administered therapy with this regimen was noninferior to DOT among those patients enrolled in the United States.(7) At present, this regimen should only be used among patients receiving an efavirenz- or raltegravir-based antiretroviral regimen coadministered with 2 drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class due to insufficient information on drug interactions between rifapentine and other antiretroviral drugs outside the NRTI class. Though the CDC/NIH/HIVMA Opportunistic Infection Guidelines have not been updated since 2013, the CDC website now recommends this weekly rifapentine/isoniazid regimen as a treatment option for latent infection as does a recent update of the CDC/NIH/HIVMA Antiretroviral Treatment Guidelines.
  4. Rifampin, rifapentine. and rifabutin have clinically significant pharmacokinetic interactions with nearly all antiretroviral drugs (also see Table 3).

    Nucleoside reverse transcriptase inhibitor (NRTI) interactions:

    All commonly used NRTIs (eg, tenofovir, abacavir, lamivudine, emtricitabine) can be coadministered with rifampin, rifapentine, or rifabutin at standard dosages. The combination of rifampin and zidovudine should be avoided because rifampin can lower zidovudine levels.

    Nonnucleoside reverse transcriptase inhibitor (NNRTI) interactions:

    Rifampin may cause reductions in serum NNRTI levels. Efavirenz is preferred to nevirapine given concerns about suboptimal HIV outcomes with nevirapine when is coadministered with rifampin. Data do not support weight-based dosage adjustment of efavirenz when it is coadministered with rifampin. Rifampin should not be coadministered with etravirine or rilpivirine.

    Rifabutin metabolism is accelerated by efavirenz; hence, the rifabutin dosage should be increased to 450-600 mg daily if efavirenz is coadministered. If rifabutin is coadministered with rilpivirine, the rilpivirine dosage should be increased to 50 mg daily. Rifabutin can be coadministered with etravirine or nevirapine at standard dosages.

    Similar to rifampin, rifapentine may have considerable impact on cytochrome P450 enzyme drug metabolism and should be coadministered only with antiretrovirals and other agents for which there are support data. At the current time, there are insufficient drug interaction data to recommend any NNRTI coadministration other than efavirenz.

    Protease inhibitor (PI) interactions:

    Rifampin substantially reduces blood levels of antiretroviral PIs and should not be coadministered with PIs.

    Rifabutin levels are increased to a variable degree with PI coadministration. If coadministration of rifabutin and a PI is necessary, the rifabutin dosage, if given daily, should be reduced to 150 mg daily. Alternate-day rifabutin dosing should be avoided as it has been associated with drug resistance and poor outcomes. Patients receiving a rifabutin/PI combination should be monitored for toxicity (particularly iritis), and monitoring rifabutin serum concentrations may be considered, as patients may be at risk of acquired rifamycin resistance if rifabutin levels are subtherapeutic.

    There are insufficient drug interaction data to recommend coadministration of rifapentine with any PI.

    Integrase inhibitor (II) interactions:

    Rifampin can be coadministered with raltegravir. Because rifampin induction of metabolizing enzymes can potentially reduce raltegravir levels, we generally increase the raltegravir dosage to 800 mg BID when coadministered with rifampin, particularly in patients with a high body mass index. However, since there is Phase II data suggesting that raltegravir 400 mg BID may be acceptable with rifampin coadministration as well, we dose reduce raltegravir to 400 mg BID if there are any side effects from this combination. Rifabutin can be administered with raltegravir at standard dosages.

    Neither rifampin nor rifabutin should be coadministered with coformulated elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild).

    Dolutegravir 50 mg BID can be coadministered with rifampin.(8) Dolutegravir 50 mg daily can be coadministered with rifabutin.

    There are insufficient drug interaction data to recommend coadministration of rifapentine with any II other than raltegravir.

  5. Initiation of ART in patients with clinical or subclinical tuberculosis may be complicated by IRIS. For recommendations regarding tuberculosis IRIS, see section on Diagnosis and Management of Immune Reconstitution Inflammatory Syndrome.

References

  1. Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for Managing Tuberculosis in HIV-Infected Patients. Mycobacterium tuberculosis Infection and Disease.
  2. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011 Oct 20;365(16):1492-501.
  3. Havlir DV, Kendall MA, Ive P, et al; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1482-91.
  4. Blanc FX, Sok T, Laureillard D, et al; CAMELIA (ANRS 1295--CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1471-81.
  5. Sterling TR, Scott NA, Miro JM, et al. Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS. 2016;30:1607-15.
  6. Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011;365:11-20.
  7. Belknap R, Borisov A, Holland D, et al. Adherence to Once-Weekly Self-Administered INH and Rifapentine for Latent TB: iAdhere. In: Program and abstracts of the 2015 Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle. Abstract 827LB.
  8. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7.

Table 1. CDC/NIH/HIVMA Guidelines for Treatment of Latent Mycobacterium tuberculosis infection

Preferred regimens: Isoniazid 300 mg PO daily (or isoniazid 900 mg PO twice weekly administered by directly observed therapy) + pyridoxine 25 mg PO daily for 9 months
* Alternative regimens: Rifampin 600 mg PO daily (or rifabutin, dose-adjusted based on concomitant ART) for 4 months (see Table 3)
* Another option is directly observed therapy with once-weekly rifapentine 600?900 mg (adjusted by weight above or below 50 kg) and isoniazid 15 mg/kg (25 mg/kg in children; rounded up to nearest 50 mg; 900 mg maximum). This should be coadministered only with an efavirenz- or raltegravir-based antiretroviral regimen along with 2 drugs from the nucleoside reverse transcriptase inhibitor class.
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Table 2. CDC/NIH/HIVMA Guidelines for Treatment of Drug-Susceptible Tuberculosis

Intensive Phase (2 months)
  • Isoniazid + (rifampin or rifabutin) + pyrazinamide + ethambutol (see Table 3 for dosing) daily (5-7 days per week); if a drug susceptibility report shows sensitivity to isoniazid and rifampin, then ethambutol may be discontinued
Continuation Phase
  • Isoniazid + (rifampin or rifabutin) daily (5-7 days per week) or 3 times weekly (see Table 3 for dosing)
Total Duration of Therapy
  • Pulmonary, drug-susceptible tuberculosis: 6 months
  • Pulmonary tuberculosis and positive culture after 2 months of treatment: 9 months
  • Extrapulmonary tuberculosis with central nervous system involvement: 9 to 12 months
  • Extrapulmonary tuberculosis with bone or joint involvement: 6 to 9 months
  • Extrapulmonary tuberculosis in other sites: 6 months
  • The total duration of therapy should be based on number of doses received, not on calendar time
  • Adjunctive corticosteroids should be administered for tuberculosis involving the central nervous system or pericardium
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Table 3. Recommended Doses of First-Line Drugs for Treatment of Tuberculosis in Adults and Adolescents (adapted from CDC/NIH/HIVMA guidelines)

DrugDaily3 Times Weekly
(Only during Continuation Phase)
Isoniazid5 mg/kg (usual dose 300 mg)15 mg/kg (usual dose 900 mg)
Rifampin (RIF)
Rifampin is not recommended in patients receiving HIV protease inhibitors (PIs), etravirine (ETR), rilpivirine (RPV), or Stribild (coformulated elvitegravir/cobicistat/emtricitabine/tenofovir)
10 mg/kg (usual dose 600 mg)10 mg/kg (usual dose 600 mg)
Rifabutin (RFBT)
Rifabutin is not recommended in patients receiving Stribild and should be avoided in patients receiving protease inhibitors; if coadministration of RFBT and a protease inhibitor is necessary, the RFBT dosage, if given daily, should be reduced to 150 mg
5 mg/kg (usual dose 300 mg; however, 150 mg if given with a protease inhibitor)5 mg/kg (usual dose 300 mg)
with EFV450-600 mg450-600 mg
Pyrazinamide (PZA)
(weight-based dosing)
45-55 kg1,000 mg (18.2-25.0 mg/kg )1,500 mg (27.3-37.5 mg/kg)
56-75 kg1,500 mg (20.0-26.8 mg/kg)2,500 mg (33.3-44.6 mg/kg)
76-90 kg2,000 mg (22.2-26.3 mg/kg)3,000 mg (33.3-39.5 mg/kg)
>90 kg2,000 mg3,000 mg
Ethambutol (EMB)
(weight-based dosing)
45-55 kg800 mg1,200 mg
56-75 kg1,200 mg2,000 mg
76-90 kg1,600 mg2,400 mg
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