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Ward 86 Management Recommendations

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

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 latent Mycobacterium tuberculosis infection and drug-susceptible tuberculosis (see Tables 1-3 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 pericardial or central nervous system tuberculosis (in which concomitant corticosteroid therapy is indicated).

    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. Rifampin and rifabutin have clinically significant pharmacokinetic interactions with nearly all antiretroviral drugs (also see Table 3).

    Nucleoside reverse transciptase inhibitor (NRTI) interactions:

    All commonly used NRTIs (eg, tenofovir, abacavir, lamivudine, emtricitabine) can be coadministered with rifampin 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.

    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. 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.

    Integrase inhibitor (II) interactions:

    Rifampin can be coadministered with raltegravir if the raltegravir dosage is increased to 800 mg BID, and Phase II data suggest that raltegravir 400 mg BID may be acceptable with rifampin coadministration as well; a confirmatory Phase III study is under way.(2) 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.(5) Dolutegravir 50 mg daily can be coadministered with rifabutin.

  4. 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. 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)

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

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