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Ward 86 Management Recommendations

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

updated July 2017

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

  1. We concur (with the following two exceptions) 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 and the Mycobacterium tuberculosis Infection and Disease section of the CDC/NIH/HIVMA Guidelines).(1)

    1. 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 has clarified optimal timing of initiating ART as follows.(2,3,4) In our opinion, ART should be started within 2 weeks of initiating antimycobacterial therapy for tuberculosis regardless of absolute CD4 count, except for patients with tuberculous meningitis, in whom a full 2 weeks of antimycobacterial therapy should be administered before ART is initiated.

    2. A recent randomized, double-blind trial initiated prednisone (40 mg/day for 2 weeks then 20 mg/day for 2 weeks) or matching placebo at the time of ART initiation in 240 ART-naive adults at high risk of TB-IRIS (initiation of ART within 30 days of TB treatment initiation and CD4 count ≤100/µL). The incidence of TB-IRIS was significantly lower in the prednisone arm, as were Grade 3 adverse events.(5) There were also trends toward fewer interruptions of TB therapy or ART, less subsequent use of prednisone to treat IRIS, and fewer serious complications of AIDS in the prednisone arm. We now consider using this regimen for patients (except those with Kaposi sarcoma) who coinitiate treatment for any form of active tuberculosis with ART.

  2. We 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.

  3. We concur with the treatment recommendations published in the CDC/NIH/HIVMA Guidelines (last updated in May 2017) for latent Mycobacterium tuberculosis infection (see Table 1 below).

  4. Rifampin, rifapentine, and rifabutin have clinically significant pharmacokinetic interactions with nearly all antiretroviral drugs (also see Table 3 and Figure 1, below).

    Nucleoside reverse transcriptase inhibitor (NRTI) interactions:

    The new single-pill antiretroviral formulations containing tenofovir alafenamide should not be coadministered with any of these rifamycins, as their interaction will lower tenofovir levels. Also, the combination of rifampin and zidovudine should be avoided because rifampin can lower zidovudine levels. All other commonly used NRTIs (eg, tenofovir disoproxil, abacavir, lamivudine, emtricitabine) can be coadministered with rifampin, rifapentine, or rifabutin at standard dosages.

    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.(6) 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.

Figure 1.

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. Meintjes G, Stek C, Blumenthal L; et al. Randomized controlled trial of prednisone for prevention of paradoxical TB-IRIS. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 81LB.
  6. 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), or
Rifapentine (weight based, 900 mg if weight >50 kg, 750 mg if 32-49.9 kg) PO weekly + isoniazid 15 mg/kg weekly (900 mg max) + pyridoxine 50 mg weekly for 12 weeks--in patients receiving an efavirenz- or raltegravir-based ART regimen

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; 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, and should be considered for all other HIV patients with active tuberculosis

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), or tenofovir alafenamide (TAF)
10 mg/kg (usual dose 600 mg)10 mg/kg (usual dose 600 mg)
Rifabutin (RFBT)
Rifabutin is not recommended in patients receiving Stribild or TAF-containing regimens 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
Rifapentine (RPT)
Rifapentine should only be coadministered weekly for treatment of latent TB infection and only with either efavirenz or raltegravir; potential pharmacokinetic interactions with other drugs have not yet been established
Pyrazinamide (PZA)
(weight-based dosing)
45-55 kg1,000 mg (18.2-25.0 mg/kg )
56-75 kg1,500 mg (20.0-26.8 mg/kg)
76-90 kg2,000 mg (22.2-26.3 mg/kg)
>90 kg2,000 mg
Ethambutol (EMB)
(weight-based dosing)
45-55 kg800 mg
56-75 kg1,200 mg
76-90 kg1,600 mg