Treatment of latent tuberculosis infection (preventive treatment)

Treatment of LTBI to prevent the development of active TB is called preventive treatment (PT; previously prophylaxis) and is often commenced irrespective of confirmed LTBI diagnosis and based on risk of LTBI. Preventive treatment can reduce the progression of LTBI to active TB in people with HIV infection by 32-62% and reduces the risk of death by one-third, irrespective of concurrent cART. Before commencing PT, it is important to exclude active TB by clinical and radiological or bacteriological assessment.

The 2018 WHO LTBI guidelines recommend that adults and adolescents with HIV infection, with unknown or a positive TST or IGRA and are unlikely to have active TB, should receive PT as part of a comprehensive package of HIV care. Treatment should be given to these individuals irrespective of the degree of immunodeficiency and also to those on cART, those who have previously been treated for TB and pregnant women. Additionally, adults and children with HIV infection who are in close contact with anyone with active TB should receive PT, regardless of their LTBI test results. In high TB burden settings, PT decreases TB risk and mortality regardless of TST or IGRA result.88

In Australia and other low incidence TB settings, people with HIV infection who have a negative TST or IGRA and no recent exposure to, or contact with, a person with active TB are unlikely to benefit from PT and it is therefore not recommended.54 All people with HIV infection who have a positive test for LTBI, recent exposure to or close contact with someone who has TB, and without a history of previous treatment for LTBI or active TB, should receive PT.

Several new regimens are currently recommended by WHO and international guidelines for PT.5,54,55 The previous standard of care was isoniazid for 6 to 9 months. The following options are recommended for treatment of LTBI in countries with a low TB incidence in people with HIV infection: 6-9 months of isoniazid (6H or 9H), or a 3-month regimen of weekly rifapentine plus isoniazid (3HP), or 3 months of isoniazid plus rifampicin (3RH), or 4 months of rifampicin alone (4R). In addition, a recent randomised multicentre trial has demonstrated the non-inferiority of 1 month of daily rifapentine plus isoniazid (1HP) to 9 months of isoniazid for the outcome of active TB and death, and more patients completed treatment.5

There are no clear data to guide duration of PT in people with HIV infection. British and WHO guidelines recommend 6 months of isoniazid, whereas US guidelines prefer 9 months. Isoniazid should be supplemented with pyridoxine at a dose of 25 to 50 mg/day to prevent peripheral neuropathy. In high TB burden and transmission settings, the recommendation is to treat with isoniazid for 6 months, with a consideration of up to 36 months (continuous PT) as clinical trials show benefit with longer duration, presumably by preventing re-infection. Two large randomised trials conducted in South Africa and North America have demonstrated the equivalence of once-weekly isoniazid plus rifapentine, given under DOT for 12 weeks, compared with 6 months of isoniazid preventive therapy. In the case of isoniazid intolerance, an alternative regimen is 4R, however, the drug interactions with cART may be problematic. The 4R regimen was shown to be non-inferior to 9H with better treatment completion and lower adverse events, although the number of participants with HIV was low. There are no data demonstrating the efficacy of rifabutin as PT. The 1HP regimen had better completion rates and lower adverse events than 9H.91 Rifapentine is currently not available in Australia. 

 Selection of PT regimen should be based on the individual’s ART regimen52:

  • Any ART regimen can be used when isoniazid alone is used for LTBI treatment
  • Only efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine [ABC/3TC] or tenofovir disoproxil fumarate/emtricitabine [TDF/FTC]) can be used with once-weekly isoniazid plus rifapentine
  • If rifampin or rifabutin is used to treat LTBI, clinicians should assess the potential for interactions with antiretroviral drugs.

Patients on PT should have baseline assessments including liver function tests monitored monthly for adverse effects. There is no value in repeating TST or IGRA on completion of PT.

For MDR-TB contacts, WHO recommends a risk versus benefit assessment and an individualised drug regimen on a case-by-case basis due to the assumption that isoniazid and rifamycins are not effective and there is limited evidence base for alternatives.5  There are ongoing randomised trials of PT for MDR-TB contacts, 2 with levofloxacin vs placebo (V-QUIN [ACTRN12616000215426], TB CHAMP [NCT02365623], and 1 with delamanid vs isoniazid (PHOENIX [NCT03568383]). The results are expected after 2022. There is observational evidence of the safety and efficacy of PT in over 600 MDR-TB contacts with regimens that include a fluoroquinolone. The benefit of PT is likely to outweigh the risks in most situations.

Co-trimoxazole preventive therapy is recommended by the WHO for all patients with active TB irrespective of CD4+ T cell count, as it has been shown to have a mortality benefit in Sub-Saharan Africa.72 The generalisability of this treatment recommendation to settings such as Australia can be questioned, as the mechanism may involve an effect on malaria and other bacterial infections.

Preventing exposure to and infection with M. tuberculosis

People with HIV infection who live or work internationally in settings with a high prevalence of TB should be counselled about the risk of TB acquisition, infection prevention measures (particularly if working in a health care setting) and the advisability of getting tested for LTBI upon returning to Australia.

The Bacillus Calmette-Guérin (BCG) vaccine is contraindicated in people with HIV infection, although universal BCG vaccine at birth is recommended in high burden TB settings. Several potential new vaccines are under development and being assessed in clinical trials