Various treatment regimens are outlined in Figure 1. Because of the relatively high proportion of adult patients in the UK with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6 month regimen to be maximally effective. From Mycobnet data the overall isoniazid resistance rate in the UK is 6% and higher in non-white ethnic groups and those with prior treatment. The highest rates have been found in London. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of two phases;
Followed by:
A continuation phase of treatment is given for either four or seven months see figure 2. The 4-month continuation phase should be used in the majority of patients.
TB therapy can be given 5 times a week with standard doses Although there are no formal clinical trial data, considerable clinical experience suggests that 5 day-a-week drug administration by DOT is equivalent to 7 day-a-week treatment – and thus either may be considered “daily”. [AII]
There are important exceptions.
A seven months continuation phase is recommended for certain groups: e.g.
A ten month continuation phase is recommended for patients with central nervous system (CNS) involvement e.g. meningitis, tuberculomata.
It is recommended that patients should receive daily therapy. However intermittent treatment is an option.13,14 The indications for this in HIV positive individuals are almost the same as for patients without HIV infection. Intermittent therapy can be given three times per week with dose modification. Two dosing strategies should be avoided, as acquired rifamycin resistance has been associated with their use in HIV patients: [AII]
In two studies, patients with acquired rifamycin resistance had very low CD4 counts at the time of TB diagnosis (<60 cells/uL). 15-17
These data have led the CDC in the USA to recommend that persons co-infected with HIV and TB who have CD4 cell counts <100 cells/uL should not be treated with highly intermittent (i.e. once or twice weekly) regimens. Patients already on highly intermittent regimens should switch over to daily or three times a week as soon as practicable.
Rifabutin has been successfully used instead of rifampicin in treatment of TB in HIV negative patients. 18.19 In HIV patients receiving complex antiretroviral regimens, where there is a risk of drug/drug interactions with rifampicin, rifabutin may be substituted. Rifabutin showed similar efficacy to rifampicin in a single blind, randomized study of 50 HIV positive patients in Uganda and in a cohort study of 25 patients in the USA. 20.21
Although rifabutin seems to be equivalent to rifampicin, there are no long-term data on which to make comparisons. Despite the paucity of data regarding use of rifabutin in HIV positive patients it is frequently used in the treatment of TB in HIV. This is because rifabutin may be administered with antiretroviral regimens that include protease inhibitors. However, non–protease inhibitor based regimens are possible, especially in HAART naïve patients.
We recommend that rifampicin should remain the drug of choice whenever possible.
Rifapentine has a long serum half-life, which theoretically would allow once weekly directly observedtherapy during the continuation phase of TB treatment. In the initial phase of treatment of TB in HIV negative patients rifapentine has unacceptable 2-year microbiological relapse rates and cannot be recommended. Data on its use in the continuation phase of treatment is encouraging, but this is accrued from studies of HIV negative patients.
There are few data regarding the interaction of rifapentine with HAART. Development of rifapentine resistance appears more frequent in TB/HIV co-infected patients and more data are needed before rifapentinecan be recommended for use in this patient group. 22
In the absence of data from clinical trials, it is not known if duration of treatment of TB in HIV infected patients should be for longer than in HIV un-infected patients. The few data that exist suggest that in HIV infected patients duration of treatment for tuberculosis sensitive to first line therapy should be no different to HIV un-infected patients.
A review of six studies of patients with HIV infection and three studies of patients without HIV infection given treatment for six months (or longer) demonstrated considerable variability in published study design, eligibility criteria, site of disease, frequency and method of dosing, and outcome definitions. In the reported studies, HIV-infected patients had cure rates of 59-97%, successful treatment rates of 34-100% and relapse rates of 0%-10%. In patients without HIV infection, cure rates were 62%-88%, successful treatment occurred in 91%-99% and relapse rates were 0%-3%. Although the relapse rates appeared higher in some studies of co-infected patients other outcomes were comparable when 6 months regimens were used.
We recommend that for drug sensitive TB, not involving the CNS, regimens of 6 months should be given. 23-28 [AII]
Some or all of these factors have a role in explaining the differences in the present data. A multicentre study from the US found no difference between TB relapses with regimens of 6 and 9 months duration. However, very few patients relapsed (2 and 1 patients respectively). 29.30
The risk of relapse of TB for HIV infected patients is the same as that for HIV uninfected patients if rifampicin is used throughout (for at least 6 months). Long-term randomized trials are needed to resolve the question of duration of TB therapy in HIV infected patients.
In HIV infected patients HAART may reduce the risk of relapse of TB31-33. This statement is supported by data showing a reduction in the incidence of TB with HAART and hence it might be hypothesized that there will be a reduced rate of exogenous reinfection and/or reactivation in patients who have HAART-induced improvements in CD4 count.
Monitoring of therapy is as follows:
Treatment for a defined number of days without accounting for the number of doses taken may result in under treatment. Therefore, determination of whether or not treatment has been completed should be based on the total number of doses taken—not solely on the duration of therapy.
For example
It is recommended that all of the doses for the initial phase be taken within 3 months and those for the 4-month continuation phase be taken within a 6-month period. The 6-month regimen should therefore be completed by 9 months.
These are common in the treatment of HIV associated tuberculosis. Data to support recommendations are scant. We agree with the CDC that there are few data to guide the management of interruptions. They suggest the following:
NB In both 1) and 2) the total number of doses prescribed for the initial phase should be given.
Regardless of the timing and duration of the interruption, DOT should be used.
If the patient was already being managed with DOT, additional measures may be necessary to ensure completion of therapy eg transport, food, social services.34