BHIVA treatment guidelines for tuberculosis (TB)/HIV infection 2005

Abstract

These guidelines have been drawn up to help physicians manage adults with HIV/TB coinfection. We recommend that coinfected patients are managed by a multidisciplinary team that includes physicians who have expertise in the treatment of both tuberculosis and HIV. We recommend that the optimal regimen be used in the treatment of tuberculosis. In the majority of cases, this will necessitate use of rifampicin and isoniazid. In the treatment of HIV, there is more flexibility of choice for many patients starting highly active antiretroviral therapy (HAART). We recommend that if HIV treatment is started in patients who are on antituberculosis therapy then HAART should be modified if necessary. TB treatment should only be modified when a patient has developed intolerance of, or severe toxicity from, HIV drugs or has evidence of genotypic resistance to specific HIV drugs, thus limiting HAART therapy to agents which are likely to interact with antituberculosis therapy. These factors (intolerance, toxicity and resistance) may sometimes necessitate prolongation of duration of TB treatment. The gold standard for diagnosis of tuberculosis is microscopy followed by culture and drug sensitivity testing. Molecular diagnostics may be valuable in reducing the time patients spend in isolation facilities when tuberculosis is suspected clinically. Confirmation, by molecular diagnostics, that acid-fast bacilli are not Mycobacterium tuberculosis (MTB) may be useful for clinical management and infection control. We recommend rapid detection of rifampicin resistance using molecular techniques in patients whose clinical course or initial assessment suggest multidrug resistant tuberculosis. These molecular tests should be used as an adjunct to standard laboratory techniques. We recommend daily tuberculosis treatment whenever possible. Treatment may be given 5 days a week, but should be intensively supervised. This option may be useful in hospitals or other highly supervised settings. Three times a week directly observed therapy (DOT) should only be given to patients where local logistics enable this to be successfully undertaken. We do not recommend twice-weekly DOT for treatment of HIV/TB coinfected patients, especially in those with CD4 counts <100 cells/μL. Treatment should be started with four drugs (typically rifampicin, isoniazid, pyrazinamide and ethambutol) until sensitivities are known. We recommend a 6-months treatment regimen for drug sensitive M. tuberculosis outside of the central nervous system (CNS) [at least 182 doses of isoniazid and rifampicin and 56 doses of pyrazinamide and ethambutol]. In drug-sensitive tuberculosis affecting the CNS we recommend 12 months of treatment. This usually consists of 2 months of a four-drug TB regimen, followed by 10 months of isoniazid and rifampicin. Drug-resistant disease should be treated in line with BTS Guidelines: http://www.brit-thoracic.org.uk Rifampicin is a powerful inducer of cytochrome P450–3A4 and, therefore, careful attention should be paid to potential drug/drug interactions between antituberculosis drugs, HAART and other concomitant therapy. The alternative use of rifabutin may overcome some of the difficulties in coadministration of rifampicin with protease inhibitors and non-nucleosides. Overlapping toxicity profiles, e.g. peripheral neuropathy with stavudine and isoniazid, or rash with non-nucleosides and rifampicin can complicate care, as ascribing a cause may be difficult. In some patients, e.g. those with chronic viral hepatitis, there is an increased rate of drug toxicity. In these patients we recommend more frequent monitoring of liver function tests. The following antiretroviral drugs may be used with rifampicin-based regimens of TB therapy. It is important to note that there are few long-term clinical outcome data to support use of these drugs in combination. (i) Nucleoside/nucleotide reverse transcriptase inhibitors There are no major interactions with rifampicin or rifabutin. (ii) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz may be used at a dose of 800 mg/day in patients weighing >50 kg and the standard dose of 600 mg/day in patients weighing <50 kg. In patients experiencing side effects on these doses, therapeutic drug monitoring may be of value. We recommend that daily rifampicin should not be used with nevirapine. NNRTI may be used with rifabutin, but the rifabutin dose is increased to 450 mg/day when used with efavirenz. No dose modification is required when rifabutin is used with nevirapine, however, we do not recommend use of this combination. (iii) Protease inhibitors (Pls) Rifampicin should not be used with un-boosted Pls. Data on boosted PI regimens, e.g. lopinavir/ritonavir with rifampicin, show an increased risk of hepatotoxicity and the need in some patients (based on therapeutic drug monitoring [TDM]) to increase the dose of lopinavir to four tablets twice daily. There is a lack of good clinical and virological outcomes using these combinations. Rifabutin can be used with un-boosted PI but dose modifications of PI are needed and the dose of rifabutin halved to 150 mg/day. There are few data to support use of rifabutin with a boosted PI but if it is used the dose of rifabutin needs to be reduced to 150 mg three times a week. The dose of boosted PI remains unaltered. In these situations TDM should be used. We recommend that TDM of NNRTI and PI should be performed when drug regimens are complex. Drug levels of antituberculosis drugs should be measured when there is clinical concern regarding absorption or response to TB therapy. When to start antiretroviral therapy in patients who have tuberculosis is a balance between potential overlapping toxicities, drug interactions and possible immune reconstitution vs. the risk of further immune suppression with its associated increase in morbidity and mortality. We recommend that patients who have a CD4 count consistently >200 cells/μL while receiving treatment of tuberculosis should wait until their antituberculosis therapy is completed before starting HIV therapy (see BHIVA guidelines for the treatment of HIV-infected adults with antiretroviral therapy in this Supplement). For patients with CD4 counts between 100 and 200 cells/μL we recommend deferring starting HIV therapy until completion of the intensive phase of antituberculosis treatment (after 2 months). For patients with CD4 counts <100 cells/μL there are no data to support either immediate or deferred HAART. In this situation we recommend that patients should be recruited to clinical trials which address this question. If that is not possible, then patients should be started on HAART as soon as is practical after starting antituberculosis therapy. This is regarded as a gold standard for treatment of TB but it may not be possible to deliver all elements of the DOT package. Witnessed supervision of treatment may be impracticable in every case and it is important to remember that patient-centred management is the core of successful TB treatment. We recommend that DOT be used in all cases of multidrug-resistant TB. Tuberculin skin testing is less useful in patients with HIV infection compared with HIV-uninfected patients. We do not recommend tuberculin skin testing in patients with suspected HIV/TB coinfection or as a screening test for tuberculosis in HIV-infected patients. New immune-based detection tests (such as those using gamma interferon production from TB specific T cells) appear to have better sensitivity than tuberculin tests, however, correlation of positive results with outcome in patients with low CD4 counts is required. We do not recommend routine chemoprophylaxis for all HIV infectious patients. Close contacts of people who have infectious TB should be followed up and offered chemoprophylaxis (see BTS guidelines). Data suggest that HAART is effective in reducing the incidence of new tuberculosis and we recommend that all HIV-positive patients should be offered HAART (based on needs as outlined in the BHIVA HIV treatment guidelines). Patients with tuberculosis, with or without HIV infection, who appear to fail treatment or who relapse despite therapy pose particular management problems and should be referred to and discussed with clinical colleagues who have expertise in the management of HIV/TB. Every hospital/trust should have in place a policy for the control and prevention of TB. Specific consideration should be made to establishing protocols for prevention of transmission of TB to and from immunosuppressed patients. Worldwide, HIV infection is the foremost risk factor for development of active TB [1–4]. All patients with TB, regardless of their perceived risk of HIV infection, should be offered an HIV test as part of their TB treatment package. In the UK, clinicians are caring for increasing numbers of HIV-TB coinfected patients. TB is now the second commonest opportunistic infection in the UK. In 2003 TB contributed to 27% of all AIDS diagnoses [5–7]. The clinical and radiographic presentation of such individual's disease may be atypical. Compared to the immune competent general population, HIV-infected patients with active pulmonary TB are more likely to have normal chest radiographs, or be smear negative/culture positive [8–11]. The clinician caring for HIV-infected patients therefore needs to have a high index of suspicion for TB in symptomatic individuals. As the investigation and treatment of both TB and HIV require specialist knowledge and expertise, it is mandatory to involve specialist HIV, respiratory and infectious diseases physicians in patient care. These guidelines have been drawn up in response to a perceived need for a clinical knowledge base covering the treatment of both HIV and TB in coinfected patients in the UK. These guidelines do not cover HIV-infected children with TB. Although we support the policy of testing all TB patients for HIV, these guidelines do not provide advice on HIV testing in adults with newly diagnosed TB. These treatment guidelines have been written to help physicians manage HIV-infected patients with confirmed or suspected TB. They are based on evidence where it is available but some recommendations have to rely on expert opinion until data from trials are made available. These guidelines are not a manual for treatment of HIV/TB coinfection and should be regarded as an adjunct to the BHIVA treatment of HIV guidelines and the BTS guidelines on TB. These documents can be downloaded from http://www.bhiva.org and http://www.brit-thoracic.org.uk BHIVA is aware of and involved in the creation of NICE guidelines on TB, which will be available in 2005 but felt that until that time some guidance on TB in HIV should be made widely available. Recommendations for the treatment of TB in HIV-infected adults are similar to those for HIV-uninfected adults. However, there are important exceptions. Some intermittent treatment regimens are contra-indicated in HIV-infected patients because of unacceptably high rates of relapse, frequently with organisms that have acquired rifamycin resistance. Consequently, patients with CD4 counts <100/μL should receive daily or a minimum of three times weekly antituberculosis treatment. Adherence strategies including DOT are especially important for patients with HIV-related TB. HIV-infected patients are often taking medication, which might interact with antituberculosis medications, e.g. rifampicin, which interacts with antiretroviral agents and other anti-infectives, e.g. fluconazole. Drug absorption may also be affected by the stage of HIV infection. There are overlapping toxicity profiles and drug/drug interactions with some antituberculosis and antiretroviral drugs that further complicate the concurrent use of HAART and TB treatment. There are also concerns about the timing of commencement of HAART in relation to the start of TB treatment in the context of preventing the risk of further HIV progression and the occurrence of paradoxical reactions. It should be noted that the treatment of tuberculosis has benefits not only for the individual but also for the community. The aim of TB therapy is: to cure the patient of TB; and to minimize the transmission of MTB to both immune suppressed and immune competent persons. The quality of any investigation is related to the quality of the specimen and the request. Therefore there must be close liaison with the mycobacterial laboratory. Microscopic smears remain an essential part of TB diagnosis. Results should be available within 1 working day. These are central to the confirmation and identification of the mycobacterium and for drug susceptibility testing. More rapid results are obtained from liquid media, which usually grows MTB in 7–28 days. Identification of mycobacterium based on morphology, growth and biochemical characteristics are performed at mycobacterium reference centres. Rapid gene probes can be used but this should be fully discussed with the laboratory. These are less sensitive than culture and are used mainly on respiratory specimens. These are often requested when it is important to differentiate the diagnosis of MTB from other mycobacteria for which treatment may be different and there are no infection control concerns. However, it should be noted that all specimens even those that are negative on PCR still require culture and that a negative PCR does not exclude TB and a positive PCR does not indicate the drug susceptibility profile. In many cases the treatment conundrum is whether the patient has Mycobacterium avium or MTB and often the physician will wait for the routine identification before altering the standard 4-drug regimen. Some physicians prefer to replace rifabutin for rifampicin in this situation. When opportunist mycobacteria are identified then the regimen can be modified appropriately. These are usually available within 10–21 days of the laboratory receipt of the isolates and are performed by standard assays. Molecular detection of rifampicin resistance (and pyrazinamide) is available although it is not 100% sensitive. These molecular tests are useful when drug resistance is suspected, as about 95% of patients who are rifampicin resistant will also be isoniazid resistant. Patients with gene probe positive rifampicin resistance should be treated as multidrug-resistant tuberculosis (MDR-TB), until the full resistance profile from cultures are available. The lack of sensitivity of the tuberculin test and the poor specificity because of antigenic cross-reactivity with BCG vaccination means that an accurate test for active or latent TB in HIV individuals is needed. Tests using either whole blood or blood mononuclear cells have been developed which measure interferon gamma production from TB-specific T cells responding to MTB antigens ESAT-6 or CFP-10 [12]. Using an enzyme linked immunospot (ELISPOT) assay, a study from Zambia and the UK diagnosed active TB in 90% of 39 individuals tested. Unfortunately, although this technology was better at picking up latent TB than PPD testing in HIV-positive persons, it was still not as sensitive when compared to HIV-negative patients. Larger studies are needed and correlations of ELISPOT responses with patient's CD4 counts need to be made. The reproducibility of the test also needs to be evaluated in HIV-positive patients and long-term outcomes measured. Because of the relatively high proportion of adult patients in the UK with TB 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 (UK TB resistance database, Health Protection Agency) 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 TB should consist of two phases. A 2-month initial phase of isoniazid, rifampicin, pyrazinamide and ethambutol. If (or when) drug susceptibility test results are known and the organisms are fully susceptible, ethambutol need not be included. This is followed by a continuation phase of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in the majority of patients. TB therapy can be given five times a week with standard doses. Although there are no formal clinical trial data, considerable clinical experience suggests that 5 days-a-week drug administration by DOT is equivalent to 7 days-a-week treatment – and thus either may be considered 'daily' [AIII]. The 6 months short course drug combination should be recommended to all HIV-positive patients with pulmonary tuberculosis wherever possible [AII]. All patients should be given pyridoxine (vitamin B6) 10–25 mg with isoniazid dosing. There are important exceptions. A 7-months continuation phase is recommended for certain groups, for example patients with drug-susceptible organisms whose initial phase of treatment did not include pyrazinamide; patients with cavitary pulmonary disease who remain sputum culture positive at month 2 of treatment. A 10-month continuation phase is recommended for patients with 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]: once-weekly isoniazid–rifapentine in the continuation phase should not be used in any HIV-infected patient; and twice-weekly isoniazid–rifampicin or -rifabutin should not be used for patients with CD4 counts <100 cells/μL. In two studies, patients with acquired rifamycin resistance had very low CD4 counts at the time of TB diagnosis (<60 cells/μL) [15–17]. These data have led the CDC in the USA to recommend that persons coinfected with HIV and TB who have CD4 cell counts <100 cells/μL 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 PIs. However, non-PI-based regimens are possible, especially in HAART-naive 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 observed therapy 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 continuing 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 coinfected patients and more data are needed before rifapentine can 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-uninfected 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-uninfected patients. A review of six studies of patients with HIV infection and three studies of patients without HIV infection given treatment for 6 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 coinfected 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 [16,23–27] [AII]. Some or all of these factors have a role in explaining the differences in the present data. A multicentre study from the USA found no difference between TB relapses with regimens of 6 and 9 months duration. However, very few patients relapsed (two and one patients, respectively) [28,29]. The risk of relapse of TB for HIV-infected patients is the same as that for HIV-uninfected patients if rifampicin is used throughout at least 6 months). randomized trials are needed to the of duration of TB therapy in HIV-infected patients. In HIV-infected patients HAART may the risk of relapse of TB This is by data a in the incidence of TB with HAART and it might be that there will be a reduced rate of in patients who have in CD4 of therapy is as A CD4 count and should be of serum and or and serum and a count should be function tests should be at if (see All patients should have tests for and at of with should be performed when ethambutol is used (see BTS guidelines). Patients with pulmonary TB who are not on treatment should have a sputum smear and culture if the patient still has a after 2 months of treatment. A chest should be performed if after 2 months is In pulmonary TB, a and of chest are necessary. e.g. chest radiographs, or may be on the clinical Treatment for a of days without for the of doses may in treatment. of whether or not treatment has been completed should be based on the of doses on the duration of therapy. For a daily regimen 7 should consist of at least 182 doses of isoniazid and rifampicin, and 56 doses of pyrazinamide; if the drugs are administered by DOT the minimum of doses of rifampicin and isoniazid is and doses of It is recommended that all of the doses for the initial phase be within months and those for the 4-month continuation phase be within a The regimen should therefore be completed within 9 months of starting treatment. These are in the treatment of tuberculosis. Data to support recommendations are We with the CDC that there are few data to the management of They suggest the If the during the initial phase of treatment and the is days or more in treatment should be from the If the is less than the treatment regimen should be in both cases the of doses for the initial phase should be For patients who were smear positive treatment to the of doses is needed. Thus, If the patient has less than of the doses and the is months or more in treatment should be from the If the is less than months in treatment should be to a full have not been performed in HIV-infected patients in to this and physicians should be when patients who have had of therapy. of the timing and duration of the DOT should be used. If the patient was already managed with may be necessary to completion of e.g. interactions between HIV and TB therapy of and are often to enzyme or important of is the cytochrome The is involved in the of many drugs including the protease inhibitors and which up the core of most HAART regimens. The and have important drug interactions with the as the are of However, the of rifampicin not only at least 2 to but will also for at least 2 after rifampicin has been If have been started or at the of TB this on enzyme should be In rifampicin the of the multidrug that to the of PI Rifabutin is a less inducer of rifampicin, it is also a of the enzyme Therefore any inhibitors will increase the of rifabutin but will have no on rifampicin Thus, when rifabutin is given with which are inhibitors of its and that of its may increase and cause toxicity. drug/drug interactions between and antiretroviral agents are in 1 and The of drug/drug interactions expertise in use of both antiretroviral and particular drug interaction should be the of is by rifampicin and therefore doses of such drugs, e.g. which are used in TB should be increased have either or in when given with rifampicin-based regimens. Rifampicin the the or drug and the of the of increased of This is not and dose is not required. In rifabutin does not appear to the of The of a which affected the and absorption of rifampicin and of the drugs had to be in This is no longer necessary as is used. Rifampicin a in serum of PI other than to of antiretroviral of regimens and can in the of resistance to one or more of the other drugs in the HAART regimen. most patients are given of which includes 100 mg per in to of its enzyme In the of the other PI and more dosing. Data from the drug/drug interaction of rifampicin with lopinavir/ritonavir suggest that at this low dose may for the of rifampicin on lopinavir data that 100 mg twice daily may be used with daily rifampicin. daily has also been used However, studies of to rifampicin twice daily with developed toxicity and this combination cannot be recommended Although there is CDC guidance on the use of PI with it is based on the available data We recommend that until more data are available should not be given with rifampicin-based regimens. In these cases rifampicin should be by rifabutin, or the PI and to an alternative antiretroviral if exist (see Rifabutin can be used with single PI However, because of the balance between rifabutin and protease of when this