Queensland Tuberculosis Control Centre

GUIDELINES FOR MANAGEMENT OF TUBERCULOSIS IN PATIENTS WITH HIV CO-INFECTION

Background: Co-infection with tuberculosis and HIV is common in many parts of the world, especially subSaharan Africa, but quite uncommon in Australia. The importance of recognizing TB/HIV co-infection is that each infection has the potential to exacerbate the course of the other. The main challenges related to management of TB/HIV co-infection are immune reconstitution and drug interactions.

Management: Ideally, a patient with TB/HIV co-infection will be managed by a physician with experience in the management of both conditions. Otherwise, close co-operation between the physicians managing the tuberculosis and the HIV infection is essential.

IMMUNE RECONSTITUTION DISEASES Immune reconstitution diseases (IRD) are the rather severe disease states experienced in the early stages of anti-retroviral therapy (ART) for HIV caused by the induction of an immune response to pathogens which had been masked by HIV-related immunosuppression. The course of previously recognised and unrecognised clinical or subclinical infections, including tuberculosis, can become dominated by the reconstituted inflammatory response, and this can cause significant morbidity. IRDs usually occur within the first three months of ART, in association with a decrease in viral load and an increase in the CD4 T cell count. The usual presentations of TB-related IRD are increasing lymphadenopathy and/or worsening pulmonary parenchymal disease. The risk is greatest when ART is commenced at the time of, or within two months of starting anti-tuberculous therapy (i.e., while there are still large numbers of viable tubercle bacilli present). It is currently recommended that ART should be deferred until at least two months of antituberculous therapy in people with a CD4 count >100/ l. Timing of ART in people with a CD4 count <100/l is more controversial, and the advice of a physician experienced in the management of HIV should be sought so that an appropriate TB treatment regimen is chosen.

PEOPLE WITH HIV/TB CO-INFECTION NOT ON ANTIRETROVIRAL THERAPY People not on ART and with CD4 counts >200/ l should have a standard course of antituberculous therapy but paying attention to the cautionary note below about treatment of TB in HIV-infected patients. People who are significantly immune suppressed and yet for one reason or another are not on ART, will require individualised assessment and management by a clinician experienced in the management of both TB and HIV.

DRUG INTERACTIONS The main source of drug interactions in the management of TB/HIV co-infection is through the effects of rifampicin or efavirenz in inducing the cytochrome p450 metabolic pathway, and protease inhibitors inhibiting components of this system.
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Some of the major interactions are outlined below, but more detailed information is available at the following websites: http://www.hiv-druginteractions.org; http://www.cdc.gov/nchstp/tb/TB_HIV_Drugs/PDF/tbhiv.pdf; or in Table 13.4 (p143) of HIV management in Australasia: a guide for clinical care. The most significant reactions between antimycobacterial and antiretroviral drugs occur with rifamycins inducing the metabolism of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Rifampicin is a more potent inducer of the cytochrome P450 system than rifapentine, which in turn is more potent than rifabutin.

Protease inhibitor Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Ritonavir (RTV) Lopinavir/Ritonavir (LPV/RTV) NNRTI Efavirenz (EFV)

With Rifampicin (RIF) Contraindicated Contraindicated Contraindicated RTV 600mg bd Rifampicin standard dose Contraindicated

With rifampicin (RIF) EFV 600-800mg daily. Standard rifampicin dose Nevirapine (NVP) Not recommended. If used incr NVP dose to 300mg bd Table adapted from Table 13.4 in Hoy and Lewin (eds) HIV management in Australasia: a guide for clinical care

With Rifabutin (RFB) Incr IDV dose (e.g. 1000mg q8h) Decr RFB 150mg daily Decr RFB 150mg daily Decr RFB 150mg daily Standard RTV dose Decr RFB 150mg thrice-weekly LPV/RTV 400/100 bd Decr RFB 150mg thrice-weekly With rifabutin (RFB) EFV standard dose RFB incr to 450-600 mg daily No dose adjustment

ACQUIRED RIFAMYCIN RESISTANCE Increased rates of acquired rifamycin resistance have been noticed in HIV-positive people being treated for tuberculosis with weekly rifapentine-based regimens or twice-weekly rifampicin or rifabutin-based regimens. The Queensland Tuberculosis Control Centre does not endorse the use of once- or twice-weekly regimens in any situation, and they should certainly not be used in people with HIV co-infection.

CAUTION 1. In general, patients with HIV infection have the same overall response to standard short course TB treatment as immunocompetent patients. However, the role of long-term preventive treatment in such patients as the CD4+ lymphocyte count declines has not been determined. This is further confounded by the predilection of such patients to be reinfected. While the role of long-term prophylaxis with isoniazid has not been clarified for such subjects, it is clear that tests to detect latent viable organisms cannot be effectively utilised, and it is possible that such subjects are more likely to live/socialise with subgroups of subjects, or within selected environments where ongoing TB transmission may be occurring. Thus the role for long-term prophylaxis for TB should be assessed for each of these patients. 2. Most randomised controlled trials of short course treatment for TB have had a small group of patients that have failed to respond (~2% overall). A recent report from the US has identified risk groups for treatment failure. Among HIV-infected patients this includes all patients who were initially sputum smear positive, had cavitary pulmonary disease related to TB or were sputum smear-positive after two months of treatment. Thus the QTBCC recommends caution in the setting of HIV-related disease and, unless there is evidence of rapid clinical and bacteriological response to anti-TB drugs, recommends extension of the TB treatment course even in uncomplicated pulmonary TB.
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References: Dlodlo RA, Fujiwara PI, Enarson DA (2005) Should tuberculosis treatment and control be addressed differently in HIV-infected and uninfected individuals? Eur Respir J 25:751-7 Hoy J and Lewin S (eds) (2004) HIV management in Australasia: a guide for clinical care Australasian Society for HIV Medicine Inc., Darlinghurst. Accessed January 2006 from http://www.ashm.org.au/index.php?PageCode=1321&SD=10&DExpand=1 Lawn SD, Becker L-G, Miller RF (2005) Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving anti-retrovirals Lancet Infect Dis 5:361-73 McShane H (2005) Co-infection with HIV and TB: double trouble International Journal of STD and AIDS 16:95-101

Queensland Tuberculosis Control Centre

26 June 2006

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