It is estimated that approximately one third of the 40 million people living with HIV or AIDS (Acquired Immune Deficiency Syndrome) worldwide are co infected with TB.1
The highest global rates of TB/HIV co-infection are reported from sub-Saharan Africa, Asia and Latin America.2
In healthy people previously exposed to and infected by TB, host cell mediated immunity keeps LTBI dormant. HIV infection interferes with cell-mediated immunity, increasing the risk of progression to active disease. People with HIV infection and LTBI are more likely to develop active disease, with a 50% lifetime chance of developing active disease compared to a lifetime risk of 5 to 10% in HIV negative people.2
In people with HIV infection, the risk of tuberculosis is influenced by3:
- the prevalence of tuberculosis in the local community
- the person's likelihood of exposure to infectious TB
- the person's degree of immunodeficiency
- the use of preventive therapy for LTBI.
In early HIV disease, TB tends to present in the 'classical' pulmonary fashion. However, as damage to the immune system increases, people with HIV are more likely to develop extra pulmonary TB.2
Tuberculosis in a person infected with HIV infection may represent reactivation of LTBI3 acquired in the past, or recent infection.
An assessment of TB risk factors should be undertaken for all patients with HIV infection. The history should include: recent or prolonged close contact with someone with infectious TB, previous treatment for TB disease or LTBI, birth or previous residence in a high burden TB country, signs and symptoms of TB, diabetes, chronic renal disease, cancer, silicosis, gastrectomy, corticosteroid treatment, immunosuppressive treatment or medication and pregnancy.
Active TB has been associated with a higher HIV viral load, which might be expected to accelerate the loss of CD4 T-cells and promote HIV/ AIDS disease progression. Tuberculosis co-infection is associated with a doubling of the mortality rate in HIV-infected people. The most significant predictor of survival for HIV-infected persons with coexistent TB is the degree of immunodeficiency.
It is essential that all TB patients diagnosed with HIV are referred to an HIV physician for assessment and care.
Clinical features of tuberculosis
In people with HIV infection, the diagnosis of TB may be problematic due to confusion with other opportunistic infections and other HIV related diseases. Tuberculosis may present as disseminated disease or with atypical clinical (or radiological) presentations including enlarged hilar and/ or mediastinal lymph nodes, pleural effusion and lower lobe infiltrates; this is particularly the case in those with severe immunodeficiency. The disease may progress rapidly in severely immune compromised patients. Extra-pulmonary disease is common.
Chest x-ray findings for TB may show lower lobe or diffuse infiltration and enlarged hilar and/ or mediastinal lymph nodes. The typical appearance of cavitation is less common than in the immune-competent host. 3,4,5 The chest x-ray may also be normal in appearance in some patients with HIV and TB co-infection. A chest x-ray is indicated in the initial assessment of HIV infected people with TB risk factors.
Confirming the diagnosis may be more difficult for several reasons. In cases of pulmonary TB, a lack of lung cavitation may result in fewer tubercule bacilli being present in expectorated sputum.3 Tuberculosis disease in HIV infected people is more often extra-pulmonary than in non-HIV infected people.3,4 All specimens from extra-pulmonary sites should be assessed by smear and culture/PCR for M. tuberculosis.
Diagnosis of Latent TB Infection (LTBI)
Tuberculin skin test (TST) remains the test of choice for the diagnosis of LTBI in people with HIV infection.6 The American Thoracic Society and the US Centers for Disease Control and Prevention (CDC) recommend that a TST reaction = 5mm induration be considered indicative of TB infection in HIV-infected persons.3
However, the ability to respond to TST correlates with the degree of cell-mediated immunity and decreases as the CD4 cell count deceases. The CD4 cut-off below which the TST is unreliable is not well defined, but clinical experience suggests that high false negative rates occur at CD4 cell counts <400 cells/uL.
In some people, the ability to mount an immunological response to mycobacterial antigens wanes over time. These people may not initially react to a TST, but the test itself may boost the immunological response for mycobacterial antigens. A repeat TST will then produce a larger response (a boosted response) which should be considered the true result. There are few data on the role of a two step TST in HIV infected persons; however in a patient where there are significant risk factors for TB or exposure to TB and a negative initial result, a two step TST should be considered.
All registered nurses performing tuberculin skin tests must be trained in accordance with Policy Directive PD2008_033 Immunisation Services - Authority for Registered Nurses and undertake screening as recommended in Policy Directive PD 2008_016, Tuberculin Skin Testing.
The interferon gamma release assay blood test (IGRA), a more recent alternative of assessing LTBI, has not been validated for use in immune compromised people.
Early diagnosis and appropriate supervised treatment promotes care of TB, reduces the risks to contacts and helps prevent the emergence of drug resistant TB.
Tuberculosis generally responds well to antibiotics and treatment should be initiated immediately upon TB diagnosis4. All TB treatment should be prescribed and monitored by a physician experienced in the management of TB. Such clinicians should work in close collaboration with those involved in health care of people living with HIV.
In HIV-infected patients with pulmonary TB a standard multi drug regimen for six months is sufficient treatment,3,4 provided it is fully supervised.3,7 If the patient is slow to respond, treatment should be extended to nine months or for at least four months after the TB culture becomes negative.
Treatment for extra-pulmonary or disseminated TB should be for nine to twelve months, while cases of miliary, meningeal7 or skeletal TB should be treated for at least twelve months.4
People with HIV infection may experience drug interactions, intolerance and hypersensitivity that may necessitate non-standard therapy, which also must be monitored by a physician experienced in TB medicine. The sequential addition of single drugs to TB drug regimens must be avoided to prevent drug resistance.
Anti-TB therapy can be either daily or thrice weekly, depending on the patient's ability to tolerate treatment. Thrice weekly treatment should be discouraged for patients receiving antiretroviral therapy because of the impact on the pharmacokinetics of these agents.
To reduce the risk of development of resistance to the rifamycin group of drugs, the administration of anti-TB therapy twice weekly is not recommended.
Premature cessation of therapy may lead to treatment failure, disease progression and infection of contacts who, in the setting of HIV care, may also be immuno-compromised and at high risk.
Anti retroviral therapy (ART)
There is no good evidence to guide the optimal timing of initiation of ART in patients newly diagnosed with TB/HIV co-infection. To date recommendations have considered the presence of other opportunistic infections, signs of severe immunodeficiency and the CD4 count.9,10
In patients with both TB disease and HIV infection who have not previously been treated with ART and who require ART before anti-TB therapy has been completed, the British HIV Association recommends that ART commence when two months of anti-TB therapy have been completed.4,7
Physicians treating people with TB disease and HIV co-infection need to balance the risk of HIV progression (if ART is delayed) against the risk of having to discontinue ART because of toxicity, side effects or unforeseen drug interactions (if ART is started).7 In co-infected people a delay in commencing ART, if clinically suitable, may simplify patient management, limit the potential of drug side effects and interactions, and reduce the risk of immune reconstitution syndrome.7
When patients with TB/HIV co-infection have a CD4 cell count < 100 cells/uL, a careful assessment needs to be undertaken by the HIV and TB physicians coordinating the treatment and care of the patient 7 prior to commencing ART.
For patients with a CD4 cell count 100 - 200 cells/uL the consensus position of the British HIV Association and International AIDS Society - USA Panel is to start ART after the intensive phase of TB therapy has been completed, i.e. after two months of TB treatment.4,7
Patients with HIV disease and a CD4 cell count > 200 cells/uL are thought to have a relatively low risk of HIV disease progression or death during the six months of tuberculosis treatment.7 It is recommended that these patients have their CD4 counts monitored regularly and complete TB treatment before ART is introduced.7
Recommendations for management and treatment of people infected with HIV can be sourced in the Australasian Society for HIV Medicine Inc. publication - HIV Management in Australasia - a guide for clinical care, 2003.
Drug interactions and reactions
ART has improved the prognosis for HIV-infected people but can complicate the clinical management of TB/HIV co-infection due to drug-drug interactions and drug reactions.4,7
Patients with HIV-related TB are more likely to experience adverse reactions when prescribed TB drugs and ART concurrently. These interactions usually occur in the first two months when TB and ART drugs are commenced concurrently.7 In some cases it may be necessary to interrupt or stop the TB or HIV drug(s). All clinicians involved in the patient's care should communicate closely before any such decisions are taken.
For detailed information related to HIV drug interactions please refer to the British HIV Association Guidelines for TB/HIV infection - February 2005, pages 26-29.
Immune Reconstitution Inflammatory Syndrome
Some HIV-infected people with low CD4 counts may experience a paradoxical worsening of their TB symptoms during treatment for TB, particularly if they are also receiving combination ART. The immune reconstitution afforded by combination ART can be associated with excessive, and sometimes serious, inflammatory reactions termed immune reconstitution inflammatory syndrome. This syndrome is associated with control of HIV replication and usually with an increase in the CD4 count, with more immunodeficient patients being at higher risk.
Immune reconstitution disease classically occurs in patients with advanced HIV disease who have never received anti-retroviral therapy and who are co-infected with another pathogen including M. tuberculosis, M. avium, Cryptococcus neoformans, hepatitis B and C viruses or cytomegalovirus. When both antiretroviral therapy and treatment of the opportunistic infection are commenced simultaneously or a short time apart, clinical symptoms may develop that are difficult to differentiate from treatment failure or the occurrence of a new opportunistic infection.
In the context of TB, these symptoms may include fever, lymphadenopathy, pleural effusion and worsening of respiratory symptoms. The pathophysiology of immune reconstitution disease has not been elucidated; however it is a common finding, occurring in approximately 30% of patients with TB and HIV.10
Signs and symptoms most often occur early in ART. Treatment is supportive, although corticosteroids may be needed in severe cases.3,4,9 Tuberculosis treatment and ART should be maintained where possible, but this may be difficult in the presence of concomitant drug reactions.9
Accurate diagnosis is essential to prevent interruption of anti-tuberculous therapy. The risk of immune reconstitution disease may be reduced by delaying the introduction of anti-retroviral therapy as long as possible after commencement of TB treatment.
Tuberculosis relapse after treatment withdrawal
Recurrences of TB disease are more common in HIV-infected patients. However, it is important to distinguish between relapse of original infection as opposed to occurrences of re-infection.4 Relapse/re-infection can only be reliably distinguished by molecular genotyping.
Relapse of TB is more common within two years following treatment completion,4 when a rifamycin-based regimen has been used.11
Directly observed therapy
Directly observed therapy (DOT) is defined as a health professional observing the patient taking their medication and documenting the administered treatment. DOT minimises the development of drug resistance and/or reactivation of disease related to non-adherence or inappropriate TB treatment. Treatment for all people with active TB must be administered by DOT.
The most appropriate person to supervise therapy has to be determined on a case by case basis. This may be a TB nurse, an HIV community nurse, a general practitioner or a medical specialist.
People with HIV infection may have specific problems in relation to treatment adherence, such as:
- multiple and complex drug regimens before TB therapy is added
- higher incidence of side effects
- clouded mental state e.g., due to a dementing illness or central nervous system infection
- psychiatric problems, and
- substance use.
Treatment of Latent Tuberculosis Infection (LTBI)
The risk of progression of LTBI to TB disease can be substantially reduced by treatment of LTBI with isoniazid for six months.7 People with HIV and LTBI co-infection should therefore be offered treatment for LTBI.
Before treatment of LTBI is initiated, active TB disease must be excluded by clinical assessment, sputum specimens (if available) and chest x-ray.
Where there is concern that the TST is a false negative because of a low CD4 count and/or where there is a high risk of infection such as recent close contact with an infectious case of TB, treatment for LTBI should be considered.
Bacille Calmette Vaccination (BCG)
BCG is a live vaccine and should not be used in people who are HIV infected, regardless of the degree of immunosuppression.
Screening of contacts of infectious TB patients must be undertaken as outlined in the NSW Health Policy Directive PD 2008_017, Tuberculosis Contact Tracing under the direction of NSW Tuberculosis Prevention and Control Services.
Airborne respiratory precautions must be used when managing patients with infectious TB.
Every health care facility that provides services to persons with suspected or confirmed TB disease should have an infection control plan that incorporates administrative and environmental controls and a respiratory protection program as outlined in the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 200511 and in accordance with NSW Health Policy Directive PD2007_ 036 Infection Control Policy.
Procedures that may generate infectious aerosols, such as sputum induction and aerosolised pentamidine, must be undertaken with appropriate infection control precautions, including the wearing of a particulate mask and the use of a room with appropriate ventilation.
Extra-pulmonary TB is not generally infectious, and does not constitute a risk of airborne spread.
HIV testing within NSW Tuberculosis Prevention and Control Services
In NSW, all patients with tuberculosis (TB) must be offered an HIV antibody test, with appropriate pre-test discussion.12
Registered Nurses within NSW Tuberculosis Prevention and Control Services can initiate HIV testing for patients with TB as long as the test is performed in accordance with NSW Health requirements and is undertaken with appropriate consent, pre test discussion, follow up of results and referral as necessary.
Further information on pre and post test discussions can be found in the National HIV Testing Policy 2006 at the web site: 3.0 Indications for HIV Testing.
It is recommended that each Area Health Service review charging arrangements for HIV tests to determine if medical sign off for testing is required. Where the intention is to recoup money for the test from the Medical Benefit Scheme, medical sign off for the test is required within 14 days.
- The World Health Organization. Frequently asked questions about TB and HIV. accessed 23 April, 2008
- The World Health Organization. TB/ HIV A Clinical Manual. Geneva: The World Health Organization; 2004.
- Hopewell PC, Chaisson RE. Tuberculosis and Human Immunodeficiency Virus Infection. In: Reichman LB, Hersfield ES, editors. Tuberculosis A Comprehensive International Approach. 2nd ed. New York: Marcel Dekker; 2000. p. 525-552.
- Aaron L, Saadoun I, Calatroni O, Launay N, Memain N, Vincent V et al. Tuberculosis in HIV-infected patients: a comprehensive review. Clin Microbiol Infect, 2004; 10: 388-398.
- Perlman DC, El-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N et al. for the Terry Beirn Community Programs for Clinical Research on AIDS and the AIDS Clinical Trials Group. Variation of chest radiographic patterns in pulmonary TB by degree of human immunodeficiency virus-related immunosuppression. Clin Infect Dis 1997; 25:242- 246.
- Markowitz N, Hansen NI, Wilcosky TC, Hopewell PC, Glassroth J, et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Internal Med 1993; 119: 185-193.
- Pozniak AL, Miller RF, Lipman MCI, Freedman AR, Ormerod LP, Johnson MA, et al. on behalf of the BHIVA guidelines writing committee. Guidelines for TB/HIV infection - February 2005. Available at http://www.bhiva.org/documents/guidelines/tb/tb_hiv_final2005.pdf, accessed 21 April, 2008.
- Hammer SM, Saag MS, Schechter M, Montaner JSG, Schooley RT, Jacobsen DM et al. Treatment for Adult HIV Infection 2006 Recommendations of the International AIDS Society - USA Panel. JAMA 2006; 296: 827-843.
- Lawn SD, Bekker L-G, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV- infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5: 361-373.
- Nahid P, Gonzalez LC, Rudoy I, de Jong BC, Unger A, Kawamura LM et al. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med 2007; 175:1199-1206.
- Centers for Disease Control and Prevention. Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health Care Settings MMWR 2005; 54 (RR-17): 1-141.
- Emerson CR, Post JJ. To routinely offer HIV testing in all cases of tuberculosis: a rational clinical approach? Med J Aust 2008; 188:162-163.