Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis and is an acquired immune deficiency syndrome (AIDS)-defining illness in Australia and other high-income countries. TB remains a global health crisis with an estimated 8.6 million new cases and 1.3 million deaths occurring each year. The intersection of the TB and human immunodeficiency virus (HIV) epidemics has contributed to an increase in the global TB burden with 13% of all new TB cases occurring in people living with HIV (PLHIV) in 2013. Globally, TB is the most common presenting illness and leading cause of mortality in PLHIV accounting for 1 in 4 of these deaths. The emergence and transmission of multidrug-resistant (MDR, resistance to at least isoniazid and rifampicin) is a growing challenge, particularly for the Asia-Pacific region. A recent meta-analysis showed a consistent but marginally increased risk of MDR-TB among PLHIV, mostly associated with primary transmission.
Australia has one of the lowest TB case notification rates in the world (4-6 cases per 100,000 population) with higher rates in Indigenous Australians (7 per 100,000 population). However absolute TB notifications are increasing and 85% of cases occur in overseas-born persons, making this the most significant risk factor. Accordingly, HIV-associated TB in Australia is mainly found in overseas-born people and occurs at low rates. In 2008, HIV testing status at the time of TB diagnosis was reported in only 83% of Australian TB notifications and of these, less than 1% (11 cases) were identified as being HIV positive.
TB infection ensues when airborne droplets containing M. tuberculosis from an infectious host are inhaled, taken up by alveolar macrophages at the terminal airways and encounter the immune system. The conventional model of TB is a binary state between latent TB infection, an inactive, non-infectious state, and active disease, the infectious form where clinical signs and symptoms are present. Transitions between the binary states result in one of three clinical outcomes – primary disease, latent TB infection and reactivation or post-primary disease. Latent TB infection is defined only by evidence of an antigen-specific T cell response to mycobacterial proteins measured by reactivity in the tuberculin skin test (TST) or an interferon-gamma release assay (IGRA). Active disease is classified as either primary TB (involving progression 1-2 years following infection due to loss of immune containment) or reactivation TB (also known as post primary). Approximately one-third of the world’s population is estimated to have latent TB infection and 90-95% of these people (HIV negative, no other risk factors) will not develop active disease, indicating that the human immune system can control TB. A recent paradigm shift has occurred to view TB infection as a continuous spectrum spanning early clearance (before adaptive immunity), delayed clearance (after adaptive immunity), immune containment (quiescent infection), subclinical active disease and fulminant active disease (see figure 1).,, However, significant biomedical knowledge gaps exist in the understanding of the factors that govern infection, pathogenesis and progression to active disease (the host-pathogen interaction). This lack of knowledge has resulted in a lack of adequate biomarkers to measure states of infection and disease and therapeutic targets for preventive, diagnostic and therapeutic tools for TB and TB-HIV co-infection.
HIV co-infection is the most powerful known risk factor for progression of M. tuberculosis infection to active disease. The risk of progression from latent TB infection to active TB in people with HIV is approximately 5 to 8% per year, in contrast to a 10% lifetime risk in HIV-negative people. This risk progression can be re-stated in view of the alternative paradigm that HIV has an impact on the host-pathogen (M. tuberculosis) relationship with a shift towards poor immune control, high bacillary numbers, and subsequent development of active infection and symptomatic disease. The risk of developing active TB increases 2-3 fold after HIV seroconversion due to an initial rapid depletion of CD4+ T cells and continues to increase thereafter with ongoing decline in CD4 T lymphocyte cell (CD4) counts.Re-infection with M. tuberculosis in endemic high prevalence settings is likely to contribute to the risk by further increasing bacillary numbers and increasing the likelihood of progression to disease. The development of TB in a person with HIV may accelerate HIV disease progression which may be related to prolonged immune activation. Combination antiretroviral therapy (cART) and isoniazid preventive therapy (IPT) have been shown to have a significant impact in decreasing the incidence of TB in HIV populations.
Figure 1 Source: Barry CE, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 2009;7:845–55.9 Used with permission.
Figure 2 Rising Bacillary Load of mycobacterium tuberculosis over time Source: Lawn SD, Wood R, Wilkinson RJ. Changing concepts of ‘latent tuberculosis infection’ in patients living with HIV infection. Clin Dev Immunol 2011; 2011: 1–9.1 Used with permission.
M. tuberculosis infection may present with pulmonary disease, extrapulmonary (including involvement of lymph nodes, central nervous system and bacteraemia) or disseminated disease. The typical presentation of TB (fever, weight loss, constitutional symptoms with or without cough) has a wide differential diagnosis in HIV infection. Tuberculosis can occur at any CD4 count. In sub-Saharan Africa, pulmonary TB cases are approximately evenly distributed between CD4 counts of < 200 cells/μL, 200-500 cells/μL and > 500 cells/μL. In these high burden TB settings, pulmonary disease is present in most patients with both HIV and M. tuberculosis infections, evidenced by autopsy studies and subclinical disease found during prevalence surveys or active case finding. Extra pulmonary and disseminated disease are more common in the setting of HIV infection, especially with advanced immunodeﬁciency. As a result, the World Health Organization (WHO) current staging system considers extrapulmonary TB as stage 4 (AIDS-defining) whereas pulmonary TB is stage 3.
The clinical manifestations of HIV-associated TB are influenced by the degree of immunodeficiency. Advanced immunodeficiency impairs the host inflammatory response, resulting in lower rates of granuloma formation and pulmonary cavitation. This result accounts for more frequent sputum-smear negative disease and increased time to positivity of automated liquid mycobacterial cultures in HIV patients with TB. A second factor influencing clinical presentation in people with HIV infection versus those without infection is that TB progresses more rapidly in HIV patients, as a more subacute than chronic illness.
The optimal diagnosis of active TB involves early and accurate bacteriological confirmation and has been a major barrier to overcome in achieving TB control. This control has been even more difficult to achieve in HIV-associated TB due to the non-specific clinical symptoms and inadequate diagnostic tools available.
The routine diagnosis of M. tuberculosis infection can be established by a combination of microscopy, mycobacterial culture, nucleic acid amplification techniques (NAAT), histological examination of samples and radiography. The first-line test remains light microscopy for acid-fast bacilli (AFB) with Ziehl-Neelsen (ZN) staining. Sputum smear microscopy allows diagnosis when there are more than 5000 bacilli/mL of sputum and only detects 40-70% of all TB cases. The sensitivity of sputum microscopy depends on the quality of sputum collection and the preparation and interpretation of microscopy slides. Techniques to improve the yield of sputum samples include induced sputum and broncho-alveolar lavage. HIV-associated TB is more often pauci-bacillary and therefore smear-negative, accounting for 24 to 61% of all pulmonary cases in people living with HIV. Light microscopy has been more recently replaced in some settings with the more sensitive fluorescence microscopy. Gold standard bacteriological confirmation requires mycobacterial culture on automated liquid or solid media or both and is highly sensitive, being able to detect 10 bacilli/mL. The limitations of culture are that it requires highly specialised laboratory infrastructure, trained technicians, quality assurance procedures and takes up to 6 weeks for the result. Drug-susceptibility testing (DST) should be performed on all culture-positive TB isolates to diagnose drug-resistant TB (DR-TB). This is a phenotypic test that evaluates the growth (or metabolic) activity of the TB isolate in the presence of the drug. Drug-resistant isolates of M. tuberculosis are common in many parts of the world, and should be considered in people who are likely to have acquired the infection outside Australia and New Zealand, and in people who have been previously treated for M. tuberculosis and have experienced a relapse.
Molecular or genotypic techniques through NAA can be used to detect drug resistance by identifying mutations in the TB isolate. NAAT have enabled a more rapid and accurate diagnosis of M. tuberculosis infection in biological specimens (increasing the yield in smear-negative pulmonary cases). The Xpert MTB/RIF test is a cartridge-based fully automated platform that detects M. tuberculosis and rifampicin resistance by automated real time polymerase chain reaction (PCR), providing results in less than 2 hours. Rifampicin resistance is a reliable predictor of multidrug-resistant TB (MDR-TB) in high burden settings (MDR-TB prevalence > 10%), however a phenotypic DST should be performed if possible.The Xpert MTB/RIF test was endorsed by the WHO in 2010 for use in high-burden countries and is the recommended initial test for TB in PLHIV. It increases the detection of smear-negative TB by 67%. The performance is not significantly affected in HIV infection, with a sensitivity of 79% and specificity of 98%. The diagnosis of extrapulmonary TB is often enhanced with the use of NAAT. The Xpert MTB/RIF test has good sensitivity (80%) and excellent specificity (>98%) when performed on cerebrospinal fluid, lymph node aspirates and gastric aspirates, where it can replace smear microscopy. Other commercially available molecular techniques are available such as the line probe assay and many diagnostic laboratories also offer an in-house PCR assay.
New diagnostic tests are in development for TB. Detection of M. tuberculosis liporabinomannan (a component of the cell wall) in urine by lateral flow assay is a low-cost, point-of-care test that has a high specificity, but variable sensitivity depending on the CD4 count (sensitivity of 66.7% when CD4 count <50 cells/μL
The radiological features of TB in people with HIV with CD4l counts >200 cells/μL are similar to the general population, with a predominance of upper lobe abnormalities, cavitatory disease and the presence of pleural eﬀusions. In immunodeﬁcient persons (CD4+ T cell count <200 cells/μL), mediastinal lymphadenopathy, middle and lower zone infiltrates, non-cavitatory disease and extrapulmonary disease are more common. Up to 10% of patients will have a normal chest X-ray. Radiography including computerised tomography and ultrasound may be a useful adjunct test in localising and defining the site of extrapulmonary disease.
People living with HIV in Australia who are from high-burden TB countries, or have travelled to them, should be systematically screened for active and latent TB given their increased risk of infection. Screening strategies based on cough only have a low sensitivity for HIV-associated TB. A WHO screening tool (one or more of cough, fever, weight loss or night sweats) has a much higher sensitivity for active TB.
The diagnosis of latent TB infection can be established with the tuberculin skin test (TST) or an interferon-gamma release assay (IGRA; commercially available as QuantiFERON-TB and T-SPOT TB). Neither assay can differentiate accurately between latent and active TB. The TST is an intradermal injection of tuberculin that stimulates a delayed-type hypersensitivity response, mediated by T lymphocytes and macrophages, that results in skin induration, measured by a clinician. False-positive TSTs can be caused by T cell responses to antigens of non-tuberculous mycobacteria (NTM) or Bacillus Calmette-Guerin (BCG; resulting from previous BCG vaccination). The IGRAs measure T-cell responses to M. tuberculosis-specific proteins in whole blood cultures (QuantiFERON-TB assay) or by enzyme-linked immunospot (ELISpot) assay (T-SPOT TB say) and do not detect T cells reactive to NTM or BCG. They therefore offer greater specificity than the TST.
As TSTs and IGRAs measure T-cell responses, they are more likely to be positive in people with HIV infection who have relatively high CD4 counts than in those with severe immunodeﬁciency. A lower cut-oﬀ for a positive TST is used in the HIV population (5 mm induration rather than 10 mm used in those without HIV infection). As there is no gold standard for latent TB infection, sensitivity is determined among culture-confirmed active TB cases. The sensitivity of QuantiFERON-TB tests is 67% in the HIV population. There is no current evidence to suggest superiority of IGRA over TST in the diagnosis of latent TB infection in people with HIV infection.
Given the high risk of progression to active TB in individuals with HIV infection, all patients from countries where M. tuberculosis infection is endemic, or who have been exposed to someone with TB, should be tested for latent TB infection. National guidelines vary in their recommendation of testing algorithm to include one, both or sequential TST and IGRA. Australian TB guidelines recommend a TST or IGRA or both and with a diagnosis of latent TB infection if either were positive.Patients with a negative TST or IGRA and advanced HIV disease (i.e. CD4 count < 200/µL) should have a repeat TST or IGRA after initiation of cART and CD4 count increase to > 200 cells/µL.
Management of active tuberculosis
The management of active TB in the setting of HIV infection follows the general principles of TB treatment in the general population. This approach involves prompt initiation of an appropriate multidrug TB regimen that is guided by DST, commencing cART and treatment monitoring. The ASHM Antiretroviral guidelines and several international guidelines include a more complete discussion of the diagnosis and treatment of TB disease in patients with HIV infection.
The usual regimen for drug-sensitive TB isolates is a standard four-drug regimen of isoniazid, a rifamycin (rifampicin or rifabutin), pyrazinamide and ethambutol for 2 months (intensive phase), followed by isoniazid and a rifamycin for 4 months (continuation phase). The optimal duration of therapy depends on the site of disease and response to treatment. In patients with pulmonary disease, short-course therapy for 6 months is adequate, unless there is persistent culture-positive sputum after 2 months of therapy without drug-resistance, when therapy should be extended to 9 months. Irrespective of HIV status, patients with miliary, meningeal or skeletal disease should be treated for a total of 9 to 12 months. Concerns about relapse rates after short-course therapy have come from trials in countries with a high prevalence of TB and re-infection may be the explanation for this phenomenon. As the prevalence of TB in Australia is low, short-course regimens are likely to be suitable.
A meta-analysis demonstrated that increasing rifamycin duration to 8 months or more was associated with reduced relapse in patients with HIV infection with active TB. However, the majority of patients were not on cART and it cannot be determined if relapse was due to re-infection or recurrence. Treatment should be administered daily, as intermittent therapy (three times a week) in the intensive phase increases relapse. The choice of rifamycin is guided by drug-drug interactions and cost as their efficacy is considered equivalent.Pyridoxine supplementation is administered to reduce the risk of peripheral neuropathy caused by isoniazid and exacerbated by HIV infection and/or certain antiretroviral drugs. See Table 1 for the side-eﬀects of antimycobacterial agents.
|Amikacin||Nephrotoxicity, ototoxicity, neuromuscular blockade|
|Azithromycin||Diarrhoea, nausea, abdominal pain, vomiting, ototoxicity, abnormal liver function tests, central nervous system toxicity, leukopenia, erythema multiforme|
|Ciprofloxacin||Anorexia, nausea, diarrhoea, vomiting, abdominal pain, headache, restlessness, insomnia, psychosis, seizures, rash, arthralgia, intestinal nephritis, tendon rupture.|
|Clarithromycin||Diarrhoea, nausea, taste change, abdominal pain, headache, taste perversion, abnormal liver function tests, rash|
|Clofazimine||Skin pigmentation, anorexia, nausea, skin dryness, pruritus, abdominal pain, conjunctival irritation, retinal crystal deposition|
|Ethambuto||Optic neuritis (usually at higher dose i.e. 25 mg/kg/day), reduced visual acuity, restricted visual fi elds, scotomata, loss of colour discrimination, peripheral neuropathy, headache, rash, arthralgia, hyperuricaemia, gastrointestinal side-eff ects|
|Isoniazid||Peripheral neuropathy (prevent with co-administration of pyridoxine), allergy, lymphadenopathy and vasculitis, hepatitis (greater risk with increasing age, alcohol consumption and chronic liver disease), antinuclear antibody, blood dyscrasia, liver failure, other neurological manifestations (optic neuritis, encephalopathy, convulsions, psychosis) fever|
|Pyrazinamide||Arthralgia, hyperuricaemia, hepatitis, gastric irritation, photosensitivity, rash, fever, pruritus, thrombocytopenia, skin discolouration, side roblastic anaemia|
|Rifabutin||Leukopenia, nausea, vomiting, diarrhoea, polyarthralgia, uveitis, rash, discolouration of urine, tears, sweat, saliva, stool and skin, neutropenia, febrile illness, hepatitis, haemolysis, myositis|
|Rifampicin||Anorexia, nausea, vomiting, diarrhoea, rash, febrile reaction, hepatitis, abnormal liver function tests, discolouration of urine, tears, sweat, saliva, stool and skin, haemolysis, febrile illness|
In cases of marked immunodeﬁciency (CD4 count < 50 cells/μL), where Mycobacterium avium complex (MAC) is in the diﬀerential diagnosis, where a histological diagnosis of mycobacterial infection is made and, in the absence of the result of a NAAT or culture, empirical therapy should cover both MAC and M. tuberculosis infections. This regime involves the addition of clarithromycin or azithromycin to the standard four-drug TB therapy (See Mycobacterium avium complex).
Multi-drug resistant tuberculosis
The management of MDR-TB and extensively drug-resistant TB (XDR-TB; MDR-TB with additional resistance to any quinolone and any second-line injectable agent) poses a major challenge due to the requirement for long duration of therapy and toxic regimens, complex clinical management issues (including drug interactions), and a paucity of evidence to guide decisions.If the DST reveals resistance to any of the drugs in the standard initial TB regimen, expert consultation is essential. The WHO recommended treatment regimen for MDR-TB is pyrazinamide with at least four ‘effective’ second-line TB drugs administered over at least 20 months. This regimen includes an injectable agent for the first 8 months in addition to a quinolone, para-aminosalicylic acid (PAS), cycloserine or ethionamide, or both. After several decades of inactivity in TB drug development, there are now some promising new drug and regimen candidates. Two new drugs have been licensed, bedaquiline and delaminid, and will be initially used in patients with MDR-TB, however the pipeline for new drug development is still weak (compared to other diseases). Several trials of new regimens are underway but it will be some years before results are available. It will take an even longer time to establish how these new drugs and regimens can be combined with cART.
All patients with HIV-associated TB infection should be treated with cART, regardless of CD4 count. There are several issues related to the treatment of co-infection: when to start cART; shared toxicity and drug-drug interactions; and the development of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS).
1. When to start cART
The decision to commence cART is a balance between the risk of high mortality and morbidity in patients with a very low CD4 count (especially counts < 50 cells/µL) and the potential for drug toxicity and interactions and TB-IRIS. Several large randomised controlled trials have now been conducted to inform guidelines.
- In patients with CD4 counts <50 cells/µL, antiretroviral therapy should be initiated within 2 weeks of starting TB treatment.
- In patients with CD4 counts ≥50 cells/µL who present with clinical disease of major severity, as indicated by clinical evaluation, antiretroviral therapy should be initiated within 2 weeks of starting TB treatment.
- In patients with CD4 counts ≥50 cells/µL who do not have severe clinical disease, antiretroviral therapy can be delayed beyond 2 to 4 weeks of starting TB therapy but should be started within 8 to 12 weeks of TB therapy initiation.
- In patients with TB meningitis, antiretroviral therapy can be deferred until 8 weeks of starting TB treatment due to the higher rates of morbidity and mortality associated with TB-IRIS of relating to the central nervous system (CNS).
- In all pregnant women with HIV infection with active TB, antiretroviral therapy should be started as early as feasible, both for maternal health and for prevention of mother-to-child transmission of HIV.
- In patients with HIV infection with documented multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, antiretroviral therapy should be initiated within 2 to 4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy.
2. Drug toxicity and interactions
Anti-tuberculosis treatment and cART have overlapping and additive toxicity profiles that include drug-induced liver injury (DILI), cutaneous reactions, renal impairment, neuropathy and neuropsychiatric adverse effects. All drugs can cause DILI but it is more common from isoniazid, rifamycins, pyrazinamide, nevirapine, efavirenz and protease inhibitors. HIV-TB co-infection has been associated with a five-fold increased risk of rash or drug fever.Renal impairment can be caused by different mechanisms; tenofovir disoproxil fumarate (tubular), injectable agents (tubular), rifampicin (interstitial). Peripheral neuropathy can occur with administration of isoniazid, didanosine, or stavudine or may be a manifestation of HIV infection. All patients receiving isoniazid should also receive supplemental pyridoxine to reduce peripheral neuropathy.
When cART is used with anti-tuberculosis treatment, consideration of potential drug interactions is paramount and a database such as http://www.hiv-druginteractions.org should be consulted. Rifamycins are potent inducers of the hepatic cytochrome P (CYP) 450 and uridine diphosphate gluconyltransferase (UGT) 1A1 enzymes and are associated with significant interactions with most antiretroviral agents including all protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs; to a moderate extent), maraviroc, and raltegravir (under investigation). The first-line cART recommended for use with first-line anti-tuberculosis treatment is well established: tenofovir disoproxil fumarate + emtricitabine + efavirenz with nevirapine as an alternative. A recent randomised trial failed to demonstrate non-inferiority of a nevirapine-based regimen (without lead-in dose) to an efavirenz-based regimen (600 mg daily) in the primary outcome of viral suppression at 48 weeks, but TB-IRIS, death and incident AIDS events did not differ between the two groups.
Second-line cART is more problematic with anti-tuberculosis treatment as rifampicin reduces the concentration of ritonavir-boosted protease inhibitors by 75-90%. Rifampicin is not recommended in combination with all protease inhibitors and the NNRTIs, etravirine, and rilpivirine. When rifampin is used with maraviroc or raltegravir, increased dosage of the antiretroviral drug is generally recommended. Rifabutin, a weaker enzyme inducer, is an alternative to rifampicin, but data on its use in TB patients receiving protease inhibitors are limited, resulting in slight discrepancies between international guidelines in dose recommendations. The ASHM antiretroviral guidelines provide guidance on dosing.
Rifapentine is a long-acting rifamycin that can be given once weekly with isoniazid for the treatment of active or latent TB infection. No systematic study has been performed to assess the magnitude of the enzyme induction effect of rifapentine on the metabolism of ARV drugs and other concomitant drugs. Significant enzyme induction can result in reduced antiretroviral drug exposure, which may compromise virological efficacy. Rifapentine is not recommended for treatment of latent or active TB infection in patients receiving antiretroviral therapy, unless given in the context of a clinical trial.
After determining the drugs and doses to use, clinicians should monitor patients closely to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, subtherapeutic drug levels (consider therapeutic drug monitoring [TDM]), and acquired drug resistance.
3. TB-associated immune reconstitution inflammatory syndrome
TB-IRIS occurs in two forms, unmasking and paradoxical. Case definitions have been published for resource-limited settings. Disease pathogenesis mechanisms are similar for both forms of TB-IRIS, and reflect restoration of an immune response against M. tuberculosis after administration of cART that results in an exaggerated inflammatory response to bacilli and antigens. Unmasking TB-IRIS refers to the clinical manifestations of active TB that occur soon after cART is started in patients with undiagnosed TB disease. Paradoxical TB-IRIS refers to the worsening of TB after cART is started in patients who are receiving TB treatment. Both forms of TB-IRIS have a wide range of clinical features such as fever, worsening respiratory symptoms, lymphadenopathy (often with suppuration), TB abscesses and serous effusions. Central nervous system TB-IRIS is particularly severe. TB-IRIS can involve multiple sites, reflecting dissemination of TB in patients with profound immunosuppression. A meta-analysis revealed a summary risk estimate of 15.7%, although the incidence depends on the definition of TB-IRIS and the intensity of monitoring.
The predictors for the occurrence of TB-IRIS include a CD4 count < 50 cells/L pre-cART; high pre-cART and lower on-cART HIV viral loads; severity of TB disease (high pathogen burden); and less than 30-day interval between initiation of TB and HIV treatments. Most TB-IRIS in PLHIV occurs within 3 months of the start of TB treatment. There is no diagnostic test for TB-IRIS and alternative diagnoses such as the failure of anti-tuberculosis treatment (drug interactions, non-adherence, drug resistance) and other opportunistic infections must be considered.
Patients with mild or moderately severe TB-IRIS can be managed symptomatically or treated with non-steroidal anti-inflammatory agents (although no clinical data exist to support their use). Patients with more severe TB-IRIS can be treated successfully with corticosteroids. A randomised, placebo-controlled trial demonstrated benefit of corticosteroids in the management of TB-IRIS symptoms (as measured by decreasing days of hospitalisation and Karnofsky performance score) without adverse consequences. In the presence of TB-IRIS, neither TB therapy nor cART should be stopped because both therapies are necessary for the long-term health of the patient.
Treatment delivery and monitoring
Close collaboration among clinicians, health-care institutions and public health programs involved in the diagnosis and treatment of patients with HIV infection with active TB disease is necessary in order to integrate care and improve patient outcomes. A specialist or specialists with appropriate expertise should supervise the management all patients with HIV-TB co-infection in Australia. Hospital admission is not mandatory and depends on clinical indications. The treatment delivery model varies between jurisdictions in Australia, but is either a community-based or ambulatory model of care. A patient-centred approach with treatment support that mitigates barriers to adherence such as patient education, social support, provision of transport and addressing any comorbidities (e.g. substance dependence, mental illness) is recommended by WHO. This approach can include directly observed therapy (DOT), although a meta-analysis revealed that it is not significantly better than self-administered therapy (SAT) in preventing failure, relapse or acquired drug resistance.
Patients should be monitored closely, in order to ensure they are making the appropriate response to treatment with minimal drug-related toxicity. Patients should have monthly clinical review, biochemical (liver and kidney function tests) and microbiological investigations (microscopy and culture until two consecutive specimens are negative in those with pulmonary TB).
Adequate infection control measures (personal, administrative, environmental) should be implemented in health facilitates where patients with TB are admitted and ambulatory points where treatment is received. Nosocomial outbreaks of TB have been document in Australia. It is unknown when patients are non-infectious after the initiation of anti-tuberculosis treatment; however evidence is gathering that non-infection occurs rapidly after the onset of effective therapy. There is a statutory requirement to notify all cases of TB (including patients started on empirical anti-tuberculosis therapy) to public health authorities. Investigation and management of contacts of the index case is carried out by the state TB services.
If active TB and HIV are untreated in a patient with co-infection, the outcome is almost universally fatal. Patients with HIV-TB co-infection respond well to anti-tuberculosis treatment and have similar culture conversion and treatment completion rates compared to HIV-negative TB patients, however, the case fatality rate is higher despite cART. The degree of immunodeﬁciency is the most important predictor of survival in people with HIV with M. tuberculosis. In resource-limited settings cART reduces the mortality risk by 64-95% in patients with HIV-TB co-infection.
Prophylaxis (treatment of latent tuberculosis infection)
Secondary prophylaxis following successful treatment of disease is unnecessary, however, re-infection can occur. All patients with evidence of latent TB infection should receive treatment for the prevention of active disease (often called prophylaxis). Treatment of latent TB infection can reduce the progression to active disease in PLHIV by 32-62% and is recommended by WHO. Current evidence suggests that only PLHIV with a positive TST (at least 5 mm) receive benefit from latent TB infection treatment. There is no beneﬁt in providing prophylaxis to anergic persons. Treatment is also recommended for PLHIV who have a positive IGRA, recent contact with a person with active TB or radiological evidence of past TB infection (e.g. fibrotic change on chest X-ray). In high TB burden resource-limited settings where the TST is not feasible, the WHO recommends latent TB infection treatment for all PLHIV. Before instituting latent TB infection treatment, it is important to exclude active M. tuberculosis disease, initially with the WHO symptom screen.
Agents that have been studied for latent TB infection treatment are isoniazid, the rifamycins (rifampicin and rifapentine) and pyrazinamide. Isoniazid is the preferred treatment in patients with HIV infection because of its known efficacy, safety and cost. Isoniazid preventive therapy is part of the WHO 3Is strategy for collaborative TB-HIV activities in resource-limited settings along with intensified case-finding and infection control. The recommendation is to treat with isoniazid for at least 6 months, with a consideration of up to 36 months as clinical trials show benefit with longer duration in TB-endemic settings, presumably prophylaxis against re-infection. The optimal duration of therapy is unknown, although many expert guidelines in resource-rich settings extrapolate from the data in HIV-negative individuals, recommending isoniazid with pyridoxine given daily for 9 months. 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. This is not currently available in Australia. In the case of isoniazid intolerance, an alternative regimen is rifampicin or rifabutin for 4 months, however, the drug interactions with cART may be problematic. Although a regimen of daily rifamycin and pyrazinamide for 2 months is eﬀective, the risk of severe hepatotoxicity is signiﬁcantly higher and is not currently recommended. Patients with co-infection on latent TB infection treatment should have baseline assessments including liver function tests monitored monthly for adverse effects. There is no value in repeating a TST or IGRA on the completion of latent TB infection treatment.
Treatment of latent TB infection in a contact where the known index case has MDR-TB has not been widely recommended, as isoniazid and rifamycins are not effective and there is no evidence for alternative regimens. Observational data have been published showing good success with quinolone-based regimens. 
Co-trimoxazole preventive therapy is recommended by the WHO for all patients with active TB irrespective of CD4 count, as it has been shown to have a mortality benefit in Sub-Saharan Africa. 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.