– Christoph Lange, Christian Herzmann, Giovanni Battista Migliori, Andrea Gori –

About 12% of all infections with the Mycobacterium tuberculosis complex (MTB, including M. tuberculosis, M. africanum, M. bovis, M. canetti and M. microti) occur in people living with HIV. In some African countries, up to 80% of tuberculosis (TB) patients are HIV seropositve, making it the most important opportunistic infection worldwide (WHO 2010, UNAIDS 2010). Although numbers of co-infection have been declining in the latest WHO report, the prevalence of HIV among TB patients remains extremely high in Africa (46%), the Americas (17%) and South-East Asia (13%). High rates of co-infection are also found in some smaller European countries like Portugal (12%), Estonia (10%), Malta (9%) and Latvia (8%) as well as in the urban metropolitan areas of European low prevalence countries (e.g. Brussels 9%). (ECDC 2011, Pimpin 2011, WHO 2010).

The spread of the TB epidemic is closely related to the HIV prevalence in the general population (Corbett 2003). The incidence of TB is more than eight times higher in HIV-positive than in HIV-negative people (Corbett 2006). In addition, there is concern that HIV may enhance the spread of multidrug resistant (MDR) TB (Dubrovina 2008, Cox 2010). With about 30.000 MDR-TB cases notified worldwide in 2009, its prevalence among all TB cases is high with up to 19% in Eastern Europe, 14% in Central Asia and 16% in the Russian Federation in comparison to 1.3-1.8% in Africa (WHO 2010).

Figure 1: HIV prevalence (%) in new TB cases (WHO 2010)

Figure 2: Percentage of HIV positive TB cases in Europe, 2009 (ECDC 2011)

Despite a steadily increasing prevalence of HIV-1 infection in Western Europe and North America in recent years, the incidence of TB has continuously declined in countries where ART is available (Kirk 2000, Girardi 2000, Nahid 2006). However, clinical management of MTB/HIV-coinfected patients is complicated due to a wide range of drug interactions, overlapping side effects of ART and anti-tuberculosis medications and low compliance caused by pill burden.

Interaction of HIV and MTB

HIV and MTB infections have synergic influence on the host immunoregulation. HIV infection impairs cell-mediated immunity largely through depletion of CD4 T cells. The impaired immunity leads to a higher susceptibility to MTB infection. In turn, it is likely that TB enhances the immunodeficiency related to HIV-infection (Toossi 2003). The incidence of primary TB and reactivated TB is greater in HIV-infected patients in comparison with HIV-seronegative individuals (Havlir 1999, Badri 2001). Although HIV-infected patients have a more than 50 times higher risk of TB reactivation, it is now clearly demonstrated that most patients develop disease after recent transmission, emphasizing the need for patient-to-patient infection control measures (Sonnenberg 2001, Horsburgh 2010, Houben 2011).

The incidence of post-primary TB ranges from 5-30% in HIV-infected subjects. The risk of active TB in patients with latent TB infection (LTBI) is approximately 8% per year in HIV-infected patients compared with a lifetime TB risk of 5-10% in HIV-seronegative individuals. In countries with a low TB prevalence HIV infected subjects have a 37-fold increased risk for TB, in countries with a high TB prevalence the risk is 21-fold increased (Getahun 2010). It has been shown that the risk of TB is already enhanced in the first year after HIV-seroconversion (Sonnenberg 2005). Low CD4 T cells, late presentation, low body mass index, anemia and a high HIV RNA despite ART are known risk factors for the development of TB (Van Rie 2011).

Despite adequate TB and HIV therapy, both morbidity and mortality remain increased in HIV-infected patients (Manas 2004, Whalen 2000). In the USA, TB mortality in 2006 was 9% in the general population but 20% in HIV-infected subjects (CDC 2010).

While most opportunistic infections, including non-tuberculosis mycobacterial infections (NTM), occur almost exclusively in advanced stages of HIV-infection, TB is prevalent at any stage regardless of the CD4 T cell counts (Ackah 1995). More than 50% of pulmonary TB cases occur in patients having more than 200 CD4 T cells/µl (Badri 2001). However, the incidence of disseminated TB is much higher in patients with advanced immunodeficiency (Wood 2000). TB is the leading cause of death among people with HIV infection (UNAIDS 2010)

Clinical manifestations

In the early stages of HIV-infection the clinical symptoms of TB are similar to those in HIV-negative patients. Fever, fatigue, night sweats and weight loss are common.

Pulmonary TB: As in HIV-negative cases, typical lesions of pulmonary TB in HIV-patients with more than 200 CD4 T cells/µl are upper-lobe lung infiltrates (with or without cavities). Tuberculosis granulomas are always present in these lesions. Cough and hemoptysis are frequent. Undefined lung opacities are often present on chest radiography as well as enlarged mediastinal lymph nodes. As immunodeficiency progresses, atypical pulmonary presentations or TB pleuritis become more frequent. Bronchopulmonary symptoms, such as cough and haemoptysis are often absent when TB occurs in the advanced stages of HIV infection. Because CD4 T cells are required for granuloma formation their cellular structure changes with increasing immunodeficiency (Diedrich 2011, Nambuya 1988). With the progression of immunodeficiency, hematogenous and lymphatic spread of mycobacteria is more common leading to miliary or disseminated TB or localized extrapulmonary TB (Elliott 1993, Kingkaew 2009).

Extrapulmonary TB occurs predominantly in patients with CD4 T cells below 200/µl, most commonly affecting the cervical lymph nodes (Schutz 2010). Lymph nodes are enlarged, hard and generally not painful on palpation. The formation of abscesses and draining fistulas as well as fever and malaise are common.

Tuberculosis meningitis often emerges with ambiguous prodromal symptoms such as headache, nausea and vomiting followed by elevated temperature and clinical signs of meningeal irritation. The basal meninges are usually involved and cranial palsies of the III and VI nerves are common. Mono-, hemi- or paraparesis as well as loss of consciousness and seizures can occur. In any patient with symptoms and signs of meningitis, a lumbar puncture should be performed without delay.

Other extrapulmonary localizations include pericarditis, osteoarthritis, the urogeni-tal tract and the skin. Tuberculosis lesions may involve adrenal glands causing Addison’s disease. Practically, any organ can be involved.

Miliary or disseminated TB: Clinical manifestations depend on multiple small granular lesions (lat. milium effusum) and their localization. Lungs may be involved and micro-nodular opacities are evident on chest x-ray. On radiological criteria alone, these lesions cannot be distinguished from pulmonary cryptococcosis. Miliary dissemination of TB can also involve the abdomen. In febrile patients with abdominal pain and ascites, peritoneal TB must be included in the differential diagnosis.


The diagnosis is established based on clinical, radiological and microbiological findings. Diagnostic steps in the management of an HIV-infected patient with suspected TB do not differ from those with HIV-negative cases (Lange 2004). The differential diagnosis includes other infections such as NTM (e.g. M. avium complex), cryptococcosis, histoplasmosis, leishmaniosis, but also sarcoidosis, lymphoproliferative diseases, in particular non-Hodgkin lymphoma, and solid malignant neoplasia.

Radiology: Radiographic images of pulmonary TB can vary substantially. Pulmonary TB can mimic a variety of other pulmonary diseases and can be present without evident changes on chest radiography. However, typical chest radiographic findings are ill-defined single or multiple opacities in the upper lobe, with or without cavities inside the opacities, and enlarged mediastinal lymph nodes. Calcifications and fibrotic scar formation may be either a sign of healed pulmonary TB or a clue of re-activated disease. In miliary TB, the chest radiography shows disseminated micro-nodular opacities. Patients with low CD4 cell counts are less likely to present with typical radiographic changes but may have a normal chest X-ray, no cavities or a pleural effusion (Chamie 2010). In case of doubt, a chest CT scan is recommended whenever possible. If extrapulmonary TB is diagnosed, lung radiographic imaging as well as abdominal ultrasound should be performed to identify possible pulmonary disease, liver and spleen abscesses, thickening of the intestinal mucosa or ascites.

Respiratory samples: When pulmonary TB is suspected, three sputum samples should be collected on consecutive days for mycobacterial culture and direct sputum smear examination for acid fast bacilli (AFB). Sputum quantity (>3-5 ml) and its origin from the lower respiratory tract is essential, since smear microscopy for AFB and mycobacterial cultures remain sterile otherwise.

If patients are unable to cough deeply or cannot produce sputum, induced sputum should be provoked by 10-15 minutes inhalation of hypertonic sodium (3%) chloride. The collection of early morning gastric aspirate is an alternative if bronchoscopy is not available. The aspirate should be buffered in phosphate solution immediately. Bronchoscopy is indicated when the clinical findings remain highly suspicious for TB. Bronchial secretions or bronchoalveolar lavage obtained by bronchoscopy do not allow a more sensitive or specific diagnosis of TB than sputum smear in patients with HIV infection (Conde 2000). However, bronchoscopy is very helpful in the differential diagnosis of TB and other diseases particularly since co-existence of several pulmonary diseases is frequent in patients with HIV-infection (Narayanswami 2003). Furthermore, histopathological examination of transbronchial biopsies may show typical tuberculosis granulomas. On the day after bronchoscopy, sputum should be collected as the microscopic yield is higher following the intervention even if no mycobacteria were detected in lavage fluid.

Mycobacterial culture: Sputum and all other biological materials (including heparinised blood, urine, fluids, biopsies) should always be sent for culture that detects MTB with a high sensitivity and specificity. The gold standard for the diagnosis of TB is culture identification of MTB after incubation of biological samples preferentially in liquid media or alternatively in solid media. Liquid media take less time (2-4 weeks) than solid media (3-5 weeks) until a positive result can be obtained. A mycobacterial culture is only considered negative if no mycobacteria are identified after 6-8 weeks of incubation. Non-tuberculous mycobacteria (NTM) usually grow much faster than MTB and can often be identified within two weeks of incubation. All new clinical isolates of MTB should undergo drug susceptibility testing for first-line and in case of MDR TB for second-line antibiotic regimens.

Microscopy: For sputum and all other biological materials direct microscopy should be performed after staining to detect AFB. The sensitivity of fluorescence microscopy (49%) is superior to conventional light microscopy (38%) (Cattamanchi 2009). Specificity of direct sputum microscopy is poor. At least 5,000-10,000 mycobacteria per slide are necessary to achieve a positive result in a routine setting. Approximately 50% of all patients with culture positive pulmonary TB are AFB smear negative on three consecutive sputum samples. AFB positive smears are present in approximately 5% of cases where pulmonary lesions are not visible on standard chest radiography (Ackah 1995). In addition, discrimination between MTB and other acid fast bacteria is not possible by microscopy. The differential diagnosis includes infections with NTM, nocardiae and rhodococci. Microscopy in HIV-infected patients with >200 CD4 T cells /µl and typical radiographic changes has the same yield as in HIV-seronegative patients. With advanced immunodeficiency, the likelihood of an AFB positive smear decreases (Chamie 2010).

Biopsies of lymph nodes, pleura, peritoneum, synovia and pericardium and diagnostic fluid aspirates from all anatomic compartments are suitable for AFB microscopy and histological examination for typical granulomas.

Nucleic acid amplification (NAAT): Mycobacterial nucleic acid (DNA or RNA) can be detected in biological samples by a routine PCR test. MTB PCR test is faster than culture and more sensitive and specific than acid-fast staining. NAAT is especially helpful for differentiation of mycobacterial species when AFB are visible on microscopy. Under these circumstances, the sensitivity of MTB PCR is >95%. Unfortunately, the sensitivity decreases to 36-82% even for new diagnostic tools like the Cepheid Xpert when smear negative morning sputa are analysed directly (Rachow 2011, Boehme 2010). Because PCR can yield false negative results, reports should always be interpreted within the clinical context. A major advantage of modern NAAT is the detection of resistance mutations within a few hours, enabling the physician to initiate an adequate antituberculosis drug regime.

In extrapulmonary TB, for example tuberculosis meningitis, where direct microscopy is often negative but a rapid diagnosis is needed, MTB PCR testing should be performed as part of the initial evaluation. For PCR analysis, biopsy samples should not be kept in formalin but rather be preserved in “HOPE” (Hepes-glutamic acid buffer-mediated organic solvent protection effect) media (Olert 2001).

Tuberculin skin test (TST): If no AFB are visible on microscopy but TB is still suspected, a TST, also known as purified protein derivative (PPD) test is recommended. A positive TST (or PPD) indicates an immunological memory to previous or ongoing contact with MTB. Positive TST results may also be found in patients who were BCG-vaccinated or who had contact with NTM. On the other hand, the TST in HIV positive patients with active TB has a sensitivity of only 31%. The sensitivity of TST is  even more decreased, when CD4 cell counts decline (Syed Ahamed Kabeer 2009).

The TST should only be administered intradermally according to the method described by Mendel and Mantoux. The standardized dose recommended by WHO and the International Union against Tuberculosis and Lung Diseases (IUATLD) is 2 Tuberculin Units (TU)/0.1ml PPD RT23/Tween 80. In the US and other countries, the standardized dose is 5 TU/0.1ml PPD-S, which is thought to be similar in strength. 48-72 hours after intradermal injection, the diameter of induration (not redness) of the injection site is measured along the short axis of the forearm (Sokal 1975). According to the Infectious Diseases Society of America (IDSA), the TST is positive if the induration diameter is >5mm in HIV infected persons (≥5 mm in HIV negative subjects). The IDSA guidelines for interpretation of the TST result are based on results of clinical studies that were conducted with 5 TU PPD-S in the US and therefore cannot be directly applied to other countries where different antigens are used.

Interferon-γ Release Assay (IGRA): Recently, IGRAs have been introduced for the diagnosis of MTB infection. They detect the secretion of IFN-γ by peripheral blood mononuclear cells (PBMC) that is induced by specific MTB peptides (ESAT-6 and CFP-10). However, the tests were developed to detect latent tuberculosis infection (LTBI, see below), not active disease (Chen 2011). Accordingly, the sensitivity of the Quantiferon TB-Gold in-tube test has a sensitivity of only 65% in HIV patients with active tuberculosis and shows no additional value in the diagnostic workup of HIV positive, AFB negative TB suspects (Syed Ahamed Kabeer 2009, Rangaka 2011). However, IGRAs are more sensitive and specific than the TST for diagnosis of MTB infection in patients with immunodeficiency (Chapman 2002, Pai 2004, Ferrara 2006, Rangaka 2007b, Jones 2007, Luetkemeyer 2007, Leidl 2009). Two IFN-gamma blood tests are currently available: an ELISA (Quantiferon TB-Gold in-tube test) and an ELISPOT (T-SPOT.TB Test). Two trials demonstrated a better sensitivity for the ELISPOT assay in HIV infection (Lawn 2007, Mandalakas 2008). Importantly, the ELISPOT test result is much less dependent on the level of CD4 T cells (Rangaka 2007a, Hammond 2008, Stephan 2008, Kim 2009), while the IFN-gamma response in the ELISA strongly correlates to the CD4 T cell count (Leidl 2009). In patients with advanced immunodeficiency ELISA can therefore not be recommended for the diagnosis of LTBI. The sensitivity and specificity of the ELISPOT assay can possibly be improved further by relating them to the CD4 T cells of the patient (Oni 2010). Sequential IGRA measurements to monitor tuberculosis activity or treatment are not useful (Connell 2010, Lee 2010).

The detection of antibodies against mycobacterial components has no role in modern tuberculosis diagnostics.


First-line drugs include rifampicin (RMP), isoniazid (INH), ethambutol (EMB) pyrazinamide (PZA) and streptomycin (SM). SM is only available as IM or IV formula and may thus not be considered “first-line”. INH and RMP are the most potent drugs. Second-line drugs include amikacin, capreomycin, cycloserine, levofloxacin, linezolid, moxifloxacin, prothionamide and rifabutin (RB).

Common cases of pulmonary TB can be treated with a standard 6-month treatment course, regardless of the HIV status. To prevent the development of drug resistance, active TB should always be treated with a combination of four drugs in the initial phase. The standard therapy consists of a 2-months course of RMP, INH, EMB and PZA, followed by a continuation phase therapy of 4 months with RMP and INH. Drug dosages are listed in Table 1. The four initial drugs should be administered until culture test results show drug susceptibility of MTB isolates.

Hospitalization is generally indicated to prevent the spread of the infection. As long as AFB are detected in the sputum or in the bronchoalveolar lavage, the patient should be treated in isolation. The duration of the infectious period in pulmonary TB depends on the extent of pulmonary lesions and cavities. Sputum should be regularly collected (weekly in the initial phase), evaluated for AFB by direct microscopy and for viable MTB by culture until the end of treatment. The infectiousness is considered to be very low once AFB are repeatedly absent in sputum smears. When at least three sputum samples obtained on different days are AFB negative, therapy can be continued as an outpatient. There appears to be no difference between HIV negative and HIV positive patients in the duration of therapy until the sputum becomes AFB negative and cultures remain sterile (Bliven 2010, Senkoro 2010). However, viable MTB can usually be cultured from sputum for a few weeks after microscopy has become AFB negative. Patients with MDR TB should be kept in isolation until both microscopy and sputum cultures remain negative.

Failure of therapy is associated with drug resistance, poor drug compliance or insufficient treatment duration (Sonnenberg 2001, Korenromp 2003). If sputum cultures are still positive after the initial phase of treatment or if the initial drug regimen was different from standard therapy (e.g. did not include RMP and INH), therapy should be extended to 9 months or longer (i.e., the continuation phase should be extended to 7 months or longer). Treatment is also longer than a standard 6-months course for AIDS patients, cavitary pulmonary TB and TB meningitis.

Adverse events

The most frequent and significant adverse events of antituberculosis drugs are listed in Table 1. INH should routinely be co-administered with prophylactic pyridoxine (vitamin B6) to prevent peripheral polyneuropathy .

Before and during therapy with EMB, colour vision should be examined and monitored as this drug may affect the optic nerve. Dosages of EMB and PZA need to be adjusted in patients with impaired renal function. In patients with liver disease (including drug induced hepatitis), the choice of first-line drugs is limited as RMP, INH and PZA can worsen the liver injury. In these cases, a combination of EMB, streptomycin, cycloserine, moxifloxacin and/or linezolid may be administered. Since this second-line therapy is no different from that of MDR TB, these patients should be treated in specialized centres. Audiometric monitoring should be performed when streptomycin is used. Following the start of TB therapy, liver enzymes, serum creatinine and complete blood count should be monitored on a regular basis (e.g. in the initial phase every week, then every 4 weeks). Hyperuricemia is common when PZA is used. A mild polyarthralgia can be treated with allopurinol and non-steroidal antiphlogistic drugs. Arthralgia can also be induced by RMP and RB.

Table 1: Antituberculosis drug doses, side effects and drug interactions

Antituberculosis drugs

Recommended daily dose

Common adverse events

Drug interactions





Also available for IV injection

10 mg/kg


> 50 kg: 600 mg

< 50 kg: 450 mg

Elevation of liver enzymes, toxic hepatitis; aller-gy, fever; gastrointestinal disorders; disco-loration (orange or brown) of body fluids; thrombopenia

Many drug interactions: induces cytochrome p450

(for ART drug interactions see Table 3)

Monitor LFTs*




Also available for IV or IM injection

5 mg/kg

300 mg/day


Administer with vitamin B6

Peripheral neuropathy; eleva-ted liver enzy-mes, toxic hepatitis; CNS side effects: psychosis, seizures

Avoid d4T, ddI

Avoid administration if pre-existing liver damage; avoid alcohol

Ethambutol (EMB)

40-55 kg: 800 mg/day

56-75 kg: 1.2 g/day

76-90 kg: 1.6 g/day 

Optic neuritis; hyperuricemia; peripheral neuropathy (rare)


Antiacids may decrease absorption

Baseline screen for visual acuity and colour perception (repea-ted monthly);

contraindicated in pts with pre-existing lesions of optic nerve

Pyrazinamide (PZA)

30 mg/kg/day


maximum 2.0 g/day

Arthralgia, hyperuricemia, toxic hepatitis, gastro-intestinal discomfort


Hyperuricemia: uricosuric drug (allopurinol); monitor LFTs.


IV/IM administra-tion only

0.75-1 g/day

< 50 kg: 0.75 g/day

> 50 kg: 1 g/day

maximum cumulative dose 50 g!

Auditory and vestibular nerve damage; renal damage; allergies, nausea, skin rash, pan-cytopenia


Audiometry; monitor renal function; should not be used in pregnancy


IV/IM administra-tion only

1 g/day

Maximum cumulative dose 50 g!

Auditory and vestibular nerve damage


Audiometry; monitor renal function; do not use in pregnancy


IV/IM administra-tion only

15 – 30
max 1 g/day
> 50 kg: 1 g
< 50 kg: 0.75 g
maximum cumulative dose: 50 g

Renal damage, Bartter-like syndrome, auditory nerve damage


Audiometry; cumulative dose should not be exceeded; monitor renal function; should not be used in pregnancy


10-15 mg/kg day


1,000 mg/day

CNS disorders,
anxiety, confus-ion,  dizziness,
psychosis, seizures, headache.

Aggravates CNS side effects of INH and prothionamide.

Contraindicated in epileptics; CNS side effects occur usually within the first 2 weeks



Also available for IV injection

500 or 1,000 mg/day


Gastrointestinal discomfort, CNS disorders, tendon rupture (rare)


Not approved for treatment in children; in adults rather use Moxifloxacin


600 mg /day

Thrombopenia, anemia, CNS disorders


Evidence for cli-nical use relies on case reports; expensive



Also available for IV injection

400 mg/ day

Gastrointestinal discomfort, headache, dizziness, hallucinations


Similar activity as rifampin, drug resistance is still rare


0,75–1 g/day

CNS disorders; liver damage, gastrointestinal discomfort


Slowly increase dosage; monitor LFTs




300 mg/day

Gastrointestinal discomfort; discoloration (orange or brown) of urine and other body fluids; uveitis; elevated liver enzymes; arthralgia

Weaker inducer of  cp450 than rifampin;

(for ART drug interactions see Table 3).

Monitor LFTs;

generally preferred instead of rifampin in patients treated with ART drugs (see Table 3)

*LFTs: Liver function tests.
**CNS: Central nervous system.

Patients who exhibit severe adverse events should always be hospitalized for diagnosis and treatment. Drugs thought to be responsible for a given adverse event ought to be discontinued. If visual disturbance occurs on EMB, renal failure or shock or thrombocytopenia on RMP and vestibular dysfunction on streptomycin therapy, re-exposure to these agents must be avoided. Other drugs can be reintroduced one by one when symptoms resolve, beginning with the drug that is least likely to cause the adverse event. All drugs should be restarted at low dosages and dosages should be increased stepwise (Table 2). When no adverse effects occur after 3 days, additional drugs can be added. The drug that is most likely to be responsible for an adverse effect should be the last one to be restarted if no alternative is available.

If toxic hepatitis occurs, then all drugs should be stopped until the serum bilirubin and liver transaminases have normalized. In many cases, it is possible to re-introduce the causative drug (usually INH, RMP or PZA) with increasing dosage without further hepatic complications.

When second-line drugs are used it is usually necessary to prolong the standard treatment duration.

Table 2: Re-introduction of TB drug following drug adverse event


Day 1

Day 2

Day 3


50 mg

300 mg

5 mg/kg/day (max 300 mg/day)


75 mg

300 mg

10 mg/kg/day (max 600 mg/day)


250 mg

1,000 mg

25 mg/kg/day (max 2 g/day)


100 mg

500 mg

25 mg/kg/day for 2 months then 15 mg/kg/day


125 mg

500 mg

15 mg/kg/day (max 1 g/day)

ART and TB therapy

Independent of the status of ART, uncomplicated non-cavitary pulmonary TB in HIV-infected patients can be treated using standard 6-months course with a similar success rate as in HIV-negative individuals (Burman 2001, Chaisson 1996, Hung 2003). If the therapeutic response is delayed (i.e. when sputum cultures are still MTB positive after 2 months of the initial phase), the TB therapy should be extended to at least 9 months.

A few issues must be considered regarding simultaneous ART and TB therapy.

Paradoxical reaction: Following initiation of TB therapy, patients already treated with ART present with paradoxical reactions (lymphadenopathy, fever or increasing pulmonary infiltrates) five times more often than ART naïve patients (Breen 2005). An acute exacerbation of a TH1 immune response against mycobacterial antigens seems to be responsible for the paradoxical reaction in ART experienced HIV/MTB co-infected patients (Bourgarit 2006).

Unmasked TB and immune reconstitution inflammatory syndrome (IRIS): Unmasked TB represents the progression of an undiagnosed subclinical TB disease which is already present before starting ART. The recovery of pathogen-specific immune responses during the initial months of ART trigger the unmasking of a subclinical disease. Screening strategies for underlying TB need to be carefully emphasized in order to prevent severe unmasking manifestations. All patients starting ART with an advanced immunodeficiency and principally those with access to ART programs in resource-limited settings, should undergo microscopic and culture screening for TB regardless of the presence or absence of symptoms.

A similar immunopathogenic mechanism is responsible for a form of tuberculosis progression termed IRIS. Patients with TB and advanced HIV infection can show a clinical progression of tuberculosis after ART is commenced. Even in the presence of TB treatment, ART is associated with immunereconstituion  and dysregulation resulting in the deterioration TB, mainly due to a strong inflammatory component (Lawn 2008). IRIS has been reported to occur in 25-60% of severely immunodeficient patients in the first three months of ART treatment and has been associated with a rapid immunologic and virologic response to ART (Michaelidis 2005, Lawn 2005a). The mortality of TB-IRIS was 10% in one Ugandan study (Worodria 2011). The criteria for the diagnosis of IRIS have been defined in an international consensus statement 2008 (Meintjes 2008). In summary, classic symptoms of TB are required (fever, lymphadenopathy, pulmonary consolidations, neurological symptoms, serositis). Notably, more than 10% of TB-IRIS cases in high prevalence countries are due to mycobacteria showing a previously undetected resistance to RMP (Meintjes 2009).

Although IRIS can lead to paradoxical exacerbations, the diagnosis of TB must trigger the introduction of ART in HIV infected patients (OARAC 2011). During IRIS, both ART and TB therapy should be continued (OARAC 2011). A trial performed in South Africa found a clinical benefit of prednisolone administration for the treatment of IRIS (1.5 mg/kg for 2 weeks, followed by 0.5 mg/kg for 2 weeks) (Meintjes 2010). However, data on IRIS therapy is sparse and no evidence based recommendations can be made yet.

Adherence to therapy is difficult to achieve due to the large number of ART and anti-tuberculosis drugs administered simultaneously and their overlapping toxicities. The most decisive determinant for the success of TB treatment is a good drug adherence for the entire duration of therapy. When compliance is impaired, the development of drug resistance and relapses are common. Therefore, WHO recommends that all patients with TB should be enrolled in directly observed therapy (DOT) programs.

Drug interactions: There are many pharmacological interactions between ART and anti-tuberculosis drugs (Table 3 and 4). Both RMP and protease inhibitors (PIs) are metabolized by cytochrome P450 3A. Concomitant therapy with PIs and RMP is generally not recommended (OARAC 2011, EACS 2009) (Table 3). The preferred antiretroviral regimen is efavirenz (<60kg: 600 mg QD; >60kg 800 mg QD) in combination with TDF+FTC when rifampin therapy is mandatory. In individual patients, screening for a CYP2B6 516G→T polymorphism may be justified to determine the interaction between efavirenz and RMP (Kwara 2011). Alternatively efavirenz (standard dose) can be combined with rifabutin (450 mg QD) that has less cytochrome P450-3A inducing potential (OARAC 2011). The combination of nevirapine and RMP appears to achieve similar outcomes (Moses 2010).

A combination of 3-4 NRTIs (AZT, Abacavir, 3TC ± TDF) could represent a short-term option for patients with a viral load <100,000 copies/ml until TB treatment with RMP is completed. Rifabutin (150 mg three times weekly) can also be combined with boosted PIs, but one trial reported increased rates of neutropenia when combined with atazanavir/r (Table 4) (Zhang 2011). Other (off-label first line) regimens may include T-20 as it has no interactions with rifamycins (Boyd 2003).

There are limited data about the combination of rifampicin and some other antiretroviral agents like tipranavir and maraviroc. Maraviroc should only be given under close observation. Rifampicin also induces the enzyme UGT1A1, leading to in-creased glucoronidation and reduced plasma levels of raltegravir (Wenning 2009) while Rifabutin increases the raltegravir AUC by 19% (OARAC 2011). No significant pharmacokinetic interactions were reported with tenofovir (Droste 2005).

Table 3: Recommendations for co-administering ART with Rifampin*


Antiretroviral dosage adjustment

Rifampin dosage adjustment


Boosted PIs

No co-administration

No co-administration


600 mg (<60 kg weight) or 800 mg (>60 kg weight) OD



No co-administration

No co-administration


No co-administration

No co-administration


No data

No data


600 mg BID



800 mg BID


TDM if possible as RAL levels decrease by 61 %


Standard dose

Standard dose

Triple NRTI therapy not recommended

* EACS 2009, OARAC 2011, CDC 2007 (modified)
Priority: Treatment of active TB always has clinical priority over ART.

Several studies suggested that simultaneous use of ART and anti-TB treatment in patients with less than 200 CD4 T cells, and most significantly in patients with less than 50 CD4 T cells (Havril 2011, Abdool 2011), could have a significant impact on survival (Schiffer 2007, Velasco 2009, Blanc 2010).

Moreover, a recent randomized trial demonstrated that, at least in resource-limited settings, ART has the potential to reduce mortality even in patients with relatively conserved immune function (CD4 T cells 200-500 cells/µl) (Abdool 2010).

When TB occurs in ART-naïve patients with 50-100 CD4 T cells/µl the mortality is high. Therefore simultaneous treatment of both infections is indicated (Dean 2002, EACS 2009, Velasco 2009, OARAC 2011). It is recommended that TB therapy is initiated first. If TB therapy is tolerated, ART can be introduced within two weeks. Patients need to be monitored closely as the risk of paradoxical reaction is high and there are some overlapping toxicities.

In TB patients with CD4 T cells of 100-350/µl, anti-tuberculosis therapy must be started as soon as possible. The initiation of ART can be delayed for 4 weeks according to US guidelines and 8 weeks according to European guidelines (EACS 2009, OARAC 2011). At a CD4 T cell count >350/µl, the US guidelines still recommend initiation of ART within 4-8 weeks after TB therapy was started. The European guidelines leave this decision at the physician’s discretion. Patients who are already on ART when TB develops should remain on ART, although antiretroviral regimen may need to be modified depending on the compatibility with anti-tuberculosis drugs (Dean 2002).

Patients with advanced immunodeficiency remain at high risk of developing TB despite ART, as function of the immune system is not fully restored by ART (Lange 2003, Lawn 2005a+b, Bonnet 2006, Sutherland 2006).

Table 4. Recommendations for co-administering ART with rifabutin*


Antiretroviral dosage adjustment

Rifabutin dosage adjustment


Boosted PIs (LPV/r, FPV/r, DRV/r, SQV/r, ATV/r)

Standard dose

150 mg every other day or 150 mg three times weekly


Standard dose

450 mg / day


Standard dose

Standard dose

Liver toxicity


No co-administration

No co-administration


No data

No data


ART without PI: standard dose

With TPV/r or FOS-APV/r: 300mg BID

With other PI/r: 150mg BID

Standard dose


Standard dose

Standard dose

* EACS 2009, OARAC 2011 (modified)

Therapy of latent TB infection (LTBI)

Latent tuberculosis infection (LTBI) is defined by a positive MTB specific immune response in the TST or an IGRA in the absence of active tuberculosis (Mack 2009). It is not clear which proportion of individuals with a positive MTB-specific immune response is indeed infected with viable MTB. Nevertheless, preventive chemotherapy is recommended for all HIV-infected individuals with a positive MTB-specific immune response in order to prevent active TB (Akolo 2010). HIV-infected persons should be given treatment if their reaction to the TST is ≥5mm. ELISPOT (T-SPOT.TB test) testing is superior to the TST and ELISA (Quantiferon-Gold in tube test) in HIV-infected individuals with low CD4 T cells (Leidl 2009).

The efficacy of prophylactic INH treatment in HIV-infected patients with LTBI has been demonstrated in several randomized studies (Bucher 1999, Elzi 2007). A 6-months prophylactic course of INH reduced the incidence of TB among HIV infected subjects from about 11.5 to 4-9 per 100 person-years (Grant 2005, Charalambous 2010). Therefore, a 6-9 months course of INH (300 mg daily) and pyridoxine is usually recommended for the treatment of LTBI. Alternatively, treatment with RMP (600 mg daily) can be offered. Other regimes consisting of rifapentine / INH weekly for 12 weeks, RMP / INH twice weekly for 12 weeks or INH daily for up to 6 years were not superior to the standard 6-months INH regime in HIV infected adults (Martinson 2011). In contrast, one study reported a 36-months INH regime to be superior to the standard 6-months course (Samandari 2011).  A two-months course of RMP+PZA was associated with adverse hepatic effects and is not recommended (Woldehanna 2004).

ART-naïve patients with negative TST do not benefit from either primary or secondary preventive chemotherapy of TB (Bucher 1999, Churchyard 2003). In addition, preventive chemotherapy with INH has no effect on the overall mortality (Woldehanna 2004). Although ART has a beneficial effect on the prognosis of HIV-positive patients with active TB, the effects of ART in LTBI are still unknown.

Multidrug resistant (MDR) TB and extensively drug resistant (XDR) TB

MDR TB means TB caused by MTB isolates resistant to at least RMP and INH, the two most efficient anti-TB drugs. Despite declining numbers of TB cases in many industrialized nations in recent years, the proportion of MDR TB is rising in many countries. For example, in Germany, 2.2% of all MTB isolates were MDR in 2004, compared to 2.5% in 2004 (Eker 2008). Of these, 90% were isolated from migrants from the Russian Federation. In this geographical region, up to 50% of MTB show INH resistance, and up to 21% show multidrug resistance (WHO 2010). In these cases, selection of the correct drug regimen for treatment of LTBI and active TB becomes problematic.

XDR TB is defined by the WHO as to be resistant to at least RMP, INH, fluoroquinolones (moxifloxacin and levofloxacin) and to at least one injectable drug (amikacin, capreomycin or kanamycin). Initial reports of a near 100% mortality of XDR-infected patients could not be confirmed in a meta-analysis (Gandhi 2006). However, a retrospective study from South Africa reported 30-day and 1-year mor-tality rates of 51% and 83%, respectively (Gandhi 2010). MDR TB continues to spread in South Africa despite good treatment adherence (Calver 2010). XDR TB has been already reported in at least 58 countries (WHO 2010). Until now, data on the management and prognosis of HIV/XDR TB coinfection is sparse.

Where possible, patients with MDR and XDR TB should be treated in specialized centers with second-line anti-tuberculosis drugs. Patients should not be discharged before repeated sputum cultures yield MTB negative results. In general, at least five anti-tuberculosis drugs that are in vitro active against the causative strain of MTB should be administered for 18–24 months after the sputum culture conversion. Long-term treatment with linezolid against MDR- and XDR TB has been associated with a high frequency of severe adverse drug events. Thus, linezolid should only be used when better options are not available (Migliori 2009).

Given the limited number of drugs available for the treatment of resistant MTB, the importance of tracing contact persons cannot be underestimated.


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Filed under 11. Opportunistic Infections, Part 3 - AIDS, Tuberculosis

2 Responses to Tuberculosis

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  2. Thanks so much for showing an analysis for Tuberculosis preference,this was very informative. As a marketer i found this helpful as most of my clients need background information especially in drug selection.

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