Tuberculosis in relation to HIV

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The co-epidemic of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major global health challenges in the present time. The World Health Organization (WHO) reported that TB is the leading cause of death in those with HIV. In 2019, TB was responsible for 30% of the 690,000 HIV/AIDS related deaths worldwide and 15% of the 1.4 million global TB deaths were in people with HIV or AIDS. [1] The two diseases act in combination as HIV drives a decline in immunity, while tuberculosis progresses due to defective immune status. Having HIV makes one more likely to be infected with tuberculosis, especially if one's CD4 T-cells are low. CD4 T-cells below 200 (usually due to untreated HIV) increases one's risk of tuberculosis infection by 25 times. [2] This condition becomes more severe in case of multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality (see Multi-drug-resistant tuberculosis). Tuberculosis can occur at any stage of HIV infection. The risk and severity of tuberculosis increases soon after infection with HIV. Although tuberculosis can be a relatively early manifestation of HIV infection, the risk of tuberculosis progresses as the CD4 cell count decreases along with the progression of HIV infection. [3] The risk of TB generally remains high in HIV-infected patients, remaining above the background risk of the general population even with effective immune reconstitution and high CD4 cell counts with antiretroviral therapy. [4]

Contents

Globally, with the initiation of highly active antiretroviral therapy (HAART) from 2000-2021 in those with HIV on a much larger scale, including in resource limited settings, the incidence of tuberculosis declined by 60% and tuberculosis deaths decreased by 72%. [2] HAART reduces the risk of tuberculosis infection in those with HIV by 67-84%. [2]

Tuberculosis and HIV infection

Classically, tuberculosis affects the upper lobes with cavitary lesions. But in those with HIV, presentation may be atypical. In those with HIV and immunosuppression, lower lobe, non-cavitary nodular consolidations may be seen, with hilar or mediastinal lymph node swelling. In advanced HIV/AIDS, the chest x-ray may be normal. [2]

Those with HIV and TB are more likely to have disseminated TB (where TB spreads to the bloodstream or to other organs outside the lungs). The most common sites of extrapulmonary TB in those with HIV are the lymph nodes, liver, spleen, and central nervous system (TB meningitis). [2] TB meningitis in those with HIV has a mortality rate of 40%. [2] TB may present as sepsis in those with HIV, with some studies having shown that 50% of inpatients with HIV have mycobacteremia (tuberculosis in the bloodstream). [2] In those infected with latent TB and HIV, there is a 5–10% chance that latent TB infection will progress into active tuberculosis disease. If proper treatment is not given in case of active disease, then death rate is about 50%. [5]

Pathogenesis of co-infection of HIV and tuberculosis

TB disease appears when the immune response is unable to stop the growth of mycobacteria. Normally CD4+ helper T-cells secrete the cytokine IFN-γ which recruits macrophages and stimulates them to destroy tuberculosis bacteria and surround them, forming a granuloma to prevent spread of infection. [2] Granulomas wall off the TB bacteria and may arrest disease in a latent phase. In patients with HIV, especially those with low CD4+ helper T cell counts, granulomas are disorganized, poorly formed, or sometimes not forming at all, leading to TB dissemination throughout the lungs and body. Those with HIV also have reduced macrophage differentiation into Langhans cells or epithelioid cells which help to form the granulomas. Granulomas are also characterized by increased neutrophil infiltration, necrosis and increased TB bacteria. [2] During HIV infection, IFN-γ production is decreased dramatically which leads to an increased risk of developing reactivation or reinfection by M. tuberculosis in these HIV/TB patients. [6]

Those with TB and HIV also have reduced CCRD+ CD4+ T-cells at mucosal sites and reduced numbers of TB specific CD4+ T-cells leading to increased susceptibility to severe TB infection. [2] Thus, those with HIV and TB are at increased risk of TB in the bloodstream (mycobacterial bacteremia). [2]

TB also influences HIV evolution. Proinflammatory cytokine production by tuberculous granulomas (in particular TNFα) has been associated with increased HIV viraemia, which might accelerate the course of disease. [7]

Prevention

When HIV-negative children take isoniazid after they have been exposed to tuberculosis, their risk to contract tuberculosis is reduced. [8] A Cochrane review [9] investigated whether giving isoniazid to HIV-positive children can help to prevent this vulnerable group from getting tuberculosis. They included three trials conducted in South Africa and Botswana and found that isoniazid given to all children diagnosed with HIV may reduce the risk of active tuberculosis and death in children who are not on antiretroviral treatment. For children taking antiretroviral medication, no clear benefit was detected.[ citation needed ]

Isoniazid, rifapentine or both may be given to those with HIV as preventative therapy and have been shown to prevent infection with TB (both in those being treated for HIV and those that were untreated). [2] Preventative therapy may be given for 3-6 months at a time or indefinitely, however the utility of indefinite TB preventative therapy is not well established. Isoniazid given for 36 months was shown to reduce the risk of TB by 38% as compared to 6 months of therapy in those with HIV. [2] [10] However, other another study showed limited benefit in preventing TB by starting another 3 month preventative regiment of rifapentine-isoniazid 12 months after the first course in those receiving therapy for HIV. [11] Rifapentine or rifampin was associated with less liver toxicity, less risk of death and increase adherence compared to isoniazid therapy. [2]

The BCG vaccine may prevent some forms of severe TB in children with HIV (such as TB meningitis, a form of chronic meningitis), but in adults with HIV, the vaccine is not recommended. [2]

The experimental M72/AS01E tuberculosis vaccine has shown to reduce the incidence of TB in adults by 50% and its immunogenicity has been demonstrated in those with HIV. [2]

Diagnosis

TB is difficult to diagnose in those with HIV as the signs and symptoms may be atypical. The classic cavitary lung lesions are not usually present and the mycobacterial load in the sputum is low making diagnosis difficult. [2] The GeneXpert MTB/RIF is a PCR based test can simultaneously detect TB as well as resistance to rifampine with a 2 hour waiting time. [2] The test can be performed on urine or blood. In contrast, a sputum culture and microscopic exam is much less sensitive and cultures may take weeks to result. The sensitivity of GeneXpert MTB/RIF was 63% in those with smear negative, culture positive sputum and 90% in those with HIV and culture-positive sputum. Specificity was 96%. [12] The XPert MTB/RIF for the diagnosis of TB is recommended by the World Health Organization. [13]

The Lateral flow urine lipoarabinomannan assay (LF-LAM) assay detects lipoaribomannan glycolipids normally in TB cell walls and can be used to diagnose TB. It has a sensitivity of 52% among inpatients and 29% in the outpatient setting. However, the sensitivity in diagnosing TB increases in those with HIV and low CD4+ cell counts. [2] The test is recommended by the WHO in places where TB and HIV are endemic, and when used as part of the diagnostic process has been shown in multiple studies to reduce mortality rates. [2] [14] [15] The LAM can be combined with XPert MTB/RIF to increase diagnostic yield, however if both tests are negative and clinical suspicion of TB in those with HIV remains high, empiric treatment may need to be started. [2]

Treatment

It is currently recommended that HIV-infected individuals with TB receive combined treatment for both diseases, irrespective of CD4+ cell count. Six months of a rifampin based regiment is the standard of care for those with HIV who develop TB. [2] Those with rifampin resistant TB may be treated with bedaquiline, pretomanid, linezolid and moxifloxacin. [2] The initiation of ART increases the risk of immune reconstitution inflammatory syndrome (IRIS) in those with HIV. TB associated IRIS presents as an inflammatory reaction within 3 months of starting ART for HIV as the immune system is reactivated, and is associated with new or worsening signs of TB. Steroids are indicated in the treatment of IRIS. [2] It may present as recurrent pulmonary TB, inflammatory lymph node swelling and has a death rate of 2%, with an incidence of 18% in those with HIV who start ART. [2] IRIS associated with inflammation of the central nervous system has the highest mortality. [2] It is recommended that therapy for HIV be started within 2 weeks of starting therapy for TB and 4-8 weeks after starting therapy TB meningitis. [2] The advantages of early ART include reduction in early mortality, reduction in relapses, preventing drug resistance to tuberculosis and reduction in occurrence of HIV-associated infections other than TB. [16]

A systematic review investigated the optimal timing of starting antiretroviral therapy in adults with newly diagnosed pulmonary tuberculosis. [17] The review suggested that early provision of antiretroviral therapy in HIV-infected adults with newly diagnosed tuberculosis improved survival in patients who had a low CD4 count (less than 0.050 x 109 cells/L). However, such therapy doubled the risk for IRIS. Regarding patients with higher CD4 counts (more than 0.050 x 109 cells/L), the evidence is not sufficient to make a conclusion about benefits or risks of early antiretroviral therapy.[ citation needed ]

Research at molecular level

A study conducted on 452 patients revealed that the genotype responsible for higher IL-10 expression makes HIV infected people more susceptible to tuberculosis infection. [18] Another study on HIV-TB co-infected patients also concluded that higher level of IL-10 and IL-22 makes TB patient more susceptible to Immune reconstitution inflammatory syndrome (IRIS). [19] It is also seen that HIV co-infection with tuberculosis also reduces concentration of immunopathogenic matrix metalloproteinase (MMPs) leading to reduced inflammatory immunopathology. [20]

Related Research Articles

<span class="mw-page-title-main">Tuberculosis</span> Infectious disease

Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease that, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other organs can cause a wide range of symptoms.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

The spread of HIV/AIDS has affected millions of people worldwide; AIDS is considered a pandemic. The World Health Organization (WHO) estimated that in 2016 there were 36.7 million people worldwide living with HIV/AIDS, with 1.8 million new HIV infections per year and 1 million deaths due to AIDS. Misconceptions about HIV and AIDS arise from several different sources, from simple ignorance and misunderstandings about scientific knowledge regarding HIV infections and the cause of AIDS to misinformation propagated by individuals and groups with ideological stances that deny a causative relationship between HIV infection and the development of AIDS. Below is a list and explanations of some common misconceptions and their rebuttals.

<span class="mw-page-title-main">Cryptococcosis</span> Potentially fatal fungal disease

Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior. It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.

<span class="mw-page-title-main">Diagnosis of tuberculosis</span> Methods for diagnosing tuberculosis

Tuberculosis is diagnosed by finding Mycobacterium tuberculosis bacteria in a clinical specimen taken from the patient. While other investigations may strongly suggest tuberculosis as the diagnosis, they cannot confirm it.

<span class="mw-page-title-main">Management of tuberculosis</span> Disease treatment

Management of tuberculosis refers to techniques and procedures utilized for treating tuberculosis (TB), or simply a treatment plan for TB.

HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe. HAND may include neurological disorders of various severity. HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia. These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. The essential features of HIV-associated dementia (HAD) are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.

Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.

Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with Mycobacterium tuberculosis, but does not have active tuberculosis (TB). Active tuberculosis can be contagious while latent tuberculosis is not, and it is therefore not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these people will go on to develop active tuberculosis. This is particularly true, and there is added risk, in particular situations such as medication that suppresses the immune system or advancing age.

<span class="mw-page-title-main">Tuberculous meningitis</span> Medical condition

Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelop the central nervous system.

<span class="mw-page-title-main">HIV/AIDS</span> Spectrum of conditions caused by HIV infection

The human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. It can be managed with treatment. Without treatment it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). Effective treatment for HIV-positive people involves a life-long regimen of medicine to suppress the virus, making the viral load undetectable. There is no vaccine or cure for HIV. An HIV-positive person on treatment can expect to live a normal life, and die with the virus, not of it.

<span class="mw-page-title-main">Extensively drug-resistant tuberculosis</span> Tuberculosis that is resistant to the most effective drugs

Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

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<span class="mw-page-title-main">HIV disease–related drug reaction</span>

HIV disease–related drug reaction is an adverse drug reaction caused by drugs used for the treatment of HIV/AIDS.

<span class="mw-page-title-main">Signs and symptoms of HIV/AIDS</span>

The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.

Harriet Mayanja-Kizza is a Ugandan physician, researcher, and academic administrator. She is the former Dean of Makerere University School of Medicine, the oldest medical school in East Africa, established in 1924.

<span class="mw-page-title-main">Henry Mwandumba</span> African professor of medicine

Henry Charles Mwandumba is an African Professor of Medicine and the Director of the Malawi-Liverpool-Wellcome Programme. He works on the tuberculosis phagosome in the University of Malawi College of Medicine, and serves as President of the Federation of African Immunological Societies. In 2019 Mwandumba was awarded the Royal Society Africa Prize.

Andrew Ddungu Kambugu is a Ugandan physician who serves as The Sande-McKinnell Executive Director at Uganda Infectious Disease Institute and a Honorary Senior lecturer at Makerere University College of Sciences. He is also an Adjunct Associate Professor at the University of Minnesota. In July 2020, he was appointed to the United Nations 2021 Food System Scientific Group.

<span class="mw-page-title-main">Chronic meningitis</span> Inflammation of the membranes surrounding the brain and spinal cord lasting longer than 4 weeks

Chronic meningitis is a long-lasting inflammation of the membranes lining the brain and spinal cord. By definition, the duration of signs, symptoms and inflammation in chronic meningitis last longer than 4 weeks. Infectious causes are a leading cause and the infectious organisms responsible for chronic meningitis are different than the organisms that cause acute infectious meningitis. Tuberculosis and the fungi cryptococcus are leading causes worldwide. Chronic meningitis due to infectious causes are more common in those who are immunosuppressed, including those with HIV infection or in children who are malnourished. Chronic meningitis sometimes has a more insidious course than acute meningitis. Also, some of the infectious agents that cause chronic infectious meningitis such as mycobacterium tuberculosis, many fungal species and viruses are difficult to isolate from the cerebrospinal fluid making diagnosis challenging. No cause is identified during initial evaluation in one third of cases. Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography and may show radiological signs that suggest chronic meningitis, however no radiological signs are considered pathognomonic or characteristic. MRI is also normal in many cases further limiting its diagnostic utility.

References

  1. ↑ "Tuberculosis & HIV". www.who.int.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Meintjes, Graeme; Maartens, Gary (25 July 2024). "HIV-Associated Tuberculosis". New England Journal of Medicine. 391 (4): 343–355. doi:10.1056/NEJMra2308181.
  3. ↑ Tuberculosis (TB) Archived 2018-07-23 at the Wayback Machine . AIDS InfoNet. February 4, 2014.
  4. ↑ Worodria, W.; Massinga-Loembe, M.; Mazakpwe, D.; Luzinda, K.; Menten, J.; Van Leth, F.; Mayanja-Kizza, H.; Kestens, L.; Mugerwa, R. D.; Reiss, P.; Colebunders, R.; TB-IRIS Study Group (2011). "Incidence and Predictors of Mortality and the Effect of Tuberculosis Immune Reconstitution Inflammatory Syndrome in a Cohort of TB/HIV Patients Commencing Antiretroviral Therapy" . Journal of Acquired Immune Deficiency Syndromes. 58 (1): 32–37. doi: 10.1097/QAI.0b013e3182255dc2 . PMID   21654499. S2CID   45100392. Archived from the original on June 24, 2012.
  5. ↑ L, Aaron; D, Saadoun; I, Calatroni; O, Launay; N, Mémain; V, Vincent; G, Marchal; B, Dupont; O, Bouchaud; D, Valeyre; O, Lortholary (May 2004). "Tuberculosis in HIV-infected patients: a comprehensive review". Clinical Microbiology and Infection. 10 (5): 388–398. doi: 10.1111/j.1469-0691.2004.00758.x . PMID   15113314.
  6. ↑ Ottenhoff, Tom H.M; Kumararatne, Dinakantha; Casanova, Jean-Laurent (November 1998). "Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria". Immunology Today. 19 (11): 491–494. doi:10.1016/S0167-5699(98)01321-8. PMID   9818540.
  7. ↑ Garrait, V; Cadranel, J; Esvant, H; Herry, I; Morinet, P; Mayaud, C; IsraelBiet, D (September 1997). "Tuberculosis generates a microenvironment enhancing the productive infection of local lymphocytes by HIV". Journal of Immunology. 159 (6): 2824–2830. doi: 10.4049/jimmunol.159.6.2824 . PMID   9300705. S2CID   28911458 . Retrieved 7 December 2015.
  8. ↑ Smieja, M. J.; Marchettu, C. A.; Cook, D. J.; Smaill, F. M. (1999). "Isoniazid for preventing tuberculosis in non-HIV infected persons". Cochrane Database of Systematic Reviews. 1999 (2): CD001363. doi:10.1002/14651858.CD001363. PMC   6532737 . PMID   10796642.
  9. ↑ Zunza, M.; Gray, D. M.; Young, T.; Cotton, M.; Zar, H. J. (2017). "Isoniazid for preventing tuberculosis in HIV-infected children". Cochrane Database of Systematic Reviews. 2017 (8): CD006418. doi:10.1002/14651858.CD006418.pub3. PMC   5618450 . PMID   28850172.
  10. ↑ Den Boon, Saskia; Matteelli, Alberto; Ford, Nathan; Getahun, Haileyesus (13 March 2016). "Continuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV". AIDS. 30 (5): 797–801. doi:10.1097/QAD.0000000000000985.
  11. ↑ Churchyard, Gavin; Cárdenas, Vicky; Chihota, Violet; Mngadi, Kathy; Sebe, Modulakgotla; Brumskine, William; Martinson, Neil; Yimer, Getnet; Wang, Shu-Hua; Garcia-Basteiro, Alberto L.; Nguenha, Dinis; Masilela, LeeAnne; Waggie, Zainab; van den Hof, Susan; Charalambous, Salome; Cobelens, Frank; Chaisson, Richard E.; Grant, Alison D.; Fielding, Katherine L. (October 2021). "Annual Tuberculosis Preventive Therapy for Persons With HIV Infection: A Randomized Trial". Annals of Internal Medicine. 174 (10): 1367–1376. doi:10.7326/M20-7577.
  12. ↑ Dorman, Susan E; Schumacher, Samuel G; Alland, David (January 2018). "Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study". The Lancet Infectious Diseases. 18 (1): 76–84. doi:10.1016/S1473-3099(17)30691-6.
  13. ↑ "Use of Xpert MTB/RIF and Xpert MTB/RIF Ultra on GeneXpert 10-colour instruments: WHO policy statement". www.who.int.
  14. ↑ "Lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis of active tuberculosis in people living with HIV, 2019 Update". www.who.int.
  15. ↑ Nathavitharana, Ruvandhi R; Lederer, Philip; Chaplin, Marty; Bjerrum, Stephanie; Steingart, Karen R; Shah, Maunank (20 August 2021). "Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV". Cochrane Database of Systematic Reviews. 2021 (8). doi:10.1002/14651858.CD014641.
  16. ↑ Lawn, Stephen D; Harries, Anthony D; Anglaret, Xavier; Myer, Landon; Wood, Robin (October 2008). "Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa" (PDF). AIDS. 22 (15): 1897–1908. doi:10.1097/qad.0b013e32830007cd. ISSN   0269-9370. PMC   3816249 . PMID   18784453.
  17. ↑ Uthman, Olalekan A.; Okwundu, Charles; Gbenga, Kayode; Volmink, Jimmy; Dowdy, David; Zumla, Alimuddin; Nachega, Jean B. (7 July 2015). "Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis". Annals of Internal Medicine. 163 (1): 32–9. doi:10.7326/M14-2979. PMID   26148280. S2CID   207538325.
  18. ↑ Ramaseri Sunder, S.; Hanumanth, S. R.; Nagaraju, R. T.; Venkata, S. K.; Suryadevara, N. C.; Pydi, S. S.; Gaddam, S.; Jonnalagada, S.; Valluri, V. L. (2012). "IL-10 high producing genotype predisposes HIV infected individuals to TB infection". Human Immunology. 73 (6): 605–611. doi:10.1016/j.humimm.2012.03.012. PMID   22507621.
  19. ↑ Tadokera, Rebecca; Wilkinson, Katalin A.; Meintjes, Graeme A.; Skolimowska, Keira H.; Matthews, Kerryn; Seldon, Ronnett; Rangaka, Molebogeng X.; Maartens, Gary; Wilkinson, Robert J. (April 2013). "Role of the Interleukin 10 Family of Cytokines in Patients With Immune Reconstitution Inflammatory Syndrome Associated With HIV Infection and Tuberculosis". The Journal of Infectious Diseases. 207 (7): 1148–1156. doi:10.1093/infdis/jit002. ISSN   0022-1899. PMC   3583273 . PMID   23303806.
  20. ↑ Walker, N. F.; Clark, S. O.; Oni, T.; Andreu, N.; Tezera, L.; Singh, S.; Saraiva, L. S.; Pedersen, B.; Kelly, D. L.; Tree, J. A.; d'Armiento, J. M.; Meintjes, G.; Mauri, F. A.; Williams, A.; Wilkinson, R. J.; Friedland, J. S.; Elkington, P. T. (2012). "Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases". American Journal of Respiratory and Critical Care Medicine. 185 (9): 989–997. doi:10.1164/rccm.201110-1769OC. PMC   3359940 . PMID   22345579.
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