World Health Organization (WHO) data show that nearly one in three HIV/AIDS deaths around the world is caused by tuberculosis co-infection. As the name indicates, co-infection is the condition of having two or more infectious diseases at the same time. This is very common in AIDS patients because they tend to be heavily immunocompromised.

WHO data also show that “people who are infected with HIV are 18 times more likely to develop active TB” than people who do not have HIV infection. This requires special management and precautions to prevent the spread of TB. Additionally, people with both HIV and active TB are likely to get AIDS (advanced stage of HIV infection) faster than people who have HIV but not TB.

Latest data show that there are 38 million people living with HIV worldwide—1.7 million of them were diagnosed in 2019 alone. Ten million new TB infections were reported worldwide in 2019—this included 3.2 million women and 1.2 million children. And of the 1.4 million people who died from TB in 2019, 208,000 also had HIV.

On World AIDS Day, we bring to you the latest information on the causes, symptoms and management of HIV/AIDS and tuberculosis coinfection.

  1. HIV TB link
  2. HIV TB coinfection symptoms
  3. Tuberculosis HIV prevention guidelines
  4. Diagnosis of tuberculosis in HIV positive patients
  5. HIV tuberculosis co-infection treatment guidelines
Doctors for HIV TB coinfection

Human immunodeficiency virus (HIV) infection causes the body’s immunity to deteriorate. While the infection can be managed by suppressing viral load with antiretroviral therapy (ART) and treating opportunistic infections, it is currently incurable. With sufficient destruction of immunity by HIV, acquired immunodeficiency syndrome (AIDS) arises.

Tuberculosis is a bacterial infection that primarily affects the respiratory system but can also impact other organs. Usually, latent tuberculosis infections are more common than active disease, however with a compromised immune system in HIV, the burden of co-infection is significant.

Additionally, HIV and tuberculosis infections potentiate (facilitate) one another. It is difficult to diagnose tuberculosis in HIV patients due to lack of immune response and therefore dirth of symptoms.

Why are HIV/AIDS patients at risk for TB?

HIV is a type of retrovirus that infects CD4+ T-cells, by merging irreversibly with the cellular genetic material, in human beings. After invading these helper T-cells, by varying mechanisms, the virus causes the destruction of  CD4+ T-cells. A steady decline in the population of these cells leads to loss of cell-mediated immunity conferred by them. And opportunistic infections occur in this state of reduced immunity. The typical opportunistic infections include:

  • Candidiasis (a white-coloured fungal infection that can affect the skin, nails and mucous membranes of the mouth and vagina)
  • Herpes simplex infections (cold sores around the mouth or genital ulcers)
  • Kaposi’s sarcoma (cancerous skin lesions)
  • Pneumocystis pneumonia (caused by a fungus known as Pneumocystis jirovecii)
  • Tuberculosis 

Tuberculosis is an infectious disease caused by the bacteria Mycobacterium tuberculosis. While typically a respiratory disease (spreads by air and droplet transmission) affecting the lung, it can affect various other parts of the body as well. Examples of extra-pulmonary (outside the lungs) tuberculosis include abdominal tuberculosis, tubercular osteomyelitis (bone infection), tubercular meningitis (infection of covering of the brain), etc. Most tubercular infections are asymptomatic, or latent infections, as even after entering human cells, the bacteria do not cause disease. Thus, in states of chronic ill-health or other conditions (like HIV) in which the body’s immune system has taken a hit, due to lowered defences, the bacteria invade cells and cause active infection. 

Usual symptoms of tuberculosis include:

  • Chronic cough (typically longer than two weeks) with sputum that may be blood-tinged
  • Persistent fever
  • Night sweats
  • Significant weight loss (with noticeable loosening of clothes, rings or slippers or documented involuntary reduction in weight by at least 5% over six to 12 months)
  • Breathlessness
  • Chest pain
  • Fever
  • Weakness
  • Fatigue

Tuberculosis is a largely preventable disease for which the BCG vaccine exists. Treatment for uncomplicated tuberculosis infection consists of quadruple antibiotic drug therapy with rifampicin, isoniazid, pyrazinamide and ethambutol.

However, with the increased use of these drugs, tuberculosis-causing bacteria have developed resistance against them. Therefore, in cases of drug-resistant tuberculosis—multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB)—alternative medicines are used and the duration of the regimen is also lengthened.

Tuberculosis HIV coinfection risks and complications

Preexisting HIV infection increases the incidence of and potentiates tuberculosis. Active tubercular disease, in turn, hastens the progress of HIV infection towards full-blown AIDS.

Of course, all HIV patients are not said to be suffering from AIDS or acquired immunodeficiency syndrome. HIV infection progresses in stages, based on the patient’s CD4+ cell count. When CD4+ cell count drops below 200 cells per millilitre of blood, that’s when certain opportunistic infections start occurring.

More opportunistic infections occur at even lower immunity levels, and AIDS-related syndromes set in. Chief among them, HIV-associated wasting syndrome, which is marked by significant involuntary weight loss (10% or more) and muscle mass loss. At this stage, the patient is said to have AIDS. 

In terms of symptoms, HIV patients may remain wholly asymptomatic at first except for some lethargy. Later, with cellular immunity plummeting, characteristic HIV-related opportunistic infections arise.

With the initiation of daily antiretroviral therapy (ART), the prognosis for AIDS patients has drastically improved by effective viral load suppression.

In those patients whose immune system has been weakened by HIV infection, and who are not receiving adequate or any, antiretroviral therapy to suppress the viral load and prevent further diminution of immunity, active tuberculosis infection is common.

While in most immunocompetent patients tuberculosis occurs as a latent asymptomatic infection, in HIV positive individuals the risk of progression to active tubercular disease is 18 times greater. Further, while individuals with strong immunity are only at a 5% to 10% risk of contracting tuberculosis in their lifetimes, an HIV positive person faces the same amount of risk of TB every single year of their lives.

The symptoms of tuberculosis in a patient with a competent immune system arise as byproducts of the body’s immunity fighting the infection (via inflammation). In HIV positive individuals with depleted CD4+ cellular defence, this mechanism of useful inflammation to ward off the bacteria is lacking. Thus, HIV positive will are unlikely to have the classical presentation of tuberculosis. While it is not necessary for the typical signs and symptoms of tuberculosis to be present, if present, they are likely to be mild. Additionally, due to poor immune response to infection, usual tuberculosis investigations (tests and diagnosis) might not be useful. For example, cavitations in the lungs may not be appreciable (seen) on chest X-ray and TB sputum smears may be falsely negative. Therefore detection, diagnosis and initiation of timely anti-tubercular treatment becomes a challenge and screening becomes paramount.

HIV TB coinfection guidelines

The WHO recommends relying on the following four symptoms to clinically suspect tuberculosis in adults living with HIV:

  • Current cough (of any duration)
  • Fever (of any duration)
  • Weight loss
  • Night sweats

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And the following four rouse clinical suspicion of tuberculosis in children (more than 12 months of age) living with HIV):

  • Poor weight gain
  • Fever (of any duration)
  • Current cough (of any duration)
  • History of contact with a tuberculosis patient

The presence of these four is assessed at each meeting and dictate the further course of action. If none are present, isoniazid prophylaxis therapy (explained ahead) is started, however, if any are present, tuberculosis testing is carried out.

The World Health Organization (WHO) recommends a “three I’s strategy”, supported by the four symptoms “4S screening” described earlier, to prevent tuberculosis in people living with HIV. Here is how this strategy is incorporated in the Indian scenario:

  • Intensified case finding by integrating tuberculosis CBNAAT testing upon clinical suspicion at antiretroviral therapy centres, and offering HIV testing to presumptive drug-resistant tuberculosis patients. Vulnerable population like drug abusers, female sex workers and homosexuals are especially encouraged to get tested.
  • Isoniazid prophylaxis therapy: Patients with HIV who are not diagnosed with active tuberculosis (clinically or with lab investigations) are initiated on isoniazid therapy to prevent conversion of latent tuberculosis to active disease and to prevent reinfection. A minimum six months of daily isoniazid is recommended as part of comprehensive HIV treatment.
  • Infection control: Airborne infection control activities are carried out at ART centres to prevent tuberculosis transmission amongst immunocompromised patients. Measures include ensuring adequate ventilation at the centre and physically separating patients with respiratory symptoms and fast-tracking their care. Use of personal protective equipment (PPE) like masks is mandated for healthcare workers.

If any one of the four symptoms (fever, cough, night sweats and weight loss in adults and difficulty putting on weight children, respectively) is seen in/reported by someone living with HIV, a cartridge-based nucleic acid amplification test (CBNAAT) has to be administered to them on priority.

Sputum smear studies, done under normal circumstances, are not reliable in HIV patients owing to their poor immune response, rendering the test incorrectly negative. Also, to test antibiotic (chiefly rifampicin) sensitivity, sputum cultures are infeasible due to the long period of time needed.

CBNAAT can, however, assess any sample (that is free of blood) within two hours for the presence of tuberculosis bacilli and rifampicin sensitivity. Those who test negative are initiated isoniazid prophylaxis therapy (IPT), while those who have active tuberculosis receive anti-tubercular treatment (ATT).

The main aim of treating tuberculosis and HIV co-infections concomitantly is to integrate antiretroviral therapy with anti-tubercular therapy to improve patient compliance, prevent HIV-associated comorbidities, monitor drug toxicity and prevent or treat immune reconstitution inflammatory syndrome (IRIS).

TB treatment in HIV TB coinfection

IRIS is a phenomenon by which, with the beginning of recovery of the immune system in immunosuppressed HIV patients, previously acquired opportunistic infections like tuberculosis, which were earlier mild to asymptomatic, flare up and present with exaggerated symptoms. 

Current Indian guidelines state that to prevent treatment failure and for ease of patients, anti-tubercular treatment (ATT) drugs be administered daily as weight-specific fixed dose combinations (FDCs). This means that the four key ATT drugs—rifampicin, isoniazid, pyrazinamide and ethambutol—are formulated as a single tablet to be taken once a day along with daily antiretroviral therapy (ART) drugs. The dose of drugs in FDCs are based on weight-bands.

Tuberculosis treatment for PLHIV (people living with HIV) is the same as that for those without HIV. Drug-sensitive pulmonary tuberculosis is treated with rifampicin, isoniazid, pyrazinamide and ethambutol for the first four months (intensive phase), followed by two months (continuation phase) of rifampicin, isoniazid and ethambutol.

In case the patient is receiving second-line ART with protease inhibitors (like lopinavir/ritonavir), rifampicin should be replaced by rifabutin.

HIV treatment in TB HIV coinfection

Conversely, if a tuberculosis patient is diagnosed with HIV, antiretroviral therapy (ART) should be initiated only after a minimum of two weeks to a maximum of two months of start of anti-tubercular treatment (ATT). This is because sudden reactivation of the suppressed immune system in a tuberculosis patient could cause immune reconstitution inflammatory syndrome (IRIS).

However, if the CD4+ cell count is 50 or less, ART must be started as soon as possible—that is, on completion of two weeks of ATT. If IRIS is suspected due to sudden worsening of symptoms, first ATT failure is ruled out and then, if the reaction is severe, steroid therapy may be considered by the doctors.

99 DOTS for HIV TB coinfection

The National AIDS Control Programme (NACP) and National Tuberculosis Elimination Program or NTEP (previously known as the Revised National Tuberculosis Control Program of India) have created a joint framework under which tuberculosis and HIV prevention and management activities are coordinated.

99 DOTS for HIV TB coinfection

To specifically target the high burden of tuberculosis-HIV co-infection due to poor patient compliance, the government launched 99 DOTS in 2015. This novel system was instituted to monitor daily intake of anti-tubercular treatment DOTS (directly observed treatment short-course) by HIV co-infected patients. Special ATT blister-packs are given to patients who can not commute to the ART centre daily. On opening each blister to take the ATT FDC tablet out, a mobile phone number, that can not be guessed by the patient, is revealed. Patients are instructed to leave a missed-call on this toll-free number. These calls register with a centralised system, providing confidence that the ATT was “in hand” and most likely taken. This allows monitoring of adherence to treatment and tracking of missed doses.

Dr Rahul Gam

Dr Rahul Gam

Infectious Disease
8 Years of Experience

Dr. Arun R

Dr. Arun R

Infectious Disease
5 Years of Experience

Dr. Neha Gupta

Dr. Neha Gupta

Infectious Disease
16 Years of Experience

Dr. Anupama Kumar

Dr. Anupama Kumar

Infectious Disease

References

  1. World Health Organization, Geneva [Internet]. TB causes 1 in 3 HIV deaths, 26 September 2018.
  2. Sabin C.A., Lundgren J.D. The natural history of HIV infection. Current Opinion in HIV and AIDS, July 2013; 8(4): 311-7. doi: 10.1097/COH.0b013e328361fa66. PMID: 23698562.
  3. Centres for Disease Control and Prevention [Internet]. AIDS and opportunistic infections. CDC, U.S. Department of Health & Human Services. Accessed on 29 November 2020.
  4. Cardona P.J. Pathogenesis of tuberculosis and other mycobacteriosis. Enfermedades infecciosas y microbiología clínica, January 2018; 36(1): 38-46. English, Spanish. doi: 10.1016/j.eimc.2017.10.015. Epub 2 December 2017. PMID: 29198784.
  5. World Health Organization, Geneva [Internet]. Tuberculosis, 14 October 2020.
  6. World Health Organization, Geneva [Internet]. Implementing the WHO stop TB strategy: a handbook for national tuberculosis control programmes, 2008: 67.
  7. Pape J.W., Jean S.S., Ho J.L., Hafner A., Johnson W.D. Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet, 31 July 1993; 342(8866): 268-72.
  8. World Health Organization, Geneva [Internet]. The three I's for TB/HIV.
  9. National AIDS Control Organisation and DOTS, Ministry of Health and Family Welfare [Internet]. Guidelines on prevention and management of TB in PLHIV at ART centres, 2016.
  10. Bruchfeld J., Correia-Neves M. and Källenius G. Tuberculosis and HIV coinfection. Cold Spring Harbor Perspectives in Medicine, 26 February 2015; 5(7): a017871. doi: 10.1101/cshperspect.a017871. PMID: 25722472.
  11. Naidoo K., Baxter C. and Karim S.S.A. When to start antiretroviral therapy during tuberculosis treatment?. Current Opinion in Infectious Diseases, February 2013; 26(1): 35-42. 10.1097/QCO.0b013e32835ba8f9.
  12. Thakkar D., Piparva K.G. and Lakkad S.G. A pilot project: 99DOTS information communication technology-based approach for tuberculosis treatment in Rajkot district. Lung India, March-April 2019; 36(2): 108-111. doi: 10.4103/lungindia.lungindia_86_18. PMID: 30829243.
  13. National Tuberculosis Elimination Programme (https://nikshay.in/). Low-cost monitoring and improving medication adherence.
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