Syndemic is the word given to TB infection and Human Immunodeficiency Virus (HIV) when they co-exist. The word is used where two diseases are persistent in a population at the same time and each one of them exacerbates the effects of the other.
These two infections, caused by foreign agents in body, are so close in their incidence rates that they are also referred as a co-epidemic.
Over the past few years the rates of new TB infection cases emerging in the countries where there were incidence of increased HIV cases has almost doubled. This syndemic is one of the most challenging public health crises of recent times.
Both diseases are life threatening if appropriate interventions are not made at the right time. There is a common misconception about the nature of TB, some individuals ask, “is TB a viral infection”. TB is in-fact a bacterial infection caused by Mycobacterium tuberculosis, it promotes TB with two kinds of infection; latent and active disease. The bacterium infects macrophages.
However, HIV is a long term disease with three different stages of acute HIV infection, asymptomatic or chronic infection, and Acquired Immunodeficiency Syndrome (AIDS).
The perfect symbiosis existing between the viral infection (HIV infection) and bacterial disease (TB Infection) has helped the worldwide spread of both. Certain specific immunological responses have been seen in patients who have acquired the coinfection. Understanding the pathogenesis of HIV and TB coinfection is fundamental to help patients and control its spread.
Tuberculosis is usually the initial opportunistic infection acquired in HIV patients as the susceptibility of MTB-specific CD4 T cells to HIV infection has been increased.
How Do You Get TB?
TB infection is usually dependent upon bacterial virulence and host resistance. The infection starts when air droplets with 1-200 mycobacterium tuberculosis from an actively infected individual, are inhaled by a person. The bacterial particles are phagocytosed (killed) by macrophages in the lungs alveoli.
This leads to a cascade of reactions which is inflammatory in nature. Following the event a granuloma may form. Cell mediated immunity in which CD4 T lymphocyte cells are activated is also an important fighting mechanism employed by the body to fight the disease acceleration and reactivation.
Pathophysiology Of HIV
A question that arises in layman’s mind is whether HIV contagious or not? Years have scientific research has found that HIV is transmitted through blood, mucosa, and genital fluids. The infection interacts with different cells and can escape the immunological responses mounted by the body and thus results in acquired immunodeficiency syndrome (AIDS).
HIV infection progression typically depends upon CD4 T lymphocyte depletion and a chronic immune inactivation state.
The decreased macrophage activity along with depleted stock of CD4 T lymphocytes in HIV infection results in a decreased immunological response of the body thus, providing a clear ground for tuberculosis disease to take hold in the body.
TB returns the favor. Initially the mycobacterium is encircled within granulomas but the disruption leads to bacterial growth and systemic dissemination to different body organs. TB disease enhances the HIV replication mechanism by increasing the expression of receptors which help viral growth.
Incidence And Demographics
The two diseases share a close relationship. Tuberculosis disease is the most common opportunistic infection which affects HIV sero-positive individuals worldwide. It is also the most common cause of death amongst patients with AIDS, with 1000 people dying of the disease every day.
On the other hand HIV infection has increased the worldwide incidence of TB by progressively declining cell mediated immunity thus altering the pathogenesis of TB and increasing risk of TB in HIV infected individuals.
TB-HIV Coinfection And Mortality — Can TB kill You?
In a year old WHO report on Global TB status, the experts estimated that 1.1 million (13 percent) people amongst the total of 9 million people, who developed TB, were in fact HIV positive in 2013. People in African region were seventy eight percent of this number, making them the highest incident group.
The number of deaths occurring from this coinfection has decreased since 2004. However HIV associated TB deaths raked at 360 000 in 2013. The number makes up twenty five percent of all TB deaths among HIV negative and HIV positive people.
In 2015 report however the WHO estimates that 0.4 million people who were HIV positive died of TB. The total death toll from TB stood at 1.5 million people with 890 000 men, 480 000 women and 140 000 children. Globally, 9.6 million new cases of TB were reported in 2014 and twelve percent of these cases were HIV positive.
Certain factors like age, gender, socioeconomic status, education level, and marital status are sometimes detrimental when it comes to this syndemic. Male are more prone to acquire these infections however in certain regions like Pakistan-Afghanistan border females have been seen to contract TB and HIV more frequently.
Patients who are receiving a specific medication might become more susceptible to both diseases owing to the drug-interaction. People with immune compromised status like the ones receiving anti-tumor necrosis factor treatment, dialysis, corticosteroids, organ or hematologic transplantation are more disposed to acquiring HIV and TB coinfection.
Single, less educated, people with lesser income and from a low socioeconomic status have been seen more prone to acquire this coinfection in the past. Poor sanitation and access to healthcare also negatively impacts disease outcomes.
The infection is most common in males with an average age of 33-45. Exceptions existlike the disease has also been seen in young people, or people who are rich, have higher income and are in a relationship.
WHO recommends that all HIV patients should be screened for TB before they start antiretroviral therapy (ART) including people who are in close contacts with such patients like household residents.
HIV and TB coinfection diagnosis follows a proper diagnostic protocol steps.
The first step is to use a clinical symptom based algorithm to check which signs of the disease exit and which do not. This can help decide if the patient needs medical attention or chemoprophylaxis to prevent active TB disease.
After initial screening if TB is suspected, use of tuberculin skin test (TST) and interferon gamma release assays (IGRA) is recommended. Skin test can be affected by previous BCG vaccination and use of IGRA is advised in such situations.
These tests have low specificity meaning they have false positives and false negative results.
When the suspicion of the disease is higher testing is performed using sputum smear microscopy. The test is inexpensive, easy and rapid to perform but has low specificity for the coinfection.
Growth based detection of TB by cultural and molecular techniques like nucleic acid amplification testing (NAAT) is more sensitive and allows drug susceptibility tests and strain characterization. These tests however are not widely available and are expensive.
Chest radiographs, computerized tomography scans with low thresholds can also be used to diagnose TB in HIV positive individuals.
Tuberculosis affected patients are however not routinely tested for HIV unless clear signs and symptoms of the disease and high risk association in patients is seen.
How To Prevent TB? Treatment & Guidelines
Tuberculosis and HIV treatment involves use of different specific therapies but in conjunction with each other. The therapies are adjusted in dosages, durations and frequency of anti retroviral therapy and anti –TB drug administration.
TB is usually treated with isoniazid, rifamycin, pyrazinamide, and ethambutol for two months. A follow up with isoziazid and rifamycin is given for four to seven months.
Treatment of TB is a priority as there is an active risk of its transmission to other people. Priority should always be given to DOT or direct observed therapy for ensuring patient compliance and treatment success.
When CD4 T cell count is less than fifty cells per millimeter cube, antiretroviral therapy specifically HAART or highly active antiretroviral therapy becomes a necessity.
Previously three major randomized control trials such as SAPiT, STRIDE, and CAMELIA have given evidence in favor of starting ART within 2 weeks of antibacterial therapy.
Several debates and recommendations on the start of HAART exist. Early start of the therapy can include benefits like:
- Higher care rates
- Reduced risk of infection with HIV associated opportunisticinfections (OIs)
- Reduced risk of relapse
- Lower mortality rates
However potential disadvantages of HAART therapy can be:
- Rifampicin and HAART drug interactions
- Limited co administration of selected protease inhibitors
- Therapeutic failure
- Risk of immune reconstitution inflammatory syndrome (IRIS)
- Cumulative toxicity
Other major problems associated with treatment of the coinfection can be fear of stigmatization, inaccessibility of treatment centers, non compliance due to pill burden, side effects of medications, and lack of proper health education.
In specific populations like pregnant women the therapy should be started as early as possible and the choice of antiretroviral therapy should be based upon safety and efficacy and any potential drug interactions.
Immune Reconstitution Inflammatory Syndrome (IRIS)
Immune Restoration Syndrome or IRIS is a pathogen specific inflammatory response often seen in HIV infected patients, which emerges as an early complication of antiretroviral therapy especially in patients who also have the TB disease.
IRIS can be often seen during the early months of initiation of ART therapy and is associated with multiple pathogens like herpes viruses, mycobacterium, and fungal infections like meningitis.
IRIS is often accompanied by rapid increase in viral load and CD4 cell count. However, IRIS can occur at any CD 4 count.
There are no diagnostic tests available to confirm the presence of the syndrome. The diagnosis is often dependent upon case definitions regarding clinical and laboratory data.
Diagnosis should fulfill two major diagnostic criteria or one major criterion with two minor criteria. Major criteria can include 1) Atypical presentation of OTIs or tumors in patients responding to ART 2) Decrease in plasma HIV RNA concentration by more than 1 log10 copies per mL.
Minor criteria can include 1) increased CD 4 T cell count 2) increased immune response specific to pathogen 3) spontaneous resolution of disease without specific antimicrobial therapy.
For tuberculosis associated IRIS three major criteria for screening and confirmation have been defined individually.
Suspected Tuberculosis associated IRIS criteria:
- Initial clinical response to tuberculosis treatment based on combination of factor like decreased lymph node size, relief of pulmonary symptoms, cessation of fever, termination of meningeal irritation
- New persistent fevers without identifiable cause or emergence of dysponea, stridor, increase in lymph node size, abdominal pain without visible ultrasound cause, unexplained CNS symptoms and development of abscesses
- Adequate adherence to Tb treatment and ART
Confirmed Tuberculosis Associated IRIS Criteria:
- Radiological exams showing worsened condition pulmonary infiltrats, abdominal lymphnodes, intrathoracic lymphadenopathy, pleural effusions, and hepatosplenomegaly
- Good virological response or increase in CD 4 count. Conversion of TST from negative to positive or adequate adherence to ART and TB treatment
- Exclusion of conditions that can explain these clinical manifestations
TWO main types of IRIS can be seen 1) Unmasking IRIS presents soon after initiation of ART 2) Paradoxical IRIS refers to worsened TB condition after ART is initiated in patients on anti-Tb medication.
IRIS is treated with anti inflammatory drugs and steroids. HAART discontinuation is usually not essential. Delaying ART for 2 to 8 weeks may help reduce the severity of the immune restoration syndrome.