HIV & TUBERCULOSIS

“Do you know he has tuberculosis?” A few decades ago, this revelation was shared by friends and acquaintances with deep foreboding, almost with an air of resignation. The disease, simply known as TB, evoked fear and brought visions of prolonged treatment and expensive visits to sanatoriums on hill-stations.

While TB can now be cured with the availability of effective drugs, its socioeconomic impact is huge. Tuberculosis affects people from all backgrounds, but is more common among the poor and economically productive age groups. Consider this: India has a third of the world’s burden of TB. The prevalence of TB in the country has recently been estimated at 8.5 million cases! This implies that over nine persons in each tiny hamlet of 1000 are suffering from TB, at any point of time. Studies have shown that most people get infected as children or adolescents and the prevalence of latent TB infection (LTBI) among adults in India is 50-60 per cent. A high proportion of Indian adults harbour latent TB infection and are prone to re-activation of TB in the presence of any risk factor. In general, about 10 per cent of infected persons develop TB in their lifetime, about half of them in the first two years after infection.

The exact mechanism of latency of this bacterium – Mycobacterium tuberculosis – and the immune mechanisms involved are not clearly understood. However, it is accepted that the bacteria can remain dormant within macrophages for years and gets re-activated in some infected persons, when the conditions are right. What triggers the re-empowerment of this bacterium that lies silently, for years? Risk factors for re-activation of latent TB include HIV infection, diabetes mellitus, silicosis, immunosuppressive drugs, corticosteroids and severe malnutrition. Smoking has also been identified as a risk factor.

The strongest known risk factor for TB reactivation is HIV. The facts speak for themselves. The incidence of TB among HIV-infected persons has been estimated to be 6.9 per 100 person-years in India. This implies that over 10 years (the average lifetime of an infected person), about 70 per cent of them will develop TB. It is obvious that with increasing numbers of HIV-infected people in India, there is likely to be an increase in tuberculosis cases also. The burden of TB in India is therefore likely to increase if the HIV situation worsens.

Diagnosis of TB among HIV+ People

The clinical and radiographic presentation of TB is different in HIV+ persons, especially among patients with advanced disease, making the diagnosis more difficult. At times,sophisticated investigations like computed tomography (CT scans) may be required to diagnose the lesions not visible on plain X-rays. This is especially true for TB of the brain and abdomen. Studies have demonstrated the presence of TB even among asymptomatic highrisk patients despite normal chest Xrays and negative sputum smears, making the detection even more difficult in this high risk population.

HIV co-infection presents us with a challenge on another front. The classical test used to identify TB infection (positive Mantoux or the tuberculin skin test) is not sensitive enough to detect latent TB in HIV+ persons. Moreover, a typical mycobacteria that do not normally produce disease in healthy individuals can do so in immunosuppressed persons. Special diagnostic tests are required for them.

Adverse impact of HIV and TB on each other

HIV and TB have a negative synergy, with each infection having an adverse impact on the other. HIV infection by virtue of reducing the body’s cellular immune defenses makes the individual more susceptible to TB. This could be a flaring up of old dormant TB or a new infection picked up from the environment. In either case, the infection tends to spread within the body and produce disease in more than one site. Once active TB occurs, it stimulates or activates the immune system to produce cytokines. Some of these cytokines further increase HIV viral replication within lymphocytes, thereby increasing viral load and the severity of HIV disease. Untreated TB leads to a rapid deterioration in the clinical condition of HIV+ patients, with increasing viral load and reducing CD4 counts.

Cytokines further increase HIV viral replication within lymphocytes, thereby increasing viral load and the severity of HIV disease. Untreated TB leads to a rapid deterioration in the clinical condition of HIV+ patients, with increasing viral load and reducing CD4 counts. In spite of anti-TB treatment, it has been observed in many studies that about 30- 40 per cent of patients die within two years after developing TB. Prevention as well as early diagnosis and treatment of TB therefore are a priority for improving the quality of life and longevity of HIV+ persons.

Treatment of TB in HIV+ People

The bacteriologic response to treatment with short course anti-TB regimens is as good as in HIV-uninfected persons. Studies comparing six-month short course regimens (daily or intermittent) between HIV+ and negative TB patients have shown similar cure rates. However, it is recommended that regimens employing less than three times a week treatment (twice or once weekly) not be used because of the higher risk of developing drug resistance. At the Tuberculosis Research Centre, a randomised clinical trial is ongoing to compare a six-month vs nine-month intermittent regimen, in order to determine if the Category I regimen used in the Revised National TB Control Program (RNTCP) would be effective in HIV+ persons. A pilot study done at the Centre showed that the smear and culture negativity during the second month of treatment was good, indicating that the drug regimen is effective in killing M tuberculosis. However, the high mortality - during and immediately after treatment of TB was cause for concern. Similarly, the recurrence rate was high and was caused by both reactivation as well as re-infection with a new strain of M tuberculosis.

Both the high mortality and recurrence rate are directly related to the degree of immunosuppression. Hence, one of the important priorities is to determine when to start anti-retroviral therapy (ART) for patients with both HIV and TB? The drug interactions, overlapping toxicities and logistic problems make the co-administration of anti-tubercular and antiretroviral drugs challenging. The best regimen as well as timing of ART in HIV TB co-infected patients needs to be worked out. Directly observed treatment (DOT) has revolutionized the treatment of TB by ensuring compliance and thereby achieving high cure rates. The feasibility and cost-effectiveness of the DOT strategy for administration of antiretroviral drugs needs further study. Preventive Therapy Preventive therapy for TB has been found to be effective in a clinical trial setting, though the optimal regimen and duration are still debatable. More field/ operational research needs to be carried. A path-breaking clinical trial at the Tuberculosis Research Centre is comparing a six-month regimen of drugs Ethambutol and Isoniazid with a three year regimen of Isoniazid alone, among patients with HIV infection.

Though preventive therapy has the potential to reduce the incidence of TB, it has operational constraints. Experience from USA, South Africa and Brazil has shown that the use of ART in populations is associated with reduced risk of TB, other opportunistic infections and death. An observational cohort study from South India also reached similar conclusions.

The war has just begun

This snapshot of the interaction between HIV and TB outlines the issues of concern and the many challenges to be overcome. No one point tactic will help us here; indeed, a combination of strategies including active case finding for TB in HIV-infected persons, improved diagnostic methods, directly observed treatment, preventive treatment and antiretroviral therapy could reduce the burden of HIV-associated TB in India. Clinical and operational research needs to be undertaken in the areas identified above in order to develop scientifically valid, operationally feasible and cost-effective strategies appropriate for implementation in India.