TB, HIV, and IRIS

In Africa and other parts of the world, health care workers and public health authorities continue to struggle with two epidemics: HIV and TB. The figures are alarming: According to the World Health Organization (WHO),¹ 9.6 million persons were estimated to have become clinically ill with TB in 2014, of whom only 6 million were actually reported to the WHO. Disease in the other 37% was either undiagnosed or not reported. In that same year, an estimated 1.2 million persons died of HIV-related complications, including the 400,000 HIV/TB co-infected persons who died of TB. It is estimated that 12% of the 9.6 million new cases of TB in 2014 were also infected with HIV.

The explanation for the high percentage of co-infected persons is relatively straightforward: Many countries have a high prevalence of latent TB infection (LTBI) together with a high prevalence of HIV infection. In those countries, many of the HIV-infected have CD4+ cell counts below 100 cells/uL, which puts them at increased risk of acquiring TB and developing active (acute) TB due to their severely immunocompromised status. In South Africa, for instance, the incidence (new cases) of TB in 2014 was 1% (450,000 new cases out of a total population of 50 million). The prevalence of HIV in South Africa is estimated to be about 12%.²

Comparable figures in 2014 for the US are a TB incidence of 0.003% (330-fold lower than South Africa) and an HIV prevalence of 1%.³ In other words, we do not see a lot of TB in the United States. In 2014, there were about 9400 cases of TB in the US, of which about 70% occurred in individuals born in other countries. The estimated prevalence of HIV/TB co-infection in the US in 2014 was 10%. Thus, in 2014, only about 1000 cases of TB occurred in those who were HIV-infected.

Obviously, when an HIV/TB co-infected person presents with active TB, the priority is treating the TB. Nevertheless, there is a theoretical advantage of treating HIV at the same time: an improved immune system likely makes it easier to eradicate TB in those individuals. However, there is an actual risk associated with improving the immune system prior to completely eradicating TB: an improved immune system is associated with the Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS, which manifests as a “paradoxical” worsening of symptoms, often occurs in the setting of treating both TB and HIV at the same time, especially in those individuals whose CD4+ cell counts are less than 50 cells/microliter.

A recent meta-analysis looked at 8 trials on the optimum timing of antiretroviral therapy (ART) in HIV-infected adults with newly diagnosed pulmonary TB.⁴ The 8 trials were conducted in Africa, Asia, and the US, and compared early initiation of ART (within 1 to 4 weeks of starting TB therapy) versus delayed initiation of ART (8 to 12 weeks after starting TB therapy). The meta-analysis found that early initiation of ART was associated with improved survival in those with CD4+ cell counts less than 50 cells/uL; there were insufficient data to make conclusions about a survival advantage of early versus delayed ART for those persons with CD4+ cell counts greater than 50 cells/uL. The meta-analysis also found a 2-fold higher frequency of TB-IRIS in those persons with CD4+ cell counts of less than 50 cells/uL.

The meta-analysis findings support the 2013 guidance from the CDC that recommends starting ART 2 weeks after initiating TB treatment for “most” persons co-infected with HIV whose CD4+ cell counts are less than 50 cells/uL.⁵ That same document gives guidance on managing drug-drug interactions (eg, rifampin and various antiretrovirals) and associated toxicities in both adults and children. As such, it is an extremely valuable resource for those of us in the US when faced with the relatively-uncommon necessity of managing TB in the HIV/TB co-infected population.

References:

1. Global Tuberculosis Report 2015. 

2. South African National HIV Prevalence, Incidence, and Behaviour Survey, 2012.

3. Tuberculosis in the United States.
4.Uthman OA, Okwundu C, Gbenga K, et al.  Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis. Ann Intern Med. 2015;163:32-39.
5.  CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis [online]. 2013.