Combating the 21st century Trojan horse: challenges posed by an unprecedented AIDS/TB coepidemic
Ohad Oren writes on the clincal and policy interactions between these two diseases.
“Confounding” has traditionally served as my confrontation-escape magic word, when it comes to analysing confusing clinical research studies. Epidemiologically, confounding refers to an extraneous variable that is correlated with both the dependent variable and the independent one, and therefore must be taken into consideration by the study conductors. It is a concept that lets you self-assuredly explain unexpected results with the tiniest of efforts. Therefore, that was my instinctive response when discussing with a student friend the crucial but paradoxical outcome of an insightful study. The study found that AIDS patients who develop Tuberculosis (TB) at some point during their follow-up survive longer after their diagnosis of AIDS, when compared to AIDS patients free of TB. The study also established that the onset of TB appeared to dramatically increase the mortality of AIDS patients. (1) Apparently, it proved that all potentially confounding factors were carefully adjusted for by the authors, leaving me completely puzzled. Evidently, there was a crucial perspective that I was lacking: the mortality time-scale of TB.
When a cluster of AIDS patients presented with TB symptoms in the early 1990’s, only 4-8 weeks passed, on average, before they died. (2) In 2005, 53 patients with extensively drug-resistant (XDR) TB were identified among HIV-infected persons in KwaZulu Natal Province, South Africa. Of those, 52 (98%) died a median of 16 days from presentation. (3) It is these statistics that help us understand the seemingly contrasting results about TB mortality in AIDS patients; patients who contract TB do indeed die sooner than the others, but the longer AIDS patients live, the higher their risk of developing TB in comparison to patients who die early after the onset of AIDS.
The unprecedented epidemic of TB in Africa is fuelled by many factors, the most important of which is the HIV epidemic. In fact, HIV infection is the strongest risk factor for the development of active TB. (4,5) Accordingly, the global HIV epidemic has caused the TB burden in many countries to rise steeply. Even in countries with well-established TB-control programs, the high HIV infection prevalence results in a 5-10% annual increase in TB notification rates. (6) In turn, TB infection results in more rapid progression of HIV infection to AIDS.
And yet, very little emphasis is placed on the treatment of serious HIV-related diseases – TB being the most deadly, prevalent and curable one. (7) Most sub-Saharan African countries mistakenly polarise prevention and treatment. They continuously focus on HIV prevention, severely neglecting new deadly TB strains, thus undermining the gains made against the HIV virus. The Highly Active Anti-Retroviral Treatment (HAART) alone accomplishes only scarce benefits, as shows a recent study, shedding light on the intimate – and concerning – convergence of AIDS and TB. (3) An urgent need exists to establish a capacity for the co-management of both TB – especially that caused by resistant strains – and HIV infections.
To reduce transmission and mortality, early identification of individuals with active TB is crucial. (8) The prevalence of undetected TB in Africa, studies claim, ranges from 2 to 3% among HIV-infected pregnant women and from 8 to 10% among people with a new diagnosis of HIV infection. Facilities, personnel, drug supplies, and laboratory capacities are significantly compromised in most African countries, creating an enormous challenge in adequately diagnosing and containing large numbers of TB carriers. Currently, identifying TB in Africa is done by detecting acid-fast bacilli in the sputum, which is particularly insensitive for HIV patients. It is estimated that only half of all persons with smear-positive TB are identified. Modern culture and nucleic-acid-amplification techniques are only rarely available. Therefore, thousands die without ever having received a diagnosis of TB, while many others remain contagious but undetected for long periods. (8)
TB resistant strains have emerged due in part to delayed diagnosis, poor adherence to TB treatment, advanced immunosuppression, treatment of other opportunistic infections, and co-treatment with antiretroviral medications. (9) Five percent of the world’s annual TB burden is caused by MDR (Multi-drug resistant) TB, with approximately 425,000 cases occurring each year. (10) The treatment period for MDR-TB is much longer than for susceptible TB, and treatment success rates are significantly lower. (6) When there is capacity for a more rapid diagnosis of MDR-TB, however, the proportion of HIV/MDR-TB patients dying while receiving treatment decreases. (11)
There are profound complexities in treating MDR-TB patients with HIV infection. HIV infection has been associated with malabsorption of anti-TB medications and there are many drug interactions of concern, some known – like those between rifampicins and multiple antiretroviral medications – and others not yet fully defined. (12)
It is a disturbing fact that recently there is an increasing reluctance of health-care workers to care for HIV patients. Public health workers and clinicians themselves are becoming infected with HIV, resulting in an elevated health-care cost, and increased personnel, drug and equipment shortages. (7) With the frightening scenario of becoming infected with a resistant TB strain, an air-borne bacteria, the risks are much more existential and intimidating than with HIV alone, says Kevin DeCock, HIV department director of WHO. (13)
Reacting quickly to the emerging TB-HIV epidemic in the 1990’s, Thailand implemented a new TB-control policy, in only four years encompassing 60% of all districts in the country. Additional measures targeting high-risk groups were introduced. At the core of those efforts are improved diagnosis and treatment of MDR-TB cases and preventive treatment for those with HIV. Results are not ideal as the death rate among TB/HIV patients is still high, implying that most patients are treated at advanced stages of infection. (7) However, the strategy signifies a partial achievement for Thailand, and its benefits are thought to be fully recognised with time.
Inside the macrophage, the 21st century version of the Trojan horse, are concealed the invading mycobacteria. They are impervious to most weapons, and are insightful enough to direct their assaults at the enemy’s most vulnerable areas. However, unlike the Trojans surprised by the Greeks’ gift, we are aware of the destructive potential those hidden soldiers entail. Perfect diagnostic measures and curing agents are not yet here; despite or perhaps because of this we must wisely and effectively use all possible means at our side to ameliorate the deadly co-epidemic of TB and AIDS.
Ohad Oren, 4th year medical student, Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
ohadoren@tx.technion.ac.il
References
(1) Perneger T, Sudre P, Lundgren J, Hirschel B. Does the onset of tuberculosis in AIDS predict shorter survival? Results of a cohort study in 17 european countries over 13 years. BMJ 1995;311:1468-1471.
(2)Wells CD, Cegielski JP, Nelson LJ, et al. HIV Infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis 2007; 196 Suppl 1:s86-107.
(3) Ghandi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575-1580.
(4) Reid A, Scano F, Getahun H, et al. Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration. Lancet Infect Dis 2006; 6:483-495.
(5) Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320:545-50.
(6) World Health Organization (WHO). Tuberculosis global report, 2006. WHO/HTM/TB/2006.343. Geneva: WHO, 2006.
(7) TB and HIV/AIDS: Overlapping Epidemics, Complementary responses. (Global Plan to Stop TB, Chapter 3). http://whqlibdoc.who.int/hq/2002/WHO_CDS_STB_2001.16_ch3.pdf (accessed June 26, 2008).
(8) Chaisson R, Martinson N. Tuberculosis in Africa – Combatting an HIV-Driven Crisis. N Engl J Med 2008;358:1089-1092.
(9) Ridzon R, Whitney CG, McKenna MT, et al. Risk factors for rifampin mono-resistant tuberculosis. Am J Respir Crit Care Med 1998; 157:1881-4.
(10) Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006; 194:479-85.
(11) Gonzalez Montamer LJ, Alberti F, Palmero D. Multidrug-resistant tuberculosis associated with AIDS (kinetics of nosocomial epidemics of multidrug-resistant tuberculosis associated with AIDS. Possible transformation into endemic disease). Bull Acad Natl Med 1999; 183:1085-1094. (In French)
(12) Taburet AM, Singlas E. Drug interactions with antiviral drugs. Clin Pharmacokinet 1996; 30:385-401.
(13) Lawrence K. Altman. Spread of tuberculosis seen slowing progress on AIDS. International Herald Tribune. June 10, 2008. http://www.iht.com/cgi-bin/search.cgi?query=By%20Lawrence%20K.%20Altman&sort=publicationdate&submit=Search