A Randomized Double Blind Placebo Controlled Trial of Adjunctive Dexamethasone for the Treatment of HIV-infected Adults With Tuberculous Meningitis

Mycobacterium tuberculosis causes ~9 million new cases of tuberculosis and ~1.5 million deaths annually, around 0.4 million of whom are co-infected with HIV. Tuberculous meningitis (TBM) is the most severe form of tuberculosis, killing around 30% of all sufferers despite appropriate anti-tuberculosis chemotherapy. It is especially common in young children, and in those infected with HIV.

There is a longstanding hypothesis that death from TBM results from an excessive intracerebral inflammatory response. The corollary of this hypothesis has been that adjunctive anti-inflammatory treatment with corticosteroids (e.g. dexamethasone) improves survival, which has been demonstrated in predominantly HIV-uninfected individuals in a small number of trials. Yet how corticosteroids improve survival, and whether they do so in HIV-infected patients, remains uncertain. The primary objective of this trial is to determine whether or not adjunctive corticosteroids reduce deaths from TBM in HIV-infected adults.

Adjunctive dexamethasone might improve outcomes from HIV-associated TBM by diverse mechanisms. First, it may control the early intracerebral inflammatory response, reducing cerebral oedema and intra-cranial pressure. Second, it may prevent the potentially life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Third, it may prevent the incidence of anti-retroviral (ARV) treatment-associated neurological immune reconstitution inflammatory syndrome (IRIS). Finally, dexamethasone may help reduce the risk of drug-induced liver injury and thereby improve outcome by enabling uninterrupted anti-tuberculosis treatment.

The current evidence-base for using adjunctive corticosteroids for the treatment of HIV-associated TBM is restricted to 98 adults recruited to a trial in Vietnam published in 2004. This trial randomized a total of 545 subjects (98 of them HIV-positive) and reported an overall reduction in 9-month mortality due to dexamethasone from 41.3% (112/271) to 31.8% (87/274) (hazard ratio of time to death 0.69; 95% CI 0.52-0.92, P=0.01). While there was no clear evidence of treatment effect heterogeneity according to HIV status, the number of included HIV-infected subjects was low and the observed benefit in that subgroup was smaller: 61.4% (27/44) in the dexamethasone group died, compared to 68.5% (37/54) in the placebo group (hazard ratio of time to death 0.86; 95% CI 0.52-1.41; P=0.55).

There are limited data from HIV-infected patients with TBM treated with dexamethasone, but findings from studies using corticosteroids in HIV-infected individuals with other forms of tuberculosis and other opportunistic infections suggest corticosteroids may cause harm in those with advanced HIV infection. There is evidence that corticosteroids may increase the risk of HIV-associated malignancies, especially Kaposi sarcoma. Furthermore, a recent trial of adjunctive dexamethasone for HIV-associated cryptococcal meningitis performed in Southeast Asia and Africa found dexamethasone was associated with worse outcomes, with increased risk of secondary infections, hyperglycaemia and electrolyte abnormalities, and disability.