Early versus delayed antiretroviral treatment in HIV‐positive people with cryptococcal meningitis

The aim of this Cochrane Review was to determine whether initiating antiretroviral therapy (ART) within four weeks of cryptococcal meningitis diagnosis resulted in a higher risk of dying or developing other complications than waiting more than four weeks to initiate ART.

Key messages

Initiating ART within four weeks of cryptococcal meningitis diagnosis may result in more deaths than initiating ART after four weeks. However, initiating ART early may result in a reduction in relapses of cryptococcal meningitis after adequate treatment. There was insufficient evidence to answer questions related to other complications.

What was studied in the review?

Cryptococcal meningitis is a fungal infection of the brain and the membranes covering the brain that occurs most frequently in people with weakened immune systems, such as people who are HIV‐positive. Some studies have shown that HIV‐positive people who start ART soon after initiating cryptococcal meningitis treatment (within four weeks) may deteriorate and die more frequently than those who delay treatment for a longer period (more than four weeks). This higher risk of death in the early ART group has been attributed to the occurrence of a condition called immune reconstitution inflammatory syndrome (IRIS). When ART is initiated, HIV‐positive people with underlying infections such as cryptococcal meningitis may paradoxically develop a deterioration in their condition as their body's immune system attacks the fungus, resulting in worsening symptoms and sometimes death. It has been proposed that IRIS is the cause of more deaths in early ART initiators than in delayed ART initiators. Despite adequate treatment of cryptococcal meningitis with antifungal drugs, a relapse of the disease may occur in some HIV‐positive people with cryptococcal meningitis. To date there have been few trials investigating the effect of ART on mortality, frequency of IRIS, or relapse.

What are the main results of the review?

We found four relevant trials that compared HIV‐positive adults who had cryptococcal meningitis and who initiated ART within four weeks of cryptococcal meningitis diagnosis with those who initiated ART after four weeks.

Pooling the results of these four trials suggested that early ART initiation may increase the frequency of death in HIV‐positive people with cryptococcal meningitis (low‐certainty evidence). Early ART initiators may be less likely to have relapses of cryptococcal meningitis (low‐certainty evidence). We were unable to draw conclusions regarding IRIS frequency as the certainty of the evidence contributing to the IRIS assessment was very low. We are uncertain as to whether or not early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (very low‐certainty evidence).

Overall, few trials met the inclusion criteria for this review, which made it hard to draw definite conclusions on the association between ART timing and cryptococcal meningitis in HIV‐positive people.

How up to date is the review?

We searched for studies up to 7 August 2017.