Unexpected findings in HIV meningitis treatment trial can save lives

UCT investigators in collaboration with Ugandan and American colleagues found that HIV patients with cryptococcal meningitis "a common AIDS-related infection" should first be fully treated for the condition in hospital, and only start antiretroviral (ARV) therapy afterwards.

These surprising findings are in contrast with worldwide HIV treatment guidelines to start ARVs as soon as possible (within two weeks) in patients with advanced HIV and AIDS. Studies in patients with HIV and tuberculosis (TB) as well as in other AIDS-related opportunistic infections have shown that this strategy improves overall survival.

The large clinical trial found that waiting five to six weeks to start ARVs after cryptococcal meningitis diagnosis resulted in 15% better survival than starting ARVs one to two weeks after diagnosis.

"The implications of these findings for when to start treatment with ARVs to maximize survival in HIV+ patients are very important," says UCT investigator Associate Professor Graeme Meintjes of the Cryptococcal Optimal Antiretroviral Timing (COAT) Trial. The findings have already informed international HIV guidelines prior to their publication in the June issue of the prestigious New England Journal of Medicine.

Cryptococcal meningitis is a deadly fungal infection around and in the brain, and is now the most common cause of meningitis in adults in Africa. The fungus is found in the environment and infection occurs through inhalation. In Africa, the initial infection progresses to meningitis almost exclusively in people with advanced HIV infection and it is the second most common AIDS-related opportunistic infection after TB.

Approximately 350 000 cases of cryptococcal meningitis are estimated to occur worldwide every year, with around 7 000 of those reported by the National Institute of Communicable Diseases in South Africa. Frighteningly, during initial hospitalisation for fungal meningitis, up to 50% of patients will die in Africa.

Excess inflammation around the brain

The investigators think that the rapid improvement in immunity due to early introduction of ARVs before the cryptococcal meningitis had been fully treated results in excess inflammation around the brain and accounts for the higher death rate. Although better immune function can help fight an infection, a severely damaged immune system which is rapidly rebounding with ARVs can generate too much inflammation and actually make patients sicker.

This paradoxical reaction to therapy is known as immune reconstitution inflammatory syndrome or IRIS. Paradoxical IRIS reactions are rarely fatal for most types of infections, however, when this inflammatory reaction occurs in the brain, death can occur.

The COAT study, funded by the US National Institutes of Health, was conducted at the GF Jooste Hospital in Cape Town, and in two hospitals in Uganda. The South African study site was led by Meintjes, who works in the Clinical Infectious Diseases Research Initiative within the Institute of Infectious Disease & Molecular Medicine (IDM). Co-researchers were from the University of Minnesota in the United States, and the Mbarara and Makerere Universities in Uganda.

The clinical trial involved 177 participants, half of whom received ARVs at one to two weeks and half received deferred ARVs at five to six weeks after meningitis diagnosis. The participants were followed for one year and received standard meningitis and HIV care.

"The implication for treatment guidelines is that cryptococcal meningitis is a special situation with respect to the timing of ARVs," says Meintjes, adding that, "patients with cryptococcal meningitis, should first be fully treated for their meningitis in hospital, which usually involves 14 days of intravenous anti-fungal medications, and only start ARVs around four to six weeks after their meningitis diagnosis."