Intensified antiretroviral therapy does not reduce deaths among people starting HIV treatment with advanced disease

04 Dec 2018

Adding a fourth drug, from a different class, to standard triple-drug antiretroviral therapy for the first 12 weeks for people starting HIV treatment with advanced disease, does not reduce deaths,  according to the results of the REALITY trial, published today in PLoS Medicine.

Many people with HIV in Africa do not start antiretroviral therapy (ART) until their immune system has been badly damaged by the disease. People with low CD4 counts (a measure of the strength of the immune system) when they start HIV treatment are at a high risk of dying within the first few weeks of treatment. Around one in five people starting ART in Africa have CD4 cell counts of less than 100cells/mm3, which is very low.

The REALITY trial looked at ways to reduce these deaths in the early stages of treatment. It tested three strategies, in addition to standard HIV treatment, for the first 12 weeks of treatment:

  • Enhanced prophylaxis to prevent infections
  • Increasing the potency of ART by adding the anti-HIV drug raltegravir to reduce the amount of virus in the blood faster
  • Ready-to-Use Supplementary Food to improve nutritional status

The results published today focus on the second of these strategies: adding raltegravir to standard triple-drug antiretroviral therapy.

Raltegravir is a drug from the integrase inhibitor class. It is highly active and well tolerated. It was thought that adding it to standard triple-drug antiretroviral therapy would bring down the viral load (amount of virus in the blood) faster, and that might reduce early deaths and illnesses.

In the REALITY trial, 902 people were randomised to receive standard triple-drug antiretroviral therapy plus raltegravir for the first 12 weeks of treatment, and 903 people were randomised to standard triple-drug antiretroviral therapy. Participants were followed-up for 48 weeks.

Raltegravir did lead to faster declines in HIV viral load, but there were no significant differences in deaths within 24 weeks of starting treatment. Nor were there differences in clinical disease progression or side-effects.

While the rapid reduction in viral loads did not lead to a reduction in deaths, it may have potential for reducing onward transmission of the disease. This might be particularly useful for women who are identified as HIV-infected during pregnancy, to prevent the virus being passed to their baby.

One of the concerns about adding raltegravir to triple-drug antiretroviral therapy was that such a rapid reduction in viral load might lead to more cases immune reconstitution inflammatory syndrome (IRIS). IRIS is when the immune system begins to recover, but then reacts too strongly to opportunistic infections. The REALITY trial saw no evidence of an increase in cases of IRIS among patients in the raltegravir group. This is reassuring, as international guidelines are changing to recommend integrase inhibitors become part of standard triple-drug first-line antiretroviral therapy.

Around 1 in 10 people in the trial, who all started ART very late, died. This shows the need for effective interventions to help people starting ART late to get through the first few months of treatment. Another of the approaches tested in the REALITY trial, an enhanced package of prophylaxis to reduce infections, was successful in reducing deaths by around one third.

The REALITY trial was led by the MRC Clinical Trials Unit at UCL, in collaboration with: Joint Clinical Research Centre (JCRC), Kampala, Fort Portal, Mbarara, Mbale, and Gulu, Uganda; University of Zimbabwe Clinical Research Centre (UZCRC), Harare, Zimbabwe; University of Malawi, Department of Medicine, Blantyre, Malawi; Moi University Clinical Research Centre (MUCRC), Eldoret, Kenya; and KEMRI Wellcome Trust Centre, Kilifi, Kenya. The REALITY trial was funded by the Department for International Development, UK (DFID), the Wellcome Trust and the Medical Research Council (MRC) UK. Additional funding support is provided by the PENTA foundation.

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