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EARNEST trial results support World Health Organisation guidelines for second-line treatment of HIV

18 July 2014

The results of the EARNEST trial, published yesterday in the New England Journal of Medicine, provide support for the current World Health Organisation (WHO) guidelines for treating people with HIV whose initial treatment is no longer working.

EARNEST was a large trial, involving 1,277 people from 5 sub-Saharan African countries. It tested how best to treat people once their initial combination of antiretroviral drugs had stopped working.

Treating HIV usually involves a combination of several drugs from different classes, which target different stages of the virus’life cycle. When people first start HIV treatment, WHO currently recommend a combination of two drugs from the NRTI class and one NNRTI drug. However, over time the virus can develop resistance to some of these drugs, meaning the treatment no longer keeps the virus under control. When this happens, people need to change to a new combination of drugs (called second-line treatment).

WHO currently recommend that the standard second-line treatment should be a combination of a boosted PI (a different class of drug) plus two NRTI drugs. EARNEST tested whether replacing the two NRTI drugs with a drug called raltegravir (which is from the INSTI class)improves second-line treatment. It was thought that it could, as the virus may already have resistance to NRTI drugs, but is unlikely to be resistant to raltegravir.

EARNEST also tested whether giving the PI drug on its own (after 12 weeks of PI plus raltegravir) was as good as a combination of PI plus two NRTIs. It was thought that this approach may reduce side-effects without losing treatment effectiveness.

After almost two years on second-line treatment, EARNEST found that the combination of PI plus two NRTIs was safe and effective. This combination does well even when the drugs are selected without resistance testing, and when routine laboratory monitoring for side-effects is not available (which is the case in most sub-Saharan African countries).

The group who received the combination of the PI plus raltegravir had similar (equally good) HIV disease control to those who received the PI plus two NRTIs. However, raltegravir did not offer clear advantages over the two NRTIs, and its higher cost means that its use is not justified in public health programmes in this setting. The group who received the PI on its own did not have as good HIV disease control as the two other groups. The virus levels were more likely to be high, and resistance to the PI drug was more common in this group after almost two years. This suggests that the NRTI drugs do play an important part in second-line treatment, even in people whose virus has developed resistance to that class of drugs.

The results of EARNEST are highly relevant to sub-Saharan African settings, and other places with limited access to laboratory facilities. The second-line drugs in the trial were chosen without the doctor being able to test which drugs the virus had developed resistance to. Patients were monitored clinically, and regular tests to check the strength of their immune system were done every 3-4 months (typical of the usual monitoring in these African settings). Patients were given adherence counselling to help them keep taking their drugs regularly. But no regular viral load monitoring was available to doctors, as this test is currently not used routinely in public treatment programmes in most parts of Africa.

These results of EARNEST are surprising, but provide good evidence to support the current WHO recommendations for using a combination of a PI plus two NRTIs to treat people whose initial HIV treatment is no longer working.