London School of Hygiene & Tropical Medicine

HIV drug resistance to tenofovir, an antiretroviral drug vital to most modern HIV treatment and prevention strategies, is surprisingly and worryingly common, according to a large study published in The Lancet Infectious Diseases.

The study involved researchers at UCL and Stanford University, and was co-authored by Dr John Gregson from the London School of Hygiene & Tropical Medicine who worked on the statistical analysis.

The research studied 1,926 HIV patients across the world with uncontrolled HIV despite being prescribed antiretrovirals. They found tenofovir-resistant strains in 60% of patients in sub-Saharan Africa, in contrast to 20% of patients treated in Europe. Around two-thirds of patients with tenofovir-resistant strains had also become resistant to both other drugs in their course of treatment, indicating that their treatment had been completely compromised.

The study suggests that in Sub-Saharan Africa, up to 15% of HIV patients treated with tenofovir-based drug combinations will develop tenofovir resistance in the first year of treatment alone, with this figure rising over time. Resistant strains could be passed on to other individuals, becoming more widespread and potentially compromising global HIV control strategies.

Study author Dr Ravi Gupta from UCL Infection & Immunity and Honorary Consultant in Infectious Diseases at University College London NHS Foundation Trust, said: "Tenofovir is a critical part of our armamentarium against HIV, so it is extremely concerning to see such a high level of resistance to this drug. It is a very potent drug with few side-effects, and there aren't any good alternatives that can be deployed using a public health approach. Tenofovir is used not only to treat HIV but also to prevent it in high-risk groups, so we urgently need to do more to combat the problem of emerging resistance."

Resistance to a drug usually occurs when a patient doesn't take their medication regularly enough. In order for first-line treatments to work, patients generally need to take their medication at least 85-90% of the time. When treatment is interrupted, the virus can develop a resistance to the drugs. Previous research has shown that tenofovir resistant strains are less able to multiply and spread in laboratory experiments. However it has not been clear whether the virus is less likely to spread in real-world conditions.

The authors say that if resistant strains of HIV were significantly less effective at spreading in people, they would expect to see lower levels of the virus in patients with the resistant strain. However, they found that virus levels were no lower in these individuals and were high enough to be fully infectious. They say the possibility that resistant strains could spread between people cannot be discounted. Further studies are underway to get a more detailed picture of how tenofovir resistant viruses develop and spread.

Patients in the study whose immune systems were already compromised when they started treatment were 50% more likely to develop tenofovir resistance, as were patients on certain other antiretroviral drugs combined with tenofovir. In many parts of Sub-Saharan Africa, particularly rural locations, drug supplies are limited so patients often can't receive treatment until they have advanced HIV disease. The problem with this approach is that by this stage the immune system is weaker so the drugs are acting alone against the virus, increasing the likelihood for failure of the drugs and also development of resistance.

Once a patient's virus becomes resistant to first-line drugs, the next stage is expensive second-line treatment with greater side effects. Many patients in rural areas do not have access to such drugs, so it is important to try to preserve the effectiveness of first-line treatments.

The authors say the study findings highlight that effective surveillance for transmission of drug resistance is crucial.

The study was funded by the Wellcome Trust.

Publication:

• John Gregson et al., Global epidemiology of drug resistance following failure of WHO recommended first line regimens for adult HIV-1 infection - a multi-centre retrospective cohort study, The Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(15)00536-8