Q+A with Professor Ravi Gupta on antiretroviral resistance

There were approximately 36.7 million people worldwide living with HIV/AIDS at the end of 2015. Of these, 1.8 million were under 15 years old. For people living with HIV, antiretroviral treatment (ART) has been a life-saver. ART stops HIV from making copies of itself and prevents HIV from attacking the body’s immune system. However, resistance can occur when ART regimens are not taken as prescribed, which allows HIV to make copies of itself and increases the risk that the virus will mutate and produce drug-resistant HIV. In addition, some patients are infected with a multidrug resistant form of HIV.

The BRC spoke to Professor Ravi Gupta about his research into the resistance of HIV to antiretroviral drugs, the global consequences and the future for new treatments and further resistance.

Tell us about yourself as a researcher and how you became interested in antiretroviral resistance research?

I am an infectious diseases clinician with an interest in how infectious diseases can impact global public health. Some years ago I became concerned about consequences of mass treatment with antiretroviral drugs, specifically drug resistance.

My research group, based in the Gupta Lab at UCL, is exploring not only population level drug resistance, but also fundamental biology into the mechanisms of drug resistance and exploration of how HIV infects and replicates in cells. This fundamental work could deepen our understanding of evolution of HIV resistance and also contribute to better understanding of HIV transmission and the establishment of viral latent reservoirs – a group of immune cells persisting in the body for decades that are infected with HIV but are not actively producing new HIV.

What could be the global consequences of HIV antiretroviral resistance?

Globally, HIV drug resistance is on the rise with some countries reporting levels at or above 10% among those starting ART, and up to 40% among people restarting ART. Because of treatment failure, HIV is progressing to Aids (the most advanced stage of HIV infection); the World Health Organization (WHO) estimates there will be almost half a million deaths directly linked to antiretroviral resistance between 2016 and 2021.

If levels of drug resistance reached critical levels for individuals with HIV their ART regimens would no longer be able to stop the HIV in their bodies from making copies of itself and they would then have to be switched to more expensive second-line regimens, if available. For countries with limited resources already struggling to provide ART to those who need it, this is likely to mean that fewer people could be started on ART. In turn, if a high percentage of the population develops drug resistance we could see large increases in Aids-related deaths and the economic burden of higher healthcare costs.

The problems we face globally are also evident here in the UK – the annual cost of providing HIV treatment and care in the UK is almost £1 billion and it is estimated that 100,000 people living with HIV will be taking antiretroviral therapy by 2019. This number could be even higher if efforts to find and treat the estimated 20-25% of undiagnosed infections are successful.

How is research investigating new ways to combat antiretroviral resistance?

There are numerous ways in which research is seeking to combat antiretroviral resistance. The development of novel therapeutics is one. We need not only new anti-HIV agents but also new drugs that reactivate ‘silenced’ HIV for subsequent eradication by existing antivirals. If successful, such an approach would convert the current therapeutic endeavours from prevention and maintenance of HIV to a treatment that may eliminate the viral reservoir. I am on the steering group for the CHERUB (Collaborative HIV Eradication of viral Reservoirs: UK BRC) collaboration, which consists of Biomedical Research Centres working to develop and promote a coordinated UK-wide response to the need to explore strategies targeting HIV eradication and remission.

My research is also looking at better ways to use existing drugs, in particular protease inhibitors – a highly potent class of drug. These drugs are usually reserved for patients whose first line regimen has failed, with accompanying drug resistance. We are learning that not all individuals respond in the same way even if they take their medication properly, this is partly due to the genetic variability in strains across the world.

As HIV is one of the most diverse viruses that infect our human population we can't look at it as a single strain. My research team investigates different virus strains in an effort to understand them better and find out more about which strains are resistant to different drugs. In January 2016 I was lead author on a paper published in Lancet Infectious Diseases which found resistance to tenofovir, an antiretroviral drug vital to most modern HIV treatment and prevention strategies, is surprisingly and worryingly common in developing countries. These results came about after studying around 2,000 HIV patients across the world with uncontrolled HIV despite being prescribed antiretrovirals. A follow up paper about to appear in the same journal on World AIDS day this year (1 December) has shown that patients appear to be seeking treatment at more than one centre without disclosing prior treatment. The impact is that such individuals frequently have drug resistance that leads to treatment failure and multi-drug resistant HIV. Such individuals are unaware of this given limited access to resistance testing in resource limited settings.

What is the outlook for new drugs and further resistance?

The outlook for the development new drugs is promising but enormous challenges remain, primarily around access to HIV drugs in developing countries, which can be divided into two broad categories:  the cost of drugs and poor health infrastructures in the context of WHO recommendations to now treat all patients with HIV regardless of immune status. Lack of adequate drug supply chains, clinics, hospital beds, laboratories and a shortage of skilled health care professionals are all important issues.

With regards to further resistance, effective surveillance for its transmission is crucial, as well as development and implementation of point of care viral loads to diagnose treatment failure quickly before virus resistance develops. We would also welcome simple drug resistance tests to use at the bedside so that appropriate drugs can be selected.