Thursday 20 September 2018
This blog post was written by Professor Jonathan Weber at:
Since 1982 Professor Jonathan Weber has conducted extensive research into HIV and AIDS. The development of an effective treatment for HIV infection through combining anti-retroviral drugs came as direct result of research led by the Medical Research Council (MRC) in close collaboration with Professor Weber’s department St Mary’s – alongside industry and colleagues in France and Holland – and has enabled people with HIV to achieve a normal life expectancy. Professor Weber is Dean of the Faculty of Medicine and Jefferiss Professor of Communicable Disease and GU Medicine at Imperial College London. He retired from clinical practice in October 2017 after 35 years at St Mary’s. Here he reflects on his career, research and plans to develop an HIV vaccine.
In April 1982, I was a young doctor with an interest in infectious diseases when my mentor, Professor Philip Marsden, mentioned a new disease he’d seen in New York, which was affecting young gay men and had all the hallmarks of a sexually transmitted infection. He suggested it would be interesting to look for this new disease in London and thought St Mary’s Hospital might be a good starting point. So in August 1982, I joined Dr Willie Harris’ Praed St Clinic, looking at the immune system of gay men who visited the clinic, guided by immunologist Professor Tony Pinching and virologist Professor Don Jeffries.
I was fortunate to be able to work on my research full-time from early 1983, thanks to a grant from the Wellcome Trust; I had gathered a cohort of 400 gay men at the clinic and examined their immune systems. What my colleagues and I discovered was that all the men in the cohort had abnormal immune systems; they all had a low number of the white blood cells known as CD4+ T-cells and low CD4:CD8 t-cell ratios. They also had enlarged lymph nodes in their necks, armpits and groin, which is usually a sign that the body is trying to fight an infection. These observations led us to believe that all the patients in the cohort had an early manifestation of AIDS; it was a chilling insight into the scale of the unfolding AIDS epidemic.
The first breakthrough came in the middle of 1983 when Montagnier and Barre-Sinoussi, French virologists, reported a novel retrovirus isolated from an AIDS patient. In mid-1984 Gallo and others confirmed this virus, now called HIV-1, as the cause of AIDS. For researchers this discovery opened up a world of opportunities in terms of understanding the nature of the virus and how it leads to AIDS, as well as the potential for a vaccine to prevent infection and drugs to treat infected patients. But while this initial discovery offered hope to researchers, at that time there was little we could do for the patients beyond treating the consequences of HIV infection – like the opportunist infections and tumours.
We treated our first patient with AIDS towards the end of 1982 and from that point onwards, there has never been a time at St Mary’s Hospital when there has not been an HIV/AIDS in-patient. Between 1982 and 1985, the number had increased dramatically and we had two full wards of HIV/AIDS patients – a fifth of the acute medical beds at St Mary’s Hospital. HIV/AIDS soon became a major public health emergency in London and around the world, and as a result, more money began to be invested in research, care and the prevention of infection. From 1988, we treated patients with a drug called Zidovudine – originally developed in a US cancer programme but shown to have anti-retroviral activity. However, in 1992, the Anglo-French Concorde trial showed that Zidovudine alone could not prevent people with HIV from developing AIDS.
The late 1980s and early 1990s were desperate times; there was one death a day at St Mary’s Hospital of young gay men – a picture seen across the globe as AIDS wiped out a generation. There was the added challenge of stigma, the public perception that AIDS was a sexually transmissible virus which only targeted gay men, intra-venous drug users and African men and women.
Through the late eighties, a series of drugs were developed by the pharmaceutical industry in the hope of effectively treating patients with HIV and AIDS. In 1991 I set up a clinical trials unit at the Winston Churchill wing at St Mary’s Hospital to look at these new drugs and their impact on patients. In 1994, the MRC Delta trial led to a significant breakthrough. We found that by using a combination of two of these drugs together, you could stop patients with HIV from developing AIDS. This was a game changer as it demonstrated that the natural history of HIV infection could be reversed by combinations of antiretroviral drugs and following Delta, and a similar US trial, there was flurry of activity to figure out how to put these combinations of drugs together. Ultimately the findings of this research led to the three-drug combinations which remain the main treatment for HIV today.
Untreated, HIV is 100 per cent fatal, unusual in infectious diseases. However, as soon as the drugs were licensed for combination use in 1996, we started to see results in patients – it was extraordinary. It became clear that you could intervene with a combination of drugs, and as a result people with HIV/AIDS could begin to lead a healthy, normal life and the mood among patient and medical communities finally began to lift. That was an extraordinary moment that I will never forget. These combination antiretroviral regimes are now so simple (one pill, once and day) and so potent that our patients are on track for a normal life expectancy.
From 1985 onwards, I have also been involved in HIV vaccine research. From 1991, we have undertaken a series of phase I and small phase II studies of experimental HIV vaccine products at St Mary’s and with European and African colleagues. I am now leading the first-ever European HIV vaccine efficacy trial in four African countries, where prevention still remains a major public health concern. We plan to trial experimental HIV vaccine products and our hypothesis is that these vaccine products, when used in combination, can induce protective immunity to commonly transmitted HIV strains in East and Southern Africa. The trial started in January 2018 and we will start actively immunising people from first quarter of 2019. We hope to see interim results in late 2021.
I’ve retired from clinical practice now, but working with HIV/AIDS patients was undoubtedly the highlight of my clinical career. In the early ‘80s, medicine did not really consider patients as partners in research. But our HIV/AIDS patients were both enthusiastic about research into the disease and desperate to see a therapy emerge. Their active contributions enabled us to take a collaborative approach – a true partnership between patients, researchers and clinicians. I think this experience has subsequently led to changes in how we work with patients on the development of treatments for a huge range of different diseases.
Over the course of my 35-year clinical career it has been amazing to see how far we have come in HIV treatment. At the beginning of this journey, it was extremely tough but the clinical translation of fundamental science from the mid-1980s onwards allowed us to transform this infection from a death sentence to a fully manageable chronic condition.
HIV/AIDS is still a global problem. Around three million new cases of HIV infections are still reported world-wide each year and in London around 3,000 gay men became infected in 2016 alone. Drugs can manage the disease, but I believe that we will need a vaccine to eradicate HIV infection, and this is my vision and hope for the future.
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