The search for a cure

It’s 30 years since Professor Sarah Fidler (PhD Medicine 1997) was a house officer at King’s College Hospital in chest medicine and infectious diseases, but she still has vivid memories of those shocking days.

“We were seeing so many young patients. I was in my mid-20s, and they were the same age as me. Some were haemophiliacs, some were gay men, and they were all dying, but there wasn’t any treatment,” she recalls.

This was eight years after the US Centers for Disease Control first reported five cases of a rare pneumonia affecting young gay men in Los Angeles, and the AIDS epidemic began.

“By 1989, the average time between coming into hospital with an AIDS diagnosis and death was two years, and there was this huge stigma,” say Fidler, now a Professor in the Department of Infectious Disease at Imperial and a consultant physician at the Imperial College Healthcare NHS Trust.

“I remember caring for patients in side rooms. Nurses and porters were too frightened to wheel patients to x-ray or change sheets, so we just did it.”

Alongside the stigma, AIDS also presented Fidler and her colleagues with a medical mystery they were determined to unravel.

“It was very interesting medicine, because nobody knew what to do, so it was hugely challenging,” she says.

“And I worked with consultants who were very inspiring and creative – we had to be, because none of us knew what to try.”

One of those inspiring figures was Professor Jonathan Weber, Dean of the Faculty of Medicine, who entered the field in 1982 – before HIV/AIDS even had a name – and set up a clinic for AIDS patients at St Mary’s Hospital.

He also conducted the first UK study into the natural history of this troublingly strange new disease.

“I recruited 400 volunteer gay men who I thought were at risk of AIDS because they had swollen lymph nodes, and followed them up for two years.

"It gave us some idea of the time course of the disease and its manifestations,” he says.

“Between 1982 and the end of 1984, big inner-city hospitals across Europe and North America began filling up with AIDS patients. It was a very frightening time.”

The first signs of hope emerged from France in May 1983, where the virus that caused AIDS was discovered. “Nailing the virus was a breakthrough,” says Weber.

“It opened up this extraordinary area of research because it meant we could now identify infected patients and start looking for both a vaccine and a treatment.”

But neither looked easy. Only one specific antiviral drug – acyclovir – had ever been invented, and developing a vaccine with no viable animal model would prove an even bigger ask. But when AZT, the world’s first antiretroviral, burst on to the scene in 1987, everything changed.

Concorde

As the Anglo-French Concorde study began in October 1988, AZT was already being used by 200,000 people with HIV/AIDS for whom the drug represented their only hope.

Weber worked on Concorde, a randomised control trial of 1,750 HIV-infected patients, half of whom took AZT and half a placebo.

Reporting in The Lancet in 1993, the results showed that AZT neither halted the progress of the disease nor lengthened people’s lives.

‘Miracle AIDS drug has flopped’ screamed British tabloids, and the news was devastating for patients and researchers. For Weber, however, the trial meant something else.

“Concorde was a negative study, but it was invaluable,” he explains .

“It showed the emergence of antiviral resistance to the drug over time, and it focused our attention on the hopelessness of using a single drug to treat the disease, but, as with TB treatment 40 years earlier, a combination of drugs might work.”

From that nadir, the only way was up. Building on Concorde’s results and an explosion of drug development and clinical trials, Weber worked on Delta, a landmark UK, French and Dutch study that posed the question: if AZT alone won’t work, what happens if we combine it with a second drug?

Reporting at the end of 1995, Delta revealed that two drugs were dramatically more effective than one, reducing mortality by up to 42 per cent.

By the end of 1996, three drug combinations were licensed and became rapidly available on the NHS, where they had an astonishing impact at a terrible time.

“I can’t begin to tell you what that time was like,” says Weber. “1994-95 was the worst year for AIDS deaths in the hospital – there was one death every working day.

When the drugs arrived, the death rate fell by 90 per cent within a year. It was a penicillin-like moment in history.

"From an invariably fatal disease that inflicted miserable, terrible deaths, suddenly we saw these drugs having this powerful impact. It was the most extraordinary period.”

Great strides have been made in treating HIV, but what worries experts such as Timothy Hallett (MSc Epidemiology 2004, PhD 2007), Professor of Global Health, is that we have not yet succeeded in driving down the incidence of HIV, which in 2018 still stood at 1.7 million new cases.

As a modelling expert, Hallett has built the increasingly sophisticated mathematical models that have become central for HIV researchers and policymakers.

“Modelling is particularly important in HIV because it’s a long-term, slow-moving disease. That means you can’t track it in real time,” he explains.

By taking into account the huge complexity of the real world – from poverty and geopolitics to age and gender – Hallett’s modelling has made it possible to get the most out of HIV programmes by tailoring them to local conditions.

“There are many tools to prevent HIV, but they need to be used in the right combinations to maximise their impact,” he says.

“Modelling helps you fit your epidemic response to local epidemic contexts and use resources wisely by investing them in the most effective interventions.”

It is new interventions, however, that are preoccupying Fidler and Weber, because both believe that only a vaccine or a cure will finally bring the epidemic under control and improve the lives of the millions living with HIV.

“Although treatment has dramatically altered survival, one of the challenges for patients is taking a tablet every day. Because, as soon as people stop treatment, the virus comes back,” Fidler explains.

“That’s because there’s a reservoir of hidden HIV that’s not detected by the immune system and not affected by the treatment.”

Fidler and her team decided on a new line of attack, dubbed ‘kick and kill’. She used one drug to wake up the silent virus hiding in the reservoir cells plus a pair of vaccines to enable the immune system to recognise and destroy the HIV.

But when she tested them in a randomised control trial, RIVER, between 2015 and 2018, they proved no more effective than existing treatments.

The RIVER medical trial (2015-18)

Antiretroviral therapy (ART) has been the mainstay of HIV treatment since 1995. ART is highly effective, but taking several tablets every day for life is stressful, costly and can cause side-effects.

The Imperial-led RIVER trial (RIVER stands for Research in Viral Eradication of HIV Reservoirs) tested the 'kick and kill' approach in 60 men recently diagnosed with HIV and who had the virus under control by taking ART.

The 'kick and kill' was a randomised controlled trial: participants were enrolled and then randomly selected (like the roll of a dice) to one of two groups.

All participants received a four-drug ART; the 'control' half continued on ART alone, the 'active' half also received a drug that would force the virus to reveal itself, plus a vaccine.

ART reduces viral load to undetectable levels, but HIV remains hidden in people’s immune cells, in what are called 'reservoirs'.

If ART is stopped, these cells wake up and HIV quickly becomes detectable again. In the trial, 30 men received just the standard ART treatment, delivered in four tablets.

For half the group, RIVER used two medicines on top of the standard ART treatment.

First, a drug called vorinostat that would 'wake up' the reservoir cells that HIV is hiding in and force the virus to reveal itself and face the immune system, and, second, two vaccines to coach the body’s immune system to recognise and destroy HIV.

The 'kick' is delivered from vorinostat and the 'kill' comes from the body’s own immune system killer cells that have been trained by the vaccines.

What did RIVER find out?

'Kick and kill' proved no better at reducing the size of HIV-infected cells than ART alone, but the vaccine was very effective at boosting the immune system – to be explored in future  trials.

RIO and PrEPVacc

Despite the disappointment, RIVER confirmed that, individually, each element worked and was safe, and Fidler will soon be testing drugs that work against HIV in a completely novel way.

Known as monoclonal antibodies, they have been shown to control virus in small pilot studies, but RIO will be the first large, randomised trial to test whether this new approach works to control virus off traditional therapy.

For Weber, 2020 marks an even bigger milestone, as the HIV vaccines he first began work on in 1999 finally enter field trials.

The European project, PrEPVacc, is based on a complex protocol involving a series of three vaccines – a DNA prime, a boost based on a modified pox virus, followed by a protein that mimics the virus’s envelope –  and is a true testament to HIV researchers’ tenacity and optimism.

Holding on to one small success amid a series of five failed HIV vaccines, and relying on public funding alone as industry lost confidence in HIV vaccine development, Weber pressed on.

“Whatever immunologists tell you, it’s not possible to design a vaccine from first principles, all you can do is try, try and try again,” he concludes. “I’m an incurable optimist, otherwise I’d never have gone into this field in the first place.” 

The search for a cure: Imperial and HIV

1982: Natural history of a new disease

The first UK cohort study of the natural history of AIDS begins at St Mary's, where the 400 gay, male volunteers give researchers vital insights into the detail of this strange disease.

1985: Delta

For the first time, a trial shows using two drugs instead of one prolongs life and delays disease progression, paving the way for today's highly effective combination therapy.

1993: Concorde

In a major setback, a three-year study shows AZT fails to protect healthy HIV-positive people from developing disease, but thestudy catalyses research into combination therapy.

2015: PROUD

Pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection, but does it increase risky behaviour? Working in sexual health clinics across England, the PROUD study refuted these concerns, paving the way to wider access to PrEP.

2016: USB stick HIV test

Imperial scientists invent a quick and accurate HIV test on a USB stick. Compared with existing photocopier-sized test equipment, the device could improve testing in sub-Saharan Africa.

2018: RIVER

The three-year ‘kick and kill’ study, which uses a drug plus vaccine combination to wake up and attack hidden HIV, fails. Researchers remain committed to testing different combinations.

2019: PopART

30 per cent of people with HIV don’t know they are infected. Working in Zambia and South Africa, the largest community trial of universal test and treat shows how effective the strategy can be.

2019: European AIDS Vaccine Initiative

Imperial announces the world’s second case of HIV remission after a stem-cell transplant. The so-called London patient was treated for Hodgkin lymphoma by Imperial doctors.

2019: Microbiome

Does our microbiome affect our susceptibility to HIV infection? A $2m study led by Imperial and Canadian researchers will use cervical and rectal tissue samples to find out.

2020: RIO

Monoclonal antibodies – a new way to target HIV – will enter trials using the 'kick and kill' model. The study builds on the 2015–18 RIVER trails and the CHERUB collaboration.

2020: PrEPVacc

Start of immunisation trails with combined HIV vaccines in east and southern Africa. The culmination of more than 20 year's European and African effort, led by Imperial.