Although HIV/AIDS cannot be cured, HIV replication in the body can be suppressed through use of combinations of antiretroviral drugs – so-called highly active antiretroviral therapy, or HAART. Long-term use of HAART protects the immune system, allowing HIV-positive individuals to lead relatively normal lives and greatly extend their life expectancy. But HAART is not without complications: the drug combinations have to be taken continuously, probably for life. Many of the drugs have side-effects, and the long-term impact of HAART is still unclear. And HAART is expensive – currently about £7500 (US$10 000) per person per year in the developed world.

So, with no effective vaccine and prevention campaigns only intermittently successful, research efforts to optimise the effects of combination antiretroviral drug therapy are of great importance.

Early infection

Since 1999, Professor Jonathan Weber of Imperial College London and Professor Rodney Phillips at the University of Oxford have been studying virus behaviour and the body’s immune responses to it on a joint Wellcome Trust programme grant. Their research is suggesting new ways in which the virus could be targeted.

HIV is a slow, insidious killer, infecting and gradually destroying immune cells – CD4 or T ‘helper’ cells – that normally protect us from infectious agents.

Early in the course of infection there is an initial phase of very rapid viral proliferation. The body then fights back as immune responses kick in (seroconversion), clearing most of the virus from the blood but never absolutely eliminating it from the body. After this acute phase, lasting two to four weeks, a war of attrition develops over ten or more years, as HIV gradually depletes the body’s remaining stock of CD4 cells, inexorably paralysing the body’s ability to fight off infections.

Research from Professors Phillips and Weber, and others, has suggested that HAART may protect HIV-specific CD4 T-helper cells from HIV-induced destruction during primary infection, and so enhance anti-HIV immunity in infected patients. However, a pilot study in 100 patients with primary HIV infection conducted at St Mary’s Hospital, London, has shown that a short course of HAART at HIV seroconversion has very variable effects.

In order to get a definitive answer to the use of HAART at primary infection, they have established an international collaboration of researchers with £4.8 million of Wellcome Trust funding to test their theory of HIV immune control: that a short course of HAART at the earliest stage of HIV infection might have long-term benefit to the immune control of the virus in those living with HIV.

As it is not clear how best to treat patients with primary infection, or even whether HAART will have a long-term benefit at all in this group, the ‘Spartac trial’, will have three arms: a short course of HAART for 12 weeks, a long course for 48 weeks, and a no-therapy arm. All patients entering the study will be randomised to one of these three arms.

“The short-course treatment won’t be a cure, but if our theory is correct a few weeks’ treatment at this critical stage of infection could help the body’s immune system make a more effective response against infection, and hence delay the time when HAART will be again required,” says study leader Professor Weber.

“We are testing the concept that early suppression of the virus might limit damage to the immune system,” adds Professor Phillips. Antiretroviral therapy at this earliest stage of HIV infection might also shorten the period when patients are highly infectious, and may lead to reduced transmission, which would have a further effect at a population level.

Multinational recruitment

The team plans to recruit around 400 patients in the UK, Dublin, Moscow, Johannesburg, Durban, KwaZulu-Natal (South Africa) and Australia. The participants will be men and women aged 18-plus from a variety of backgrounds. The clinical trial itself has been designed in close collaboration with Professor Abdel Babiker of the UK Medical Research Council Clinical Trials Unit in London, which will be responsible for the overall coordination of the trial, including monitoring, collection and analysis of data. The MRC Unit has an outstanding track record in HIV clinical trials, and is already working on the complex statistical analysis that will be required to understand the relationship between the immunology and virology data from the Spartac trial.

In KwaZulu-Natal the trial will be monitored at the Africa Centre for Health and Population Studies, a Wellcome Trust-funded research base in Hlabisa District, where the prevalence of HIV is up to 38 per cent. The centre has already established a demographic surveillance survey of 80 000 residents and has various AIDS-related studies underway.

Dr Michael Bennish, Director of the Africa Centre, is well aware of the ethical difficulties of carrying out research in a population that currently has little or no access to the products being tested.

“We carry out research and do not currently have the capability to provide lifelong care. But I think it’s fair to say that five years of assured therapy is better than the other currently available option – which is nothing and then death.” Moreover, the possibility of antiretroviral drugs being more routinely available in KwaZulu-Natal is beginning to look more promising.

The Russian arm of the study will be coordinated by Professor Vadim Pokrovskiy, Head of the Russian Federal Aids Centre (RFAC) in Moscow, and virologist colleague Dr Aleksei Bobkov at the D I Ivanovsky Institute of Virology, also in the capital. There has been a long-standing research collaboration between Moscow and Imperial College initiated in 1988 by the UK Department of Health, and latterly funded by a Wellcome Trust collaborative award.

They hope to recruit at least 120 patients comprising a mix of factory workers and office staff, with more than half being heterosexual partners of those known to be infected with HIV. They will be under continual observation at the RFAC and will get free antiretrovirals for life once their CD4 count has declined to critical levels, as prescribed by federal AIDS law. “We have a letter from the Russian Ministry of Health confirming this,” says Professor Pokrovskiy.

Russia’s HIV epidemic is believed to be growing faster than anywhere else in the world. There are 240 000 registered cases but health officials fear the true figure could be four times as high. The disease first took hold of drug users and has now moved into its second wave as infection is being passed on through sexual contact.

In Australia, the trial will be coordinated by the National Centre in HIV Epidemiology and Clinical Research (NCHECR) in Sydney. The NCHECR, headed by Professor David Cooper, has an outstanding history in the design and coordination of HIV clinical trials.

In the British Isles, where there are estimated to be over 40 000 people with HIV, patients will be recruited at clinics in London and Brighton, both high-risk areas, as well as Dublin.

Treatment

Eligible patients will be randomised into the Spartac trial, and those in the short or long treatment arms will be treated with a cocktail of lopinavir/ritonavir (Kaletra, Abbott laboratories) and a combination zidovudine (AZT) and lamivudine (3TC), known as Combivir (GlaxoSmithKline) which will cost in the region of £125 per month per patient. Levels of HIV-specific immunity will be monitored for just over a year, and virus levels and CD4 T cell numbers will be assessed thereafter.

The speed of intervention is crucial, says Professor Phillips. “This is when the virus can cause most damage to the immune system. We aim to see if using antiretrovirals at this earliest stage will dampen down the virus long after the drugs have ceased. If this works it should mean shorter-term treatment with drugs that often have pretty bad side-effects and are, of course, expensive.”

Even if the theory doesn’t stand up, the study will still provide useful information: “We expect this study to give a definitive answer to the question of the use of HAART at primary HIV infection,” says Professor Weber, “but whatever the result, we will better understand the biology of primary infection and the pathogenesis of AIDS.”