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Early treatment for HIV slows damage to immune system and reduces risk of transmission, study suggests

17 January 2013

A 48-week course of antiretroviral medication taken in the early stages of HIV infection slows the damage to the immune system and delays the need for long-term treatment, according to research published today in the ‘New England Journal of Medicine’ (1). However, the delay was only marginally longer than the time already spent on treatment.

The study, the largest clinical trial ever undertaken looking at treating people with recent HIV infection, also suggests that the treatment lowers the amount of virus in the blood for up to 60 weeks after it is stopped, which potentially reduces the risk of onward transmission.

SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion), a randomised controlled trial, took place over five years and involved 366 adults - mainly heterosexual women and gay men - from Australia, Brazil, Ireland, Italy, South Africa, Spain, Uganda and the UK. It was funded by the Wellcome Trust and coordinated by researchers from Imperial College London and the Medical Research Council's Clinical Trials Unit, with immunology research conducted by the University of Oxford.

Unless regularly tested, most people will be unaware that they are HIV positive in the first few years after they have become infected. Initial symptoms can be similar to those of flu or other viral infections, and for most people, there follows a period of many years when they carry the virus but are not sick.

The immune system never successfully clears HIV, however; instead, the virus hides away, slowly weakening the body's defences and destroying CD4 T-cells, which play a key part in the immune response. Without treatment, the immune system steadily becomes more compromised, leaving the individual at increased risk of developing other life-threatening infections.

To stop this from happening, when the number of remaining CD4 T-cells reaches a certain level (350 cells per cubic millimetre), international treatment guidelines recommend that an individual begins lifelong treatment with antiretroviral drugs. These drugs not only prevent further damage to the immune system but also allow it to recover.

Several observational studies have suggested that treatment at the time HIV infection occurs could delay the amount and speed of immune damage and so delay the need to start lifelong antiretroviral medication. SPARTAC is the first large randomised study to test this hypothesis.

All volunteers in the SPARTAC trial were identified within six months of becoming infected with HIV and were randomly allocated to receive antiretrovirals for 48 weeks or 12 weeks, or to receive no medication (the standard practice in HIV management at this stage of infection). The researchers then measured the time until each volunteer's CD4 T-cell count fell below 350 cells per cubic millimetre and/or they began a lifelong course of antiretroviral medication.

The researchers found that on average, participants who had received no medication needed to begin taking a lifelong course of treatment 157 weeks after infection. Those in the group receiving antiretrovirals for 12 weeks began their lifelong course of treatment on average 184 weeks after infection (a delay of 27 weeks, but not considered by the researchers to be a significant effect).

However, those volunteers who received antiretrovirals for 48 weeks took an average of 222 weeks before beginning long-term treatment - a delay of 65 weeks. This represents an important delay compared with no treatment or 12 weeks of medication, but overall was not significantly longer than the time those participants had already spent on treatment.

In addition, over the whole time in the study, participants on the 48-week course had higher CD4 T-cell counts than those in the other two treatment groups, potentially reducing their risk of developing secondary infections such as tuberculosis. They also had lower levels of HIV in the blood for more than a year after stopping treatment compared to the other volunteers, which could play a part in reducing the risk of passing on the virus to sexual partners.

The researchers found no evidence that treatment within the first six months of infection led to the virus becoming resistant to the drugs or that coming off the course led to unexpected deaths or damage to the immune system.

A separate analysis of the results suggested that the 48-week treatment was more beneficial the closer it was started to the time of infection. Participants who were enrolled closer to the time of HIV infection tended to have faster declines in the number of CD4 cells if they did not receive treatment, indicating greater damage to their immune systems. It was among this group that the 48-week treatment seemed to have the biggest benefit.

It is unclear why these people were coming to see a clinician so early after infection, however; the researchers believe it may be that they had felt unwell. More research focusing on people in the very early stages of infection, a challenging group to identify, needs to be done to confirm this observation.

Dr Sarah Fidler from Imperial College London, who led the study, says: "These results are promising and suggest that a year-long course of treatment for people recently infected with HIV may have some benefit on the immune system, as well as helping control the virus.

"The treatment also reduces the amount of virus in the body for some time after the patient has stopped taking the medication. This could be very important for helping reduce the risk of passing on the virus to a sexual partner."

Professor Jonathan Weber, the chief study investigator, says that the study reinforces the importance of frequent testing for HIV, particularly among high-risk groups: "Early testing and diagnosis are incredibly important. When a person first contracts HIV, they are at their most infectious, but they are also often unaware that they have contracted the disease and hence are more likely to spread the infection.

"The sooner they can be diagnosed, the better our chances of limiting the spread of the virus and the sooner they can be offered appropriate guidance and counselling. If, as our study suggests, they can then be treated in such a way as to slow the progression of the disease and reduce their risk of secondary infections from potentially deadly diseases such as TB, then this offers a win-win situation."

Professor Gita Ramjee, Director of the South African Medical Research Council's HIV Prevention Research Unit, who led from the South African sites, adds: "We now need to weigh up whether the benefits offered by early intervention are outweighed by the strategic and financial challenges such a change in policy would incur, particularly in resource-poor settings such as Africa, although this may be where the most benefits are seen in terms of TB rates."

In the same edition of the 'New England Journal of Medicine', a large observational study (2) of immune function among individuals with recent infection shows that early initiation of antiretroviral therapy - within four months of infection - is accompanied by an enhanced recovery of the immune system that is not seen to the same extent if treatment is started in later stages of infection.

These findings support the main trial result of the SPARTAC study. In an accompanying editorial addressing both these studies, Walker and Hirsch comment that there is now increasing evidence of the value of early treatment to the individual and inferred benefit at a population level of reducing infectiousness.

Combating infectious diseases is one of the strategic priorities of the Wellcome Trust, which funded the SPARTAC study. Commenting on the research, Dr Jimmy Whitworth, Head of International Activities at the Wellcome Trust, said: "This study adds to increasing evidence that early initiation of HIV treatment is of benefit to the individual in preventing severe disease and in reducing infectiousness to his or her partners. Questions remain about whether a longer course at an early stage could be more beneficial or whether early treatment should be continued for life."

Image: AIDS ribbons marching. Credit: Stevie Taylor, Wellcome Images.

Contact

Craig Brierley
Media Relations Manager
Wellcome Trust
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+44 (0)20 7611 7329
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c.brierley@wellcome.ac.uk

Notes for editors

References
(1) SPARTAC Trial Investigators. The effect of short-course antiretroviral therapy in primary HIV infection: final results from SPARTAC, an international randomized controlled trial. NEJM 2013 (epub ahead of print).

(2) Le T et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. NEJM 2013 (epub ahead of print).

About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.

About Imperial College London
Consistently rated among the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14 000 students and 6000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.

In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK's first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

The International Clinical Trial Research Management Office is part of the Division of Medicine at Imperial College and manages a number of large international research grants which include multi-centre clinical trials of HIV prevention technologies and treatment of HIV infection as well as other non-HIV related trials.

About the Medical Research Council Clinical Trials Unit
The Medical Research Council Clinical Trials Unit is one of the UK's leading centres for clinical research. It specialises in cancer and HIV/AIDS, but also undertakes research in other areas, including tuberculosis, rheumatoid arthritis, and mental health. Unit staff design, conduct, analyse and publish clinical trials, observational studies, meta-analyses and other systematic reviews of clinical or public health importance.

About Oxford University's Medical Sciences Division
Oxford University’s Medical Sciences Division is recognized internationally for its outstanding research and teaching, attracting the brightest minds from all over the world. It is one of the largest biomedical research centres in Europe, with over 2500 people involved in research and more than 2800 students, and brings in around two-thirds of Oxford University's external research income. Listed by itself, that would make it the fifth largest university in the UK in terms of research grants and contracts.

Oxford is home to the UK's top-ranked medical school, and partnerships with the local NHS Trusts enable patients to benefit from the close links between medical research and healthcare delivery. 14 winners of the Nobel Prize for Physiology or Medicine worked or were educated at Oxford, and the division is home to 29 Fellows of the Royal Society and 68 Fellows of the Academy of Medical Sciences.

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