Even HIV (human immunodeficiency virus) patients with relatively high CD4 counts are at an increased risk of death compared to people in the general population, according to a new EU-funded study published in the journal The Lancet. Although the increased risk is relatively small, the findings underline the importance of carrying out further studies into the risks and benefits of starting anti-retroviral therapy (ART) at higher cell counts. EU support for the work came from the NEAT ('European AIDS (acquired immune deficiency syndrome) treatment network') project, which was funded under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6). CD4 cells are white blood cells that represent an important component of the immune system, playing a role in the body's efforts to fight infection. In healthy, HIV negative people, there are usually between 600 and 1,200 CD4 cells per microlitre of blood. In people with HIV, the virus breaks into CD4 cells and destroys them, thereby weakening the immune system. Clinicians therefore routinely check the levels of CD4 cells in the blood of HIV positive people. Currently, guidelines suggest that patients start taking ART when their CD4 count falls below 350 cells per microlitre. However, some studies have suggested that it may be beneficial for patients to start taking antiviral drugs while their CD4 counts are higher. The question of when to start treatment is far from simple, as the drugs used to treat HIV are highly toxic; therefore, giving them to patients that do not need them could be harmful. This study is the first to investigate the risk of death in HIV positive people with higher CD4 counts who have never taken ART. In total, the team tracked the fate of over 40,000 patients in Europe and North America. The patients were categorised into four groups: men who have sex with men; injecting drug users; heterosexual people and those whose risk factors are unknown. Overall, the study revealed that death rates in HIV positive people with CD4 counts over 350 are higher than in the general population. However, there was a lot of variation between the groups. The risk of death was highest for injecting drug users (who were more than nine times more likely to die) and heterosexual people (who were almost three times more likely to die than people in the general population). In contrast, the risk of death in men who have sex with men was just 30% higher than in the general population. 'The increase in risk was substantial in injecting drug users and the heterosexual group but was small in men who have sex with men,' the researchers write. 'This finding suggests that much of the raised risk in the former two risk groups probably results from confounding by socioeconomic and lifestyle factors rather than being an effect of HIV infection itself. The magnitude of the raised risk in the MSM [men who have sex with men] group is more likely to reflect the effect of HIV itself.' According to the researchers, this finding is in line with earlier studies that some patients' social circumstances raise their risk of death more than the HIV itself. In addition, the team compared the risk of death for patients with differing CD4 counts. They found that compared to those with CD4 counts of 350-499 cell per microlitre, people with counts in the range of 500-699 cells per microlitre were 23% less likely to die and people with counts of 700 cells per microlitre were 34% less likely to die. 'These data suggest that people with HIV who have not taken ART and have a CD4 count greater than 350 cells per microlitre have a raised risk of death compared with the general uninfected population, although the increase seems to be small,' the researchers conclude. 'Because ART might reduce the risk of death in such patients, these findings support the need for continuing studies... of the risks and benefits of starting ART at CD4 counts greater than 350 cells per microlitre.' In an accompanying editorial, Ingrid Bassett of Massachusetts General Hospital in the US and Paul Sax of Harvard Medical School in the US note that many of these deaths are from diseases and conditions that are not covered by the clinical definition of AIDS. 'A proposed mechanism for how HIV infection might increase the risk of these non-AIDS events includes the harmful effects of chronic inflammation, immune activation and subclinical immunodeficiency,' they explain. Commenting on the fact that many of the deaths can probably be attributed to lifestyle factors, and not HIV itself, they recommend that clinicians 'aggressively screen, prevent and treat' risk factors such as tobacco use, injecting drug use, high blood pressure, obesity and diabetes that may be driving these raised levels of mortality among people in the early stages of HIV infection. They conclude with a warning: 'Even for those with relative immune competence, HIV infection remains a foe with many faces.'