Increased mortality risk for treatment-naive patients with CD4 count below 500

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Mortality rates are higher amongst HIV-positive patients with a CD4 cell count above 350 cells/mm3 who are not taking antiretroviral treatment than those in the general population, an analysis published in the Lancet shows.

Over 40,000 patients in Europe and North America were included in the study. When compared to HIV-negative individuals of the same sex, those with HIV had a higher twelve-month mortality rate. The risk of death fell as a CD4 cell count increased, and was lowest amongst gay men.

“Death rates in ART [antiretroviral therapy]-naive people with HIV who have CD4 counts greater than 350 tend to be higher than in the general population of industrialised countries.” The investigators attribute the especially high risks of death observed for HIV-positive injecting drug users and heterosexuals to “socioeconomic and lifestyle factors”.



In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.


When using a diagnostic test, the probability that a person who does have a medical condition will receive the correct test result (i.e. positive). 

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.


Confounding exists if the true association between one factor (Factor A) and an outcome is obscured because there is a second factor (Factor B) which is associated with both Factor A and the outcome. Confounding is often a problem in observational studies when the characteristics of people in one group differ from the characteristics of people in another group. When confounding factors are known they can be measured and controlled for (see ‘multivariable analysis’), but some confounding factors are likely to be unknown or unmeasured. This can lead to biased results. Confounding is not usually a problem in randomised controlled trials. 

Mortality rates were lower for patients with a CD4 cell count above 500 cells/mm3 – and especially for those with a count above 700 cells/mm3 – a finding which is likely to contribute to the ongoing debate about the best time to start antiretroviral treatment.

Indeed, the international team of investigators undertook the study because they wished to address a “fundamental” question about the possible benefits of starting HIV therapy at a CD4 cell count above the currently recommended 350 cells/mm3: “are ART-naïve patient with CD4 cell counts greater than 350…at higher risk of death than the general population?”

They therefore pooled data from 23 cohort studies in Europe and North America. Their analysis included 40, 830 patients who had at least one CD4 cell count above 350 cells/mm3 when HIV therapy naive. These individuals contributed a total of 80, 682 person years of follow-up.

A total of 419 (1%) individuals died, giving an overall mortality rate of 5.2 per 1000 person years. Of these deaths 61 (15%) were categorised as AIDS-related, 188 (45%) as non-AIDS-related, and the cause was unrecorded for 170 deaths (41%).

The risk of death was higher for patients with HIV than for the general population. However, the magnitude differed according to HIV-risk group. It was only modestly elevated for gay and other men who have sex with men (standardised mortality ratio [SMR] = 1.30; 95% CI: 1.06 to 1.58), but was notably higher for heterosexuals (SMR = 2.95; 95% CI: 2.28 to 3.73), and was especially elevated for injecting drug users (SMR = 9.37; 95% CI: 8.13 to 6.53).

Analysis was then restricted to the patients with HIV, and the investigators compared the twelve-month death rate of that recorded in patients in different CD4 cell strata (350-499; 500-699; and above 700 cell/mm3).

An adjusted analysis that took into account potentially confounding factors showed that, compared to those with a CD4 cell count between 350-499 cells/mm3, the mortality rate was 23% lower amongst patients with CD4 cell counts in the 500 to 699 cells/mm3 strata, and 34% lower for those with CD4 cell counts above 700 cells/mm3.  A series of sensitivity analyses did not substantially affect these results. 

“These data suggest that people with HIV who have not taken ART and have CD4 count greater than 350 cells/mm3, have a raised risk of death compared with the general uninfected population, although the increase seems to be small,” conclude the investigators.

They add, “because ART might reduce the risk of death in such patients, these findings support the need for continuing studies (such as the START trial and the further exploration of existing observational databases) of the risks and benefits of starting ART at CD4 counts greater than 350”.


Study Group on Death Rates at High CD4 Count in Antiretroviral Naïve Patients. Death rates in HIV-positive antiretroviral-naïve patients with CD4 count greater than 350 cells/mm3 in Europe and North America: a pooled cohort of observational study. The Lancet; online edition: DOI:10. 1016/S0140-6736(10)60932-4, 2010.