Start treatment at 500 or 350? UK cohort data show clear difference in risk of death

Analysis of data from a large UK HIV cohort has shown that, amongst untreated patients with CD4 cell counts above 350 cells/mm³, the higher the current CD4 cell count, the lower the risk of AIDS and death. The study, published in the August 20^th edition of AIDS demonstrated that patients with a CD4 cell count between 500 – 649 cells/mm³ were 55% more likely to develop an AIDS-defining illness than patients with a CD4 cell count above 650 cells/mm³.

Individuals with a CD4 cell count between 200 and 350 cells/mm³ were five times more likely to experience an AIDS-defining illness or die than individuals with a CD4 count above 650 cells/mm³.

The investigators suggest that their finding “contributes to the rationale for evaluating the risk/benefits for initiation of antiretroviral therapy in patients with high CD4 cell count (e.g. above 500 cells/mm³) in a randomized controlled trial, for example comparing with deferral to 350 cells/mm³.”

Clinicians are increasingly optimistic that, thanks to the success of antiretroviral therapy, and the prospect of new classes of anti-HIV drugs, HIV-positive individuals have the opportunity of living a normal life-expectancy. This is leading some investigators to suggest that the potential benefits of early initiation of anti-HIV treatment outweigh the risks.

For this issue to be adequately addressed it will be necessary to design a randomised controlled trial, comparing outcomes in individuals who start treatment with a CD4 cell count of 500 cells/mm³ with those who start treatment in line with current treatment guidelines. Looking at the risk of AIDS or death in patients with higher CD4 cell counts (above 350 cells/mm³), would, investigators from the UK Collaborative HIV Cohort (UK CHIC), provide useful background information for the design of such a study.

Over 25,000 patients have now been enrolled in the UK CHIC, which was established in 1996. The current analysis included 17,609 patients who were antiretroviral-naïve. The rate of AIDS-defining illness and death (from all causes, the data did not allow the exact cause of death to be determined) were analaysed according to current CD4 cell counts. A total of 30,313 person-years of follow-up was available for analysis.

In all, 1,557 AIDS-defining events or deaths were recorded (overall rate, 5.1 per 100 person years). The investigators found that, even amongst patients with a CD4 cell count above 350 cells/mm³, the risk of AIDS or death fell at higher CD4 cell counts. Indeed, patients with a CD4 cell count between 500 – 649 cells/mm³ had an AIDS or death rate ratio of 1.55 (95% confidence interval [CI], 1.11 - 2.17) compared to patients with a CD4 cell count of 650 cells/mm³ or above, a statistically significant difference (p = 0.01).

The risk of AIDS or death was even higher for patients with lower CD4 cell counts. For patients with a CD4 cell count between 350 – 499 cells/mm³ the rate ratio of AIDS was 2.49 (95% CI, 2.16 - 2.82, no P value provided), and the rate ratio for patients with a CD4 cell count between 200 cells/mm³ (the current threshold for the initiation of HIV therapy in the UK) and 349 cells/mm³ was 4.91 (95% CI; 4.39 - 5.43).

Unsurprisingly, patients with a CD4 cell count between 50 – 199 cells/mm³ had a much higher rate ratio of AIDS or death at 20.81 (95% CI, 18.8 - 22.8), with individuals with a CD4 cell count below 50 cells/mm³ having a rate ratio of 102.71 (95% CI, 92.2 - 113.3) .

The investigators found that for patients with a CD4 cell count above 350 cells/mm³, each additional 100 cell/mm³ increase in CD4 cell count significantly reduced the risk of AIDS or death (p 10 increase in viral load (p = 0.006), each additional ten years of age (p = 0.001), and injecting drug use (p = 0.002).

When the investigators controlled for these additional factors, they still found that each additional 100 cell/mm³ increase for patients with a CD4 cell count above 350 cells/mm³ was protective against AIDS and death (p

In all, 289 AIDS-defining events occurred in patients with CD4 cell counts above 350 cells/mm³. When the investigators examined these in more detail, they found that 20% of cases were Kaposi’s sarcoma, 20% oesphageal thrush, 14% tuberculosis, 6% herpes simplex, 12% recurrent bacterial infections, 6% PCP pneumonia, 5% cryptosporidiosis, and 4% lymphoma.

Although the highest incidence of death and AIDS-defining events occurred at CD4 counts below 200, analysis of the rate of death per 100 person-years of follow-up showed that the rate of AIDS or death fell from 4.91 per 100 person-years (confidence interval 4.39–5.43) in those with CD4 counts between 200-349 to 2.49 per 100 person-years (CI (2.16–2.82) in those in the 350-500 band and 1.54 per 100 person-years (CI 1.22–1.86) in the 500-650 band.

The investigators stress that although the risk of AIDS or death for patients with a CD4 cell count above 350 cells/mm³ is low compared to individuals with lower CD4 cell counts, “the risk at higher counts is not negligible.” As the efficacy of anti-HIV therapy has improved, and drugs become more potent, tolerable and easy to take, the investigators believe “it is appropriate to focus on risk at these higher levels.”

“Our findings suggest that risk of AIDS or death might be reduced by using antiretroviral therapy to raise CD4 cell counts even among patients with higher CD4 cell counts”, add the investigators. They also note that the SMART treatment interruption study found that individuals with higher CD4 cell counts had a lower risk of some serious non-AIDS illness, such as heart, kidney and liver disease as well as some non-AIDS defining cancers.

“In summary, the trend of decreasing rate of AIDS and death with higher CD4 cell count is present across the CD4 cell count range above 350 cells/mm³ and may even persist across CD4 cell counts above 500 cells/mm³. These are important observations for consideration in a randomised controlled trial of early antiretroviral therapy.”