Two and a half years extra ART if treatment starts at 500 CD4s, not 350

New European HIV treatment guidelines recently recommended that anti-HIV therapy should be initiated when a patient’s CD4 cell count is in the region of 350 cells/mm³. But a new study by UK investigators shows that starting antiretroviral therapy when a patient’s CD4 cell count is above 500 cells/mm³ would mean that treatment would need to be started two and a half years earlier. The study is published in the November 1^st edition of the Journal of Acquired Immune Deficiency Syndromes.

The same team of UK investigators have previously found that patients with a CD4 cell count between 500 and 350 cells/mm³ have an increased risk of death compared to patients with a CD4 cell count above 500 cells/mm³. They suggest the results of their studies support the design of a trial to compare the outcomes of patients who start anti-HIV treatment with CD4 cell counts of 500 cells/mm³ versus 350 cells/mm³.

There is now substantial evidence to demonstrate the long-term efficacy of potent antiretroviral therapy. Studies have also shown that patients who start anti-HIV therapy when their CD4 cells counts are above 350 cells/mm³ have better long-term CD4 cell gains than patients who start treatment at around 200 cells/mm³. Furthermore, the SMART treatment interruption study showed that lower CD4 cell counts were associated with an increased risk of some serious non-AIDS related illnesses.

Treatment guidelines are now starting to endorse the initiation of anti-HIV therapy when an individual has a CD4 cell count below 350 cells/mm³. It remains uncertain, however, if there would be any additional benefit starting antiretroviral therapy at an even higher CD4 cell count, around 500 cells/mm³.

To answer this question it will be necessary to design a trial comparing long-term outcomes in patients starting therapy at 500 cells/mm³ compared to patients who defer starting treatment until their CD4 cell counts are in the region of 300 – 350 cells/mm³. Before such a trial is designed it is necessary to determine how many patients have higher CD4 cell counts at the time of diagnosis, and how long it would take for patients who deferred the initiation of treatment to reach a CD4 cell count or state of clinical health requiring the commencement of treatment.

Investigators from the UK CHIC (a collaborative cohort study that includes data collection from patients who have receive care at ten large HIV clinics in the UK), therefore look at data collected from 13,572 patients to see how many patients had a CD4 cell count in the 500 – 650 cells/mm³ range at the time of diagnosis.

At the time of diagnosis, 3,631 patients (27%) had a CD4 cell count above 500 cells/mm³, of whom 1852 (51%) had a CD4 cell count between 500 and 650 cells/mm³. Median viral load was a little over 10,000 copies/ml.

The investigators also looked at a ‘snap-shot’ of treatment-naïve patients receiving care at UK CHIC centres who had a CD4 cell count above 500 cells/mm³ in July 2005. They found that 959 patients who had not yet started treatment had a CD4 cell count above this level and that 54% of these individuals had CD4 cell counts in the 500 – 650 cell/mm⁴. Median viral load in these patients was 10,000 copies/ml.

In further analysis, the investigators looked at the time it took for the CD4 cell count to fall from a first measurement in the 500 – 650 cells/mm³ range to 350 cells/mm³ or the initiation of antiretroviral therapy. A total of 4,268 patients were included in this analysis. Median baseline CD4 cell count was 560 cells/mm³ and median viral load was 15,800 copies/ml.

A total of 2,341 patients experienced a fall in their CD4 cell count to 350 cells/mm³ or started treatment in a median of 2.5 years, with a range of 2.5 – 3.1 years depending on the sensitivity analysis used.

Viral load at baseline was a strong predictor of the time taken for the CD4 cell count to fall to 350 cells/mm³ or less. Patients whose baseline viral load was above 500,000 copies reached this endpoint in a median of 0.7 years, compared to almost five years for individuals whose baseline viral load was below 1,000 copies/ml. The investigators also found that older patients (7% increase in risk per ten years, p =0.04) were significantly more likely to experience a faster fall in their CD4 cell count. Although women were likely to reach the endpoint faster than men, the investigators believe that this was due to the initiation of antiretroviral therapy due to pregnancy.

“A trial of immediate…therapy in patients with CD4 cell counts of 500 cells/mm³ [or above] should be relevant to a substantial proportion of patients presenting with HIV”, write the investigators.

The investigators estimate that starting anti-HIV therapy when the CD4 cell count is 500 cells/mm³ rather than waiting until it fell to 340 cells would mean an addition 2.5 to three years of anti-HIV therapy.

Would these additional years of treatment have any benefit? The quote the results of their earlier research that showed, “for untreated patients with a CD4 cell count in the 350 – 500 cells/mm³ range, the rate of AIDS or death is approximately 2.5 per 100 person years, which translates to a predicted 6.1% cumulative risk over the 2.5 years spent with a CD4 cell count in this range while deferring antiretroviral therapy.”