French National Drug Agency re-commends use of IL-2 if HAART does not lead to an increase in CD4 count to greater than 200 cells/mm3
Harvey S. Bartnof, MD, hivandhepatitis.com
As a result of significant CD4 count benefits in the ANRS 082 Study, the French National Drug Agency has endorsed a recommendation to add interleukin-2 (IL-2, aldesleukin, ProleukinTM) to a patient’s antiretroviral drug regimen if there is not a sufficient CD4 count increase.
In some patients with later stage HIV disease, HAART does not lead to a substantial CD4 count increase, even if the HIV RNA viral load is undetectable. A count greater than 200 cells/mm3 is needed to avoid most of the severe, life-threatening AIDS related opportunistic infections. Christine Katlama, MD, from Hopital Pitie-Salpetriere in Paris, France presented a 50-week update of Study ANRS-082 (ILSTIM) that enrolled 70 patients. 
Patients entered the study if they met the following criteria: (1) CD4 count still less than 200 cells/mm3 after six months of HAART; and (2) HIV RNA viral load controlled with a level less than 1,000 copies/mL. A total of 70 HIV positive patients (11% women) were enrolled. They were randomised into one of two arms: (1) continue HAART for 24 weeks; or (2) continue HAART and add IL-2 4.5 million international units (MIU) self-injected subcutaneously twice daily for 5 days, every six weeks for 24 weeks (four cycles). After 24 weeks, both arms rolled over into continuing HAART and continuing (or starting) IL-2. For the arm that was taking IL-2 for the first 24 weeks, the dose after 24 weeks was raised to 9 MIU self-injected once daily, five days per week every eight weeks. The arm that first started IL-2 at 24 weeks began with a dose of 4.5 MIU self-injected once daily for five days every eight weeks for four cycles, followed by 9 MIU once daily for five days every eight weeks.
The median baseline viral load was less than 3 log copies/mL, while the median baseline CD4 count was approximately 145 cells/mm3. The pre-HAART nadir (lowest) CD4 count was approximately 65 cells/mm3. At study entry, the median time on HAART was 18 months.
The results at week 24 revealed a significant CD4 count increase of 65 cells/mm3 for the arm taking IL-2 plus HAART. The HAART alone arm had an increase of 18 cells/mm3. 81% of subjects in both arms chose to remain in the study and continue beyond 24 weeks. The next interim analysis was performed at 50 weeks. At that time, the ‘all IL-2’ group had had seven cycles, while the group who took IL-2 only after week 24 had had four cycles. At week 50, the interim CD4 count increases were 190 cells/mm3 in the arm taking IL-2 the entire time and 120 cells/mm3 in the arm that started IL-2 after week 24. A significant fraction of the CD4 count increases were ‘na•ve’ cells that can respond to new antigens or infections. The median viral load at 24 and 50 weeks was not specifically reported. However, the researchers did report that only 16% of the 70 patients experienced a viral load increase to greater than 1,000 copies/mL that spontaneously decreased to less than 2,000 copies/mL in all of them.
Adverse events were common during IL-2 therapy and included ‘flu-like’ symptoms that are known to occur with this drug. They included: fever 97%, fatigue 91%, muscle pain 68%, nausea 68%, runny nose or congestion 59%, sweats 41%, dry skin and/or mouth 41%, rash 44%, joint aches 38%, insomnia 32%, and headache 25%. As a result, 14% of patients taking IL-2 had a dose decrease, while 8% discontinued IL-2. Tolerability as rated by the researchers was ‘quite acceptable.’
The authors performed several analyses that demonstrated clear statistical benefits from IL-2 in terms of CD4 count increases. For example, the mean daily increase in CD4 counts in cells/mm3 was 0.12 cells (per day) while not taking IL-2, compared to 0.54 cells/mm3 (per day) while receiving IL-2. In a 6-month period, the mean CD4 increase in cells/mm3 was calculated to be 20 while not taking IL-2 and 100 while taking IL-2. The calculated time to reach a CD4 count of 250 cells/mm3 was three years while not taking IL-2 and six months while taking IL-2. (All analyses assumed that all patients are still taking HAART and maintained a suppressed or nearly-suppressed viral load.)
These results demonstrate in the first randomised trial the benefits of adding IL-2 to HAART for those who do not generate a significant CD4 count increase, even with a suppressed viral load. In spite of the high rate of side effects that are known to occur with IL-2, the discontinuation rate was very low. This study is ongoing. Limitations of the study include specific numerical end-points that were not reported, as above.
There was a similar presentation about adding low dose daily IL-2 to HAART versus HAART alone in patients with less advanced disease. Entry criteria included an undetectable viral load (limit 500 copies/mL) for at least two months and a CD4 count that was no greater than 300 cells/mm3. The dose used for the 115 patients in this study was 1.2 MIU per square meter self-injected once daily for six months. The lead author was Jay Lalezari, MD, from Quest Clinical Research in San Francisco, California. 
The 6-month results showed an insignificant trend towards a greater CD4 count increase in the IL-2 plus HAART arm (increase of 61 cells/mm3) when compared to the HAART alone arm (increase of 35 cells/mm3). However, the IL-2 arm did have a significant increase in the CD4 percentage (3.6% increase) when compared to the HAART only arm (1.4% increase). Similar to the findings by Dr. Katlama in the above report, Dr. Lalezari determined that the IL-2 arm did have a higher percentage of ‘na•ve’ CD4 cells than the HAART only arm. Moreover, in the current report, it was determined that the number of Natural Killer (NK) cells were significantly increased in the IL-2 arm (+ 157 cells/mm3), when compared to the HAART only arm (+ 20 cells/mm3). No significant differences in plasma viral loads were noted in either group at six months.
Interestingly, IL-2 appeared to block the increase in triglycerides that commonly occurs when a protease inhibitor (PI) drug is administered. Moreover, the IL-2 apparently led to a decrease in the cholesterol level that often becomes increased with the use of HAART. Adverse events were those known to occur with IL-2 (see above).
Even considering the differences between these two studies with regard to dose of IL-2 used, dosing schedule and stage of HIV-disease, these two randomised, controlled studies add to our knowledge about the benefits of adding IL-2 to HAART in patients who have had less than optimal CD4 count increases, even with undetectable viral loads. It is noteworthy that the French National Drug Agency has endorsed using IL-2 as standard of care in this population.
- Katlama C et al. ILSTIM (ANRS 082)-a randomised comparative open-label study of interleukin (IL-2) in patients with CD4<200/mm3 despite effective HAART. Abstract and poster presentation 543 at the 7th CROI; January 30-February 2, 2000; San Francisco, CA.
- Lalezari J et al. Low-dose subcutaneous (IL-2) in combination with HAART therapy induces significant increases in NK cells and naive T-cells in patients with <300 CD4+ T-cells/mm3: results of a randomised controlled trial MA-9801. Abstract and poster presentation 381 at the 7th CROI; January 30-February 2, 2000; San Francisco, CA.