Immunotherapy at the 1st IAS conference

1 September 2001. Related: Treatment strategies.

Mike Youle, MD for NATAP
www.natap.org

The 1st International AIDS Society Conference on HIV Pathogenesis and Treatment was laden with new information on immunotherapy of HIV specifically concerning interleukin-2 (IL-2).

Whilst several recent additions to the antiretroviral armamentarium got a good airing most studies of drugs were longer term follow-up of already presented data. When it came to interleukin-2, the most advanced of the immunotherapeutic agents there was a wide range of studies that which increased both clinical knowledge as well as basic science.

The French have always been great proponents of this approach from the early years of the epidemic and this perhaps the more balanced European view that the immune system is as vital, if not more vital than the virus in terms of a therapeutic target.

IL-2 raises CD4s in patients with <200 CD4s to over 200 CD4s

Christine Katlama from the Hopital Pitie Salpetriere in Paris presented week 80 data on the ILSTIM study (ANRS 082) [1]. In this trial patients who still had less than 200 T4 cells after 6 months of HAART were randomised to receive 4 cycles over 24 weeks of IL-2 (4.5 MIU twice daily for 5 days). The idea of the study was to establish if IL-2 as an additional treatment could raise the T4 count out of the under 200 danger zone to potentially reduce the likelihood of opportunistic infections. After week 24 all patients could opt to take cycles of IL-2. Seventy-two subjects with a median HAART duration of 19 months entered the study of whom 31 received IL-2 therapy. The median age was 45 with pre-HAART T4 levels of 65 which rose after treatment to 145 (15% were <100 at baseline). During the first 24 weeks a statistically significant rise in T4 cells occurred in the IL-2 group compared to the HAART alone group (220 versus 138 p<0.0001) with 81% versus 33% achieving greater than 200 T4 cells. By week 80 the median T4 cell level in the IL-2 arm was 380 with 93% over 200 whilst the delayed IL-2 arm had increased to 270 with 83% over the 200 T4 cell threshold. This median increase of almost 250 T4 cells was achieved with an average of 10 cycles of IL-2. The speaker was asked a question as top whether there was any clinical benefit to this treatment and responded that the study although not designed to assess this had raised T4 cell levels into a range at which clinical disease was less likely. In addition there were clinical endpoints studies (SILCAAT and ESPRIT) that were ongoing and designed to address this issue.

Tolerability of IL-2

Albert Wu from Johns Hopkins University in Baltimore then presented quality of life data from the ACTG328 study that evaluated 150 subjects on HAART for 12 weeks [2]. They were randomised to receive HAART alone (51), cycles of intermittent subcutaneous (SC) IL-2 (54) or cycles of continuous intravenous (CIV) infusion IL-2 (55) every 8 weeks for 52 weeks. The study used an ACTG quality of life (QOL) tool with 21 elements that addressed general well being, pain, energy, social functioning, physical functioning and several other areas of health. Subjects were assessed at baseline, and at days 0 and 5 of cycles 1, 3 and 6 (approximating weeks 16, 28 and 52). Whilst no significant changes were seen at week 16 by weeks 28 and 52 subjects in the SC IL-2 group scored significantly better on certain elements and the summary score for this group was better than for either for the other groups (P<0.05). The QOL of subjects receiving IL-2 dipped at days 5 as would be expected since the symptoms of IL-2 treatment are well documented with fever, bodily pain and flu-like symptoms. However the decrease in QOL scores diminished over time suggesting that either patients became used to coping with the side effects of IL-2 or that the management of side effects was better. Wu pointed out that although not a clinical endpoint study these data were the first to assess the tolerability and effect on QOL of IL-2 in a randomised fashion which may be of greater significance to the patient than the incidence of new AIDS defining events.

Preliminary data suggests IL-2 stimulates thymus

Several investigators presented information as to the effects of IL-2 on various areas of the immune system. Brigitte Autran gave an elegant talk on her studies of patients in ILSTIM attempting to ascertain the action of IL-2 on thymic function [3]. She examined 13 subjects from the ILSTIM study over 80 weeks by measuring naive T cells and signal joint T-cell receptor excision circles. These are the by products of part of the alignment of the immune system in response to particular foreign material during the development of immunity. It would appear from the work that Autran presented that the effect of Il-2 is to stimulate the activity of the remaining thymus in HIV infected subjects leading to an improved immune capacity. This is good news at it suggests that this agent can re-teach the immune system in a way that will produce persistent benefits form intermittent therapy.

Does IL-2 induce HIV replication?

One concern that as been voiced is that the use of IL-2 in the absence, or even the presence of antiretroviral medication may induce viral replication and thereby either establish a new set point of HIV viraemia or speed progression of HIV disease. Anne Sullivan presented data from the UK-Vanguard IL-2 study in which 36 subjects with CD4 cell counts >350/cumm were randomised to receive no treatment or IL-2 at two dosage levels (3 cycles of 4.5MUI or 7.5MIU twice daily for 5 days at 8 week intervals over 24 weeks) [4]. She showed data on markers of T cell activation (CD38) as well as markers of IL-2 receptors (CD25). No sustained rises in either occurred although transient blips per cycle were observed that paralleled the rises in viraemia that have been seen previously. This is important in the sense that further immune activation is seen as disadvantageous and that previously several groups have reported CD38 levels to be an independent predictor of progression in HIV disease.

So all in all there was plenty of new data to suggest that intervening with at least IL-2 may be a good therapeutic strategy. This agent is now available in France for subjects CD4 cell counts less than 200/cumm through a government sponsored program although the licensed indication has not yet been changed.

Remune

Remune has not fared as well and as the conference closed Pfizer announced they were closing the development program with the Immune Response Corporation (IRC) thereby putting the continued research of this agent in jeopardy. With no clinical endpoint data and limited evidence of any surrogate marker changes in studies so far conducted it seems unlikely that this will go ahead.

References:

1. Tubiana R, Carcelain G, De Sa M et al. ILSTIM (ANRS082) – Interleukin 2 (IL2) accelerates CD4 cells reconstitution in patients with CD4 <200/mm3 despite effective HAART. Abstract 102
2. Wu A, Martin B, Gelman R et al. Quality of life in a randomised controlled trial of highly active antiretroviral therapy with intermittent IL-2 by IV or SC routes in patients with CD4 50 – 350 cells/mm3 (ACTG 328). Abstract 105
3. Korthals Altes H, Saint-Mezard P, Tubiana R et al. Adjuvant SCIL2 increases thymic production in patients with advanced HIV infection under antiretroviral therapy. Abstract 104
4. Sullivan A, Abstract 109