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Low-Dose Prolonged Intermittent Interleukin-2 Adjuvant Therapy: Results of a Randomized Trial among Human Immunodeficiency Virus Positive Patients with Advanced Immune Impairment (<200 CD4s)
  The Journal of Infectious Diseases Sept 2002;186:606-616
Giulia Marchetti,1,a Luca Meroni,1,a Stefania Varchetta,1 Velislava Terzieva,3 Alessandra Bandera,1 Daniele Manganaro,1 Chiara Molteni,1 Daria Trabattoni,2 Sabrina Fossati,2 Mario Clerici,2 Massimo Galli,1 Mauro Moroni,1 Fabio Franzetti,1 and Andrea Gori1
1Institute of Infectious Diseases and Tropical Medicine, "Luigi Sacco" Hospital, and 2Department of Immunology, Dipartimento di Scienze Precliniche, LITA VIALBA, University of Milan, Milan, Italy; 3Department of Immunology, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria
It has been demonstrated that IL-2 can significantly raise CD4 counts. But IL-2 can be difficult to tolerate & patients can experience a significant CD4 increase from HAART alone. So if a patient gets a nice CD4 increase to an acceptable level the use of IL-2 may not be worthwhile. But what about the patient who cannot get an increase in CD4 count to above 200 from HAART? And although study results have suggested the CD4 increase from IL-2 can have a positive clinical effect it has not yet been proven. Two large studies are ongoing to try to prove that. This study is very small but sets out to see if IL-2 has clinical benefit & significantly increases CD4s in individuals unable to rise above 200 with HAART.
Before receiving IL-2 study patients were 36 yrs old, were mostly men but there were a few women; 3 patients in each group had prior AIDS diagnosis. And all patients had <50 copies/ml. The baseline CD4 count was 144 in the HAART+IL2 group (n=12) and 166 in the HAART group (n=10). Patients were randomized to stay on HAART or continue HAART with added IL-2. Patients had been on HAART for 3-4 years and were mostly on PI+NRTI regimens.
This is a small study but patients receiving HAART + IL-2 had CD4 increases from 144 to 300 after 48 weeks while patients receiving HAART alone did not experience a CD4 increase for the most part. IL-2 patients did not experience any clinical events but 3/10 in the HAART alone group experienced clinical events. Interestingly, all patients receiving IL-2 experienced at least 1 transitory increase in HIV viral load during the IL-2 administration. Except for 1 patient the others had undetectable HIV RNA after 48 weeks of study. This 1 patient did not have detectable drug resistance. IL-2 patients had increased na´ve CD4 counts while HAART alone patients did not. IL-2 patients had greater increases in memory cells while HAART patients did have some increase.
Only the 2 patients with a more-compromised immune system at baseline (pre IL-2 treatment CD4+ cell count of <50 cells/L) did not reach this threshold of CD4 increase, although they did experience an overall increase in CD4+ cell counts.
Recombinant human IL-2 (Chiron) was administered at a dosage of 3 million IU daily as a single subcutaneous injection at days 1-5 and 8-12 of a 4-week cycle, for a total of 3 cycles (overall, 10 weeks' duration), in addition to the ongoing antiretroviral treatment. The low-dose, prolonged intermittent schedule was chosen to obtain a sustained immunologic response with good tolerance, on the basis of lymphocyte growth patterns observed in patients with cancer, consisting of maximum increase after 23 weeks of treatment. All the patients enrolled maintained the same HAART throughout the study period; patients who changed treatment were excluded from the study.
Twenty-two patients with CD4+cell counts 200 cells/L after 12 months of stable highly active antiretroviral therapy (HAART; "immunologic nonresponders") were randomly assigned to receive subcutaneous low-dose prolonged intermittent interleukin (IL) 2 in addition to HAART (n = 12) or to continue HAART alone (n = 10). At 48 weeks of follow-up, no IL-2related serious adverse events and no significant differences in plasma human immunodeficiency virus (HIV) RNA level were observed in the 2 groups. A higher incidence of HIV-related clinical events was observed among patients receiving HAART alone (3/10) than among subjects receiving HAART plus IL-2 (0/12). Significant increases in CD4+, naive, and CD4+CD7+ cells and plasma levels of IL-7 were observed in patients receiving IL-2 versus patients receiving HAART alone. A significant increase in cell turnover did not lead to a decrease in the frequency of T cell receptor excision circles, which remained stable. Rather, increased numbers of T cell receptor excision circles per microliter of blood were observed (not statistically significant). Thus, adjuvant IL-2 therapy in immunologic nonresponders resulted in a clinical benefit, suggesting that the quantitative cell recovery involves functionally competent immune cells.
Twenty-two INRs attending the Institute of Infectious and Tropical Diseases of the University of Milan (Milan) were recruited between November 1998 and June 2000. Twelve patients received IL-2 treatment in addition to continuing HAART, whereas 10 were randomly assigned to continue the ongoing HAART regimen only. There were no baseline differences between the 2 groups with respect to age, epidemiologic data, CD4+ T cell counts, HIV RNA load, HIV-related parameters, and HAART regimen at enrollment (table 1). In particular, none of the patients enrolled in the study had ongoing or prior opportunistic infections up to 1 year before study initiation.
All the IL-2 treated patients reached the end of the IL-2 treatment (week 10); 3 patients were lost to follow-up. In particular, 1 patient was monitored up to week 34 but then moved to another city; 2 patients were monitored until week 10, and after that 1 moved to another city and 1 went to jail. These 3 patients tolerated IL-2 treatment well, and none of them was lost to follow-up because of clinical events, nor were they excluded from the study because of a bad response to IL-2 therapy. Mild constitutional symptoms, such as fever (grade 12), fatigue, and myalgia, were experienced by 10 of 12 patients receiving IL-2; a reversible localized erythematous nodule at the site of injection was observed in 11 of 12 patients. No grade 3 or 4 adverse events were observed. None of the IL-2 treated patients developed HIV-related clinical events or pathologic disorders linked to immunosuppression during the 1-year study period; and none of the patients enrolled interrupted their treatment because of the development of side effects.
All 10 patients in the control group completed the study. Two patients developed oropharyngeal candidiasis, and 1 patient experienced 1 episode of cutaneous herpes zoster.
All the IL-2 treated patients experienced at least 1 transitory increase in HIV RNA level during the 10 weeks of IL-2 administration, ranging from 1 to 3 log10 copies/mL. In all 9 patients who completed the follow-up period, HIV RNA returned to undetectable levels by week 48. In 1 patient, HIV RNA remained detectable (3.8 log10 copies/mL) at week 34; the patient was then lost to follow-up. Resistance tests for this patient constantly evidenced a fully susceptible HIV-1 strain. In all the patients receiving HAART alone, HIV RNA levels remained <50 copies/mL for the whole study period.
CD4+ T cell changes
In IL-2 treated patients, both mean absolute CD4+ T cell counts and CD4+ T cell percentages peaked at the end of each IL-2 treatment cycle (weeks 2, 6, and 10), with a significant increase at the end of the IL-2 treatment, from 147 cells at baseline to 304 cells at week 10. The mean CD4+ T cell percentage increased from 13% at baseline to 18% at week 10 (p=.004). At weeks 34 and 48 (6 and 12 months, respectively, after IL-2 therapy), the mean absolute CD4+ T cell count and percentage remained significantly higher than baseline levels (261 cells [P = .002] and 17% [P = .05] for week 34 and 298 cells [P = .001] and 18% [P = .004] for week 48). All 12 patients experienced an overall increase in their CD4+ T cell counts during the study period, even though the 2 patients with a baseline count of <50 cells/L did not reach the threshold CD4+ cell count of 200 cells. The pre-baseline nadir Cd4 count was 48 in the HAART- IL2 group & 35 in the HAART group.
In contrast to these results, no significant change was observed for patients undergoing HAART alone in mean CD4+ T cell count at weeks 10 and 34 (week 0, 166 cells; week 10, 175 cells [P = .221]; week 34, 192 cells [P = .212]). A significant increase was observed after 1 year (week 48, 228 ▒ 29 cells/L [P = .002]), but 4 of 10 patients did not reach the threshold of 200 CD4+ T cells. No significant change was observed in the mean percentage of CD4+ T cells during the whole study period. The mean increase in absolute CD4+ cell count at week 48 among IL-2treated patients was significantly higher than that among control subjects (P = .012).
Changes in the CD4+CD45RA+CD62L+ (naive) and CD4+CD45RA- (memory) compartments.
In IL-2 treated patients, the mean number of both CD4+ naive and memory cells increased significantly during the study period. In particular, naive cells increased from 27 cells/L at baseline to 74 cells at the end of the IL-2 treatment cycles (week 10, P =.012); at the completion of IL-2 treatment, they remained stable at 74 cells (week 34, P = .034) and increased even more, to 97 cells/L, by the end of follow-up (week 48, P = .015; figure 3A). Memory cells increased from 113.4 cells at baseline to 216 cells at week 10 (P = .004), 183 cells at week 34 (P = .016), and 205 cells at week 48 (P = .004). Similar to results for total CD4+ cells, each patient experienced a relative increase in both memory and naive CD4+ T cells, compared with baseline, the degree of which was again strictly dependent on pre IL-2 treatment levels.
In the control group, no significant change was observed in the mean absolute counts or percentages of naive cells from baseline to week 48 (week 0, 43 cells/L and 27%; week 48, 53 cells/L [P = .188] and 25% [P = .325]). Mean absolute numbers of memory cells significantly increased from 116 cells/L at week 0 to 156 cells/L at week 48 (P = .0130. The mean increases in absolute numbers of both naive and memory cells at week 48 in IL-2 treated patients were significantly higher than those of control subjects (P = .034 for naive cells and P = .046 for memory cells).
Author Conclusions
In the present study, all the patients with baseline preIL-2 treatment CD4+ cell counts of >50 cells/L (10/12) actually reached a CD4+ cell count of 200 cells/L by the end of IL-2 treatment cycles; only the 2 patients with a more-compromised immune system at baseline (preIL-2 treatment CD4+ cell count of <50 cells/L) did not reach this threshold, although they did experience an overall increase in CD4+ cell counts. This finding allows a tentative stratification as to the extent of CD4+ T cell recovery according to baseline levels possibly identifying 50 CD4+ cells/L as the threshold value which could eventually turn out to be a useful tool for the clinician in therapeutic decision-making when considering IL-2 as adjuvant treatment for severely immunocompromised HIV-positive patients. Patients treated with HAART alone still experienced an increase in CD4+ T cells, which was nevertheless significantly less relevant and much slower than that in IL-2 treated patients, appearing after 1 year of antiviral therapy; moreover, only 6 of 10 patients reached the 200 CD4+ cells/L threshold. This finding suggests that the accelerated IL-2 driven CD4+ T cell increase was indeed effective in preserving an adequate cellular immunity, and, indeed, none of the IL-2treated patients experienced HIV-related pathologic disorders, whereas 3 of 10 control subjects did. This is the first evidence, in a randomized study, of a potential clinical benefit of IL-2 therapy, suggesting that the quantitative increase in CD4+ cells involves functionally competent immune cells.
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