Interleukin‐2 as an adjunct to antiretroviral therapy for HIV‐positive adults

Jennifer Onwumeh; Charles I Okwundu; Tamara Kredo

doi:10.1002/14651858.CD009818.pub2

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Figure 1

Study flow diagram

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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial

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Analysis 1.1

Comparison 1 Interleukin‐2 versus control, Outcome 1 All‐cause mortality.

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Analysis 1.2

Comparison 1 Interleukin‐2 versus control, Outcome 2 HIV RNA levels < 50 cells/mL.

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Analysis 1.3

Comparison 1 Interleukin‐2 versus control, Outcome 3 HIV RNA levels < 500 cells/mL.

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Analysis 1.4

Comparison 1 Interleukin‐2 versus control, Outcome 4 Opportunistic infections.

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Analysis 1.5

Comparison 1 Interleukin‐2 versus control, Outcome 5 Adverse events (grade 3 or 4).

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Summary of findings for the main comparison. 'Summary of findings' table 1

Interleukin‐2 compared to control for HIV‐positive adults
Patient or population: HIV‐positive adults Settings: high‐ and middle‐income settings Intervention: interleukin‐2 (IL‐2) plus antiretroviral therapy (ART) Comparison: ART alone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	IL‐2
All‐cause mortality	60 per 1000	58 per 1000 (48 to 70)	RR 0.97 (0.80 to 1.17)	6565 (6 trials)	⊕⊕⊕⊕ high	There is little or no effect on all cause mortality
CD4 cell count	Tended to increase in all but one study			7600 (21 trials)	—	Tended to increase in all but one study
HIV RNA levels less than 50 cells/mL	636 per 1000	617 per 1000 (515 to 732)	RR 0.97 (0.81 to 1.15)	805 (5 trials)	⊕⊕⊕⊕ high	There is little or no effect on viral suppression
HIV RNA levels less than 500 cells/mL	81 per 1000	77 per 1000 (66 to 90)	RR 0.96 (0.82 to 1.12)	5929 (4 trials)	⊕⊕⊕⊕ high	There is little or no effect on viral suppression
Opportunistic infections	46 per 1000	39 per 1000 (26 to 54)	RR 0.79 (0.55 to 1.13)	6141 (7 trials)	⊕⊕⊝⊝ low¹	There may be little or no effect on opportunistic infections
Adverse events (grade 3 or 4)	197 per 1000	242 per 1000 (193 to 303)	RR 1.47 (1.10 to 1.96)	6291 (6 trials)	⊕⊕⊕⊝ moderate²	There is probably an increase in adverse events
The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations:* CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.
¹Downgraded by 2 for imprecision due to low event rate resulting in a wide 95% CI is wide. The overall meta‐analysis remains underpowered to confidently exclude effects. ²Downgraded by 1 for imprecision.

Summary of findings for the main comparison. 'Summary of findings' table 1

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Table 1. Details of the interleukin‐2 intervention regimen

Number	Trial ID	Follow‐up duration	Dosing regimen for interleukin‐2 (IL‐2)	Comparisons	Outcomes	ART experienced or naive
1	Abrams 2002	16 months	Dose: 2 doses (4.5 and 7.5 miu) Route: subcutaneous Duration: twice daily for 5 days every 8 weeks	ART not specified	Viral load CD4 cell count	ART experienced
2	Abrams 2009b	7 years	Dose: 4.5 miu Route: subcutaneous Duration: twice daily, 6 cycles	ART not specified	Opportunistic infections Death from any cause Adverse events	Not specified
3	Abrams 2009a	7 years	Dose: 7.5 miu Route: subcutaneous Duration: twice daily, 3 cycles	ART not specified	Opportunistic infections Death from any cause Adverse events	Not specified
4	Amendola 2000	28 weeks	Dose: 1 miu Route: subcutaneous Duration: daily for 5 days/week every alternate week for 3 months	Indinavir, stavudine, and lamivudine	CD4 cell count Viral load	ART naive
5	de Boer 2003	12 months	Dose: 12 miu Route: intravenous Duration: for 3, 4, or 5 days every 8 weeks for 6 cycles	ART not specified	CD4 cell count Viral load Adverse events and serious adverse events AIDS defining complex	ART experienced
6	Caggiari 2001	12 months	Dose: 6 miu Route: subcutaneous Duration: from days 1 to 5 and days 8 to 12 of a 28‐day cycle for 6 cycles	2 nucleoside reverse transcriptase inhibitors (NRTIs) or 2 NRTIs and indinavir	CD4 cell count Viral load	ART naive
7	Carr 1998	12 months	Dose: 1 miu Route: subcutaneous and intravenous Duration: Group A: 12 miu daily for 5 days every 8 weeks (27 participants) Group B: 1 miu per cycle in equal divided doses in day 1 and 3 every 8 weeks (58 participants)	Zidovudine + didanosine + zalcitabine	CD4 cell count Adverse events Viral load Opportunistic infections	ART experienced
8	Davey 2000	48 weeks	Dose: 7.5 miu Route: subcutaneous Duration: 6 cycles every 12 hours for 5 days every 8 weeks	ART not specified	CD4 cell count Viral load Adverse events	ART experienced
9	Dybul 2002	12 months	Dose: 7.5 miu Route: subcutaneous Duration: 3 cycles for 5 days every 8 week	ART not specified	CD4 cell count Viral load	Not specified
10	Hengge 1998	12 months	Dose: 9.6 miu Route: subcutaneous Duration: 5 cycles were given. One cycle was given every 6 weeks over a period of 52 weeks. Treatment group A : subcutaneous administered daily in cycles consisting of 5 days. Treatment group B: subcutaneous administered at a dose of 9.6 miu daily whenever CD4 counts dropped to below 1.25 fold of individual's baseline value	Saquinavir, lamivudine, and zidovudine	CD4 cell count Viral load Opportunistic infections	ART experienced
11	Katlama 2002	24 weeks with outcomes measured at weeks 1, 6, 12, 18, and 24	Dose: 4.5 miu Route: subcutaneous Duration: every 6 weeks for 4 cycles, every 12 hours for 5 days	2 nucleoside analogues and one PI	CD4 cell count Viral load Adverse events ART experienced	Not specified
12	Kelleher 1998	48 weeks	Dose: 12 miu Route: intravenous Duration: Group A: 12.6 miu as continuous intravenous infusions for 5 days every 8 weeks for 6 cycles. Group B (IL‐2 linked to polyethylene glycol plus ART): subcutaneous injections on days 1 and 3 of each 8‐week cycles	ART included nucleoside analogues such as lamivudine	CD4 cell count Viral load	ART experienced
13	Kovacs 1996	14 months	Dose: 18 miu Route: intravenous Duration: daily for 5 days every other month for 6 cycles from month 0 to 10	ART included didanosine, zidovudine, zalcitabine, or stavudine	CD4 cell count Plasma HIV RNA	Not specified
14	Lalezari 2000	6 months	Dose: 1.2 miu, and then increased by 0.3 miu every 2 weeks for 6 months until a participant experienced grade 2 or greater toxicity. Route: subcutaneous Duration: once daily for 2 weeks	ART not specified	CD4 cell count Viral load Adverse events	ART experienced
15	Levy 1999	14 months	Dose: 12 miu and 3 miu Route: 12 miu intravenous and 3 miu subcutaneous intravenously (12 miu/day, N = 22) or subcutaneously (3 miu/m² twice daily, N = 24) for 5 days, or 2 miu/m² intravenous bolus, N = 22) administered every 2 months from week 2 to week 50 (7 cycles).	Zidovudine (600 mg/day) plus didanosine (400 mg/day)	CD4 cell count Viral load Adverse events	ART naive
16	Levy 2003	18 months	Dose: 5 miu Route: subcutaneous Duration: twice daily for a 5 day cycle given every 4 weeks for the first 3 cycles and then subsequently every 8 weeks for the next 7 cycles	ART included lamivudine (300 mg/day), stavudine (60 to 80mg/day) and indinavir (2400 mg/day)	CD4 cell counts Viral load AIDS defining events	ART naive or naive to PIs alone
17	Losso 2000	24 weeks	Dose: escalating doses of 1.5 miu, 4.5 miu, 7.5 miu Route: subcutaneous Duration: twice daily for 5 consecutive days every 8 weeks	ART not specified	CD4 cell counts . Viral load	Both naive and experienced participants were included in the study.
18	Marchetti 2002	48 weeks	Dose: 3 miu Route: subcutaneous Duration: administered as a single subcutaneous injection at days 1 to 5 and 8 to 12 of a 4‐week cycle, for a total of 3 cycles	ART was either 2 nucleoside reverse transcriptase inhibitor and one PI or at least one non nucleoside reverse transcriptase inhibitor	CD4 cell count Viral load Adverse events	ART experienced
19	Marchetti 2004	48 weeks	Dose: 3 miu Route: subcutaneous Duration: administered at day 1 to 5 and 8 to 12 for 10 weeks	ART not specified	CD4 cell count	ART experienced
20	Mitsuyasu 2007	84 weeks	Dose: Group A 9 miu and Group B 7.5miu Route: intravenous and subcutaneous Duration: Group A: intravenous infusions 5 days every 8 weeks. Group B: subcutaneous injections 7.5 miu twice daily for 5 days every 8 weeks	Received ART alone, 2 nucleosides and a PI	CD4 cell count Viral load	Not specified
21	Ruxrungtham 2000	24 weeks	Dose: Group A 1.5 miu, Group B 4.5 miu, and Group C 7.5 miu Route: subcutaneous Duration: twice daily for 5 days, every 8 weeks for three cycles 8‐weekly	ART not specified	CD4 cell count Viral load	ART experienced
22	Stellbrink 2002	601 days	Dose: 9 miu Route: subcutaneous Duration: once daily (with an option to switch to 4.5 miu twice daily) for 5 consecutive days per cycle administered at 6‐weekly intervals	ART consisting of stavudine 30 to 40 mg twice daily, and lamivudine 150 mg twice daily, nelfinavir 750 mg 3 times daily and saquinavir 600 mg 3 times daily.	CD4 cell count Viral load	ART naive
23	Tambussi 2001	12 months	Dose: 3 regimens of IL‐2 Route: intravenous and subcutaneous Duration:differed by group see details below Group A: 12 miu by continuous intravenous infusion followed by subcutaneous 7.5 miu twice a day for 5 days every 8 weeks for the remaining 4 cycles. Group B: subcutaneous 7.5 miu twice a day for 5 days every 8 weeks for 6 cycles. Group C: subcutaneous 3 miu twice a day every 4 weeks	2 NRTIs and saquinavir	CD4 cell count Viral load	ART experienced
24	Tavel 2003	12 months	Dose: 7.5 miu Route: subcutaneous Duration: Group A: 7.5 miu twice daily for 5 days versus placebo plus ART. Group B: 7.5 miu twice a day for 5 days	Nucleosides analogue reverse transcriptase inhibitor and either a non‐nucleosides analogue reverse transcriptase inhibitor or PI	CD4 cell count Viral load	ART experienced
25	Vogler 2004	24 weeks	Dose: 1 miu Route: subcutaneous Duration: once daily	2 nucleoside reverse transcriptase inhibitors	CD4 cell count Viral load	ART experienced
Abbreviations: ART antiretroviral therapy; IL‐2 Interleukin 2; NRTI nucleoside reverse transcriptase inhibitors; PI protease inhibitor

Table 1. Details of the interleukin‐2 intervention regimen

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Table 2. Effect of intervention: change in CD4 count

Increase in CD4 cell count with statistically significant difference
Abrams 2002 (at 12 months follow‐up) n = 511	The average difference change in CD4 cell count between the IL‐2 group and control group was 217.1 cells/mm³ (95% CI 188.6 to 245.5; P < 0.001) measured at 12 months.
Carr 1998 (at 12 months follow‐up) n = 115	Median CD4 cell count increases of 359 and 44 cells/mm³ and a decline of 46 cells/mm³ in the cyclical continuous intravenous IL‐2, subcutaneous IL‐2, and ART alone group, respectively, over 12 months (P < 0.0001 for each intergroup comparison).
Davey 2000 (at 12 months follow‐up) n = 82	The median increase in CD4 count at 12 months was 279 cells/mm³ in the IL‐2 group compared with 50 cells/mm³ in the control (P < 0.001).
de Boer 2003 n = 81	The mean per cent increase in CD4 cell counts was 24.5% for IL‐2 recipients compared to a mean per cent decrease of 30.5% for control participants (P < 0.005).
Hengge 1998 (at 12 months follow‐up) n = 64	The median CD4 cell counts increased from 363 to 485 (+ 33.6% standard deviation) in the IL‐2 group Group A (P < 0.01) and from 358 to 462 (+ 29.1%) in Group B (P < 0.01) and from 350 to 375 (+ 6.9% in the control group (not significant), respectively.
Katlama 2002 (at 24 weeks, that is 6 months follow‐up) n = 72	The median increase in CD4 cells at week 24 was significantly higher in the IL‐2 group than in the control group (65 versus 18 cells/mm³; P < 0.0001).
Kovacs 1996 (at 12 months follow‐up) n = 60	There was an increase in the mean (± SE) CD4 count from 428 ± 25 cells/mm³ at baseline to 916 ± 128 in the IL‐2 group, compared to a decreased from 406 ± 29 cells/mm³ to 349 ± 41 cells/mm³ in the control group (P < 0.001).
Lalezari 2000 (at 26 weeks follow‐up) n = 115	The percentage increase in CD4 count from baseline of 3.59% in the IL‐2 group compared to 1.33% in the control group (P < 0.001).
Levy 1999 (at 56 weeks follow‐up) n = 94	The median increase in CD4 count from baseline at 56 weeks was 564 cells/mm³ (P > 0.0001), 105 cells/mm³ (P = 0.58), and 676 cells/mm³ (P = 0.0002) in the subcutaneous (SC), polyethylene glycol modified, and intravenous (IV) IL‐2 group respectively, compared to 55 cells/mm³ in the control group
Levy 2003 (at 74 weeks follow‐up) n = 118	The median increase in CD4 count from baseline at week was 865 cells/mm³ in the IL‐2 group compared to 262 cells/mm³ in the control group (P < 0.00001).
Losso 2000 (at 24 weeks follow‐up) n = 73	The mean increase in CD4 count from baseline at week 24 of 27 cells/mm³ (P = 0.105), 105 cells/mm³ (P = 0.006), and 492 cells/mm³ (P < 0.001) in the 1.5, 4.5, and 7.5 miu dose groups of IL‐2. Overall 14 out of 36 (41%) of the IL‐2 group and 3 out of 37 (8%) of the controls had a magnitude increase of ≥ 1000 cells/mm³.
Marchetti 2002 (48 weeks follow‐up) n = 22	IL‐2 treated participants had mean absolute CD4 T cell counts (S.E) significantly increase at the end of the IL‐2 treatment (week 48) from 147 (18) cells/mm³ at baseline to 298 (43.3) cells/mm³ (P=0001). The control participants also had a significant increase was observed 16 weeks 228 (29) cells/mm³ (P = 0.002).
Mitsuyasu 2007 (at 48 weeks follow‐up) n = 159	Reported median increases of CD4 cell count were 459, 312, and 102 cells/mm³ in the intravenous, SC Il‐2, and control groups respectively at 48 weeks (P < 0.001 for both).
Tavel 2003 (at 12 months follow‐up) n = 19	Reported a mean increase in CD4 count from baseline of 452 cells/mm³ in the IL‐2 group compared to 135 cells/mm³ in the control group (P < 0.05).
Ruxrungtham 2000 n = 82	Reported an increase in the time weighted mean CD4 cell count 252 x 10⁶ cells/mm³ over 24 weeks for the overall scIL‐2 group compared with 42 x 10⁶ cell/mm³.
Increase in CD4 cell count but statistical significance not reported in the trials
Abrams 2009a (at 12 months follow‐up) (at 6 years follow‐up) n = 4111	Six trials measured at 1 year; median CD4 increase of 206 versus 21 cells/mm³ in the IL‐2 group versus the control group and reported an average median increase of 109 more in the IL‐2 group more than the control group over the entire 7 years (95% CI 40 to 60 over 6 years)
Abrams 2009b (at 12 months follow‐up) n = 1695	Six trials measured at 1 year; median CD4 increase of 131 versus 32 cells/mm³ in the IL‐2 group versus the control group over 12 months and reported an average median increase of 53 more in the IL‐2 group more than the control group over the entire 7 years (95% CI 40 to 60 over 6 years)
Dybul 2002 (at 12 months follow‐up) n = 9	Four participants treated with HAART plus 3 cycles of intermittent IL‐2 had an increase in median absolute CD4+ T cell count from 529 cells/mm³ (range: 502 to 738 cells/mm³) at enrolment to 1995 cells/mm³ (range: 1112 to 3064 cells/mm³; 268% increase) after 12 months of treatment (Figure 1A). Five participants treated with HAART alone had an increase in median CD4+ T cell count from 580 cells/mm³ (range: 416 to 662 cells) at enrolment to 712 cells/mm³ (range: 667 to 1160 cells/mm³; 52% increase) after 12 months of treatment
No significant increase in CD4 cell count
Vogler 2004 (at 24 weeks) n = 115	Mean change in CD4 count in the IL‐2 group and the control group was 40 and −1 respectively
Tambussi 2001 n = 61	Reports that there was a progressive increase in circulating CD4 cells, determined at the beginning of each IL‐2 cycle, was observed in all participants receiving ART plus IL‐2, in comparison with those receiving ART alone but gave the values for the within subgroup variation
Amendola 2000 (at 6 months follow‐up) n = 22	No significant difference between changes in CD4 counts in both groups
Abbreviations: ART: antiretroviral therapy; ESPIRIT: Evaluation of Subcutaneous Proleukin in a Randomised International Trial; IL‐2: interleukin‐2; SILICAAT: subcutaneous recombinant human interleukin‐2 in HIV‐infected patients low CD4 counts under active antiretroviral therapy

Table 2. Effect of intervention: change in CD4 count

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Comparison 1. Interleukin‐2 versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	6	6565	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.80, 1.17]

1.1 ART experienced	2	626	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.16, 7.11]
1.2 ART naive or not specified	4	5939	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.80, 1.17]
2 HIV RNA levels < 50 cells/mL Show forest plot	5	805	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.81, 1.15]

3 HIV RNA levels < 500 cells/mL Show forest plot	4	5929	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.82, 1.12]

4 Opportunistic infections Show forest plot	7	6141	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.55, 1.13]

4.1 ART experienced	2	97	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.05, 1.86]
4.2 ART naive or not specified	5	6044	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.56, 1.19]
5 Adverse events (grade 3 or 4) Show forest plot	6	6291	Risk Ratio (M‐H, Random, 95% CI)	1.47 [1.10, 1.96]

Comparison 1. Interleukin‐2 versus control

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