In HIV-infected patients, there is a reduced endogenous production of IL-2 and a defect in IL-2 receptor expression, responsible in part for the characteristic reduction in CD4 counts. While some patients may experience a sustained control of HIV viral load with antiviral therapy, the CD4 cell counts do not recover. This situation may be referred to as “immunologic non-response.” Therefore, exogenous IL-2, in conjunction with antiretroviral therapy, has been investigated as a technique to increase CD4 counts, preserve immune function, and, it is hoped, decrease the incidence of opportunistic infections. In addition, it has been proposed that IL-2 in conjunction with combination antiretroviral therapy may be a useful approach for purging HIV from the latently infected CD4 cells.

Note: Interleukin-2 may be used as component of adoptive immunotherapy. Adoptive immunotherapy is addressed separately in policy No. 8.01.01. Interleukin may also be used as monotherapy for a variety of oncologic indications. These indications are addressed separately in policy No. 8.01.04. Interleukin-2 may be used as a component of a melanoma vaccine. Melanoma vaccines are considered as part of policy No. 2.03.04.

Interleukin-2 therapy as a treatment of HIV is considered investigational.

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While initially IL-2 was administered at high doses requiring hospital admission, recent studies have focused on the use of intermittent, self-administered subcutaneous infusions. Therefore, this route of administration of IL-2 may be adjudicated under the pharmacy benefits.

In HIV-infected patients, the critical outcome of IL-2 therapy is a documented reduction of HIV-associated opportunistic infections, HIV-associated malignancies, and/or improved survival. Although there are data to show that the use of IL-2 is associated with an increase in CD4 counts, there are inadequate data to confirm that this results in the outcomes defined above. As an example of the reported literature, in 1996 Kovacs and colleagues published the results of a controlled trial, which randomized 60 HI-infected patients to receive either IL-2 plus antiviral therapy or antiviral therapy alone. (1) IL-2 was administered every 2 months for 6 cycles of 5 days each, starting at a dosage of 18 million IU per day. In patients treated with IL-2, there was a significant increase in the CD4 count compared to a decrease in the CD4 count in the control group. There were no significant differences between and within groups of serial measurements of viral load. No clinical outcomes were included in this study.

The Kovacs study required hospitalization for intravenous IL-2 administration; significant toxicities were reported. Therefore, research has also focused on different dose schedules, including subcutaneous administration to decrease the toxicity and permit outpatient therapy. For example, in 2000, Davey and colleagues reported on a study that included 82 HIV+ patients with baseline CD4 counts of 200-500/mm-3 with a baseline viral load of less than 10,000 copies/mL. (2) The patients were randomly assigned to receive a combination of subcutaneous IL-2 in combination with antiviral therapy or antiviral therapy alone. The IL-2 protocol included 5-day courses every 8 weeks at a starting dosage of 7.5m IU twice a day, a regimen that has now been used in multiple trials. The main outcome measures included CD4 counts, CD4 cell percentages, and HIV viral loads. Intermittent therapy with IL2 and antiretroviral therapy produced a substantially greater increase in CD4 cells. A variety of other studies focusing on patients with different CD4 levels using different dosages and schedules of IL-2 have also reported that the use of IL-2 is associated with an increase in CD4 cell counts. (3-10)

Trials with clinical endpoints will be necessary to determine whether improvements in these intermediate outcomes will translate into improved clinical outcomes. Two large-scale randomized trials looking at final health outcomes are currently underway. The ongoing ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) is a randomized international 5-year 4,000-person study of IL-2 in HIV+ patients with early asymptomatic disease. (11) The goal of the study is to evaluate and compare the effectiveness of subcutaneous IL-2 therapy in conjunction with antiretroviral therapy compared to antiretroviral therapy alone. Patient selection criteria include an absolute CD4 cell count ≤ to 300/mm-3, without evidence of active clinical disease for at least 1 year. All patients must be receiving combination antiretroviral therapy at the time of randomization. After an initial 3 cycles of IL-2, given for 5 consecutive days every 8 weeks, additional cycles are given at the discretion of the treating physician, based on the patient's CD4 counts. The primary endpoint is new or recurrent disease progression. The SILCAAT trial, initiated in 1999, is an international study of 1,400 HIV+ patients with CD4 counts between 50 and 299 cells/mm-3 and a viral load of less than 10,000 copies/ml who will be randomized to receive antiretroviral therapy with and without additional IL-2. Therefore, in contrast with the ESPRIT study, the SILCAAT study focuses on HIV+ patients with lower CD4 counts. The primary endpoint is time to the first AIDS-defining event. In 2002, the study was withdrawn when it was unable to achieve its primary endpoint: time to first AIDS-defining event or death.

Other Information

There is currently no Medicare policy regarding the use of IL-2 for treatment of HIV infection.

2005 Update

A literature search was performed for the period of 2004 through October 2005. No additional studies were identified that would prompt reconsideration of the policy statement; therefore, the policy statement is unchanged. Specifically, final results of large randomized trials with final health outcomes have not yet been published in the peer-reviewed literature.

2006-2007 Update
A literature search was performed using MEDLINE through July 2007. While studies continue to show that use of IL-2 can increase CD4 counts; the clinical impact of this change is still unknown. Thus, the policy statement is unchanged. Results from the Phase III randomized trials noted above have not been published. Results from the AIDS Clinical Trials Group 328 Study reported on effects of IL-2 in patients with moderately advanced HIV infection who were also receiving highly active antiretroviral therapy (HAART). (12) In this study, 204 patients who were treatment naïve (or had only received reverse transcriptase inhibitors), with CD4 counts from 50 to 350 per microliter, and who were virologic responders, were randomized to receive only continued HAART therapy or the addition of intravenous (IV) or subcutaneous (SC) IL-2. At week 84, median increases in CD4 were 459/microliter, 312/microliter, and 102/microliter in the IV IL-2, SC IL-2, and HAART only groups, respectively. Increases of greater than 50% at week 60 (primary endpoint) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P less than 0.001). Treatment with IL-2 did not increase plasma HIV RNA levels.  There were fewer new AIDS-defining events in the IV and SC IL-2 groups than in the HAART group: 0,1, and 7 respectively.  Drug-related adverse events were more frequent with IL-2 treatment.  The authors comment that whether IL-2 produces long-term clinical benefit will be answered by large, ongoing clinical trials.

2008 Update
Results from induction phase of the ESPRIT study noted above showed a dose related response to treatment with IL-2 and increases in CD-4 counts. However, it is important to note that toxicity was much higher at the higher doses of therapy. (13) To date, final results of the ESPRIT study with final health outcomes have not yet been published in the peer-reviewed literature.
Currently, a new drug BAY 50-4798 is being investigated for the treatment of HIV “immunologic non-response.” BAY 50-478 is an IL-2 mutein with a 2700-fold greater affinity for the IL-2 receptor. Since it activates fewer natural killer cells, it is thought to have a better tolerability profile. In a phase I/II randomized, placebo-controlled trial, 32% of patients in the BAY 50-478 treatment arm versus 14% in the placebo arm discontinued the study. (14) Of the withdrawals in the treatment arm, 60% were due to adverse events. At the end of the 6-month study, patients receiving placebo had an 8-cell drop per cubic millimeter of blood, while patients in the highest dose treatment group had an 18-cell per cubic millimeter gain in blood count.
Given the uncertain impact of this treatment on clinical outcomes, the policy statement remains unchanged; this is considered investigational.

References:

1. Kovacs JA, Vogel S, Albert JM et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996; 335(18);1350-6.
2. Davey RT, Murphy RL, Graziano FM et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy. A randomized controlled trial. JAMA 2000; 284(2):183-9.
3. Abrams DI, Bebchuk JD, Denning ET et al. Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm-3: CPCRA 059. J Acquir Immune Defic Syndr 2002; 29(3):221-31.
4. Lalezari JP, Beal JA, Ruane PJ et al. Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial. HIV Clin Trials 2000; 1(3):1-15.
5. Tambussi G, Ghezzi S, Nozza S et al. Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus load: a controlled study of 3 IL-2 regimens with antiviral drug therapy. J Infect Dis 2001; 183(10):1476-84.
6. David D, Nait-Ighil L, Dupont B et al. Rapid effect of interleukin-2 therapy in human immunodeficiency virus-infected patients whose CD4 cell counts increase only slightly in response to combined antiretroviral treatment. J Infect Dis 2001; 183(5):730-5.
7. Marchetti G, Meroni L, Varchetta S et al. Low-dose prolonged intermittent interleukin-2 adjuvant therapy: results of a randomized trial among human immunodeficiency virus-positive patients with advanced immune impairment. J Infect Dis 2002; 186(5):606-16.
8. De Boer AW, Markowitz N, Lane HC et al. A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells. Clin Immunol 2003; 106(3):188-96.
9. Levy Y, Durier C, Krzysiek R et al. Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial. AIDS 2003; 17(3):343-51.
10. Stellbrink HJ, van Lunzen J, Westby M et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 2002; 16(11):1479-87.
11. Emery S, Abrams DI, Cooper DA et al. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials 2002; 23(2):198-220.
12. Mitsuyasu R, Gelman R, Cherng DW et al. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial—AIDS Clinical Trials Group 328. Arch Intern Med 2007; 167(6):597-605.
13. Fox Z, Davey R, Gazzard B et al. Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with CD4 count '> or = 300 cells/microL who were assigned to 7.5 MIU interleukin-2. HIV Medicine 2007; 8(2):112-23.
14. Davey R, Pertel P, Benson A et al. Safety, tolerability, pharmacokinetics, and efficacy of an Interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy. J Interferon Cytokine Res 2008; 28(2):89-100.

Aldesleukin, HIV
IL-2, HIV
HIV, IL-2