One participant in the continuous HAART arm withdrew from the study after 4 months in order to stop ARV. Inclusion of that participant as a treatment nonsuccess gives P value 0.041 for the difference in treatment success rates, and the noninferiority criterion is still not met. As month 6 data are unavailable for that participant, he was excluded from all other analyses.
No significant differences were observed in anthropometric indices between the interrupted and continuous HAART groups at baseline or month 6 (Mann–Whitney test; data not shown). For laboratory measures (Table 3), significantly lower values were seen at month 6 in the interrupted compared with continuous HAART group for total cholesterol (161 versus 190 mg/dl, P < 0.05) and apolipoprotein A1 (98.5 versus 111 mg/dl, P < 0.05). In contrast, HgbA1c was significantly higher in HAART interrupters at month 6 (5.4 versus 4.95%, P < 0.001). However, medians in both groups at baseline and month 6 were within normal range (<6%).
Physical and mental health scores on the MOS-HIV did not differ significantly between the groups at either time point (data not shown). However, the change in score from baseline to month 6 on the Energy/Fatigue subscale (a vitality measure from 0 to 100) was significantly greater in HAART interrupters compared with continuous HAART participants (interrupted: median change = 5, 95% CI: 0, 15; continuous: median change = −5, 95% CI: −25, 0; P < 0.001). Of note, completion rates for the MOS-HIV were lower at month 6 (interrupted = 74.1%, continuous = 84.6%) than at baseline (interrupted = 96.3%, continuous = 92.3%).
Treatment success rates at month 6 versus month 12 within early HAART interrupters (48.1 versus 22.2%; P = 0.016; McNemar test) indicated declines in CD4 T cells observed in the primary study phase did not abate during the extension phase. Treatment success rates in early HAART interrupters at month 6 (n = 27) and late HAART interrupters at month 12 (n = 10) revealed no difference whether HAART interruption occurred immediately (48.1%) or 6 months (50%) after the baseline IL-2 cycle (Fisher's exact test; P = 1.0).
Logistic regression analysis was used to calculate median rates of change in HIV viral load and CD4 T cell count over the first 6 months of HAART interruption, using all data points until first HAART reexposure (i.e., either IL-2 cycling or resumption of HAART). To evaluate the effects of timing of HAART interruption relative to the baseline IL-2 cycle, median rates of change were compared between early and late HAART interrupters. No significant difference in rate of HIV viral load increase was seen (early: 6356 copies/ml per month, late: 1162 copies/ml per month; P = 0.16; Mann–Whitney test). However, the rate of CD4 T cell decline was steeper in late (−96 cells/μl per month) than in early (−38 cells/μl per month) HAART interrupters (P < 0.001), indicating that 6 months of HAART following a baseline IL-2 cycle did not mitigate and, in fact, may have exacerbated this decline (Fig. 2b).
Median rates of change were also compared in intragroup analyses within early or late HAART interrupters between subjects considered treatment successes versus nonsuccesses. Within early HAART interrupters, although the rates of HIV viral load increase did not differ significantly (nonsuccesses: 7631 copies/ml per month, successes: 3174 copies/ml per month; P = 0.20), treatment nonsuccesses had a steeper CD4 T cell decline compared with treatment successes (77 versus 3 cells/μl per month; P < 0.001; Fig. 2c). Similar comparisons among late HAART interrupters did not reveal any significant differences (data not shown).
Grade 3 adverse events were constitutional symptoms previously reported with IL-2 therapy , including fatigue (n = 8), fever (n = 2), and abdominal pain (n = 2). The only Grade 4 event was an episode of transient hyperbilirubinemia due to underlying Gilbert's syndrome. Significant clinical events were detailed in the section on HAART resumption.
HIV genotypic analysis indicated no novel resistance mutations emerged following HAART interruption, although two changes were noted. An early HAART interrupter with a reverse transcriptase T215Y change prior to enrollment developed a T215NTDA mutation, which reflects preexisting polymorphisms in ARV-naive individuals, as reversion from T215Y often occurs after HAART interruption. Another common polymorphism in ARV-naive individuals (protease I15V mutation; Stanford HIV Drug Resistance Database ) was observed in a late HAART interrupter. All participants who restarted HAART had virologic suppression to less than 50 copies/ml, except for two who continued treatment interruption beyond end-of-study: the first had documented medication nonadherence and the second had no prior HIV viral loads of less than 50 copies/ml, though after restarting HAART, his viral load decreased by more than 1 log from 9742 to 781 copies/ml.
The present prospective, randomized trial demonstrated IL-2 alone was inferior in maintaining CD4 T cell counts at least 90% of baseline in IL-2-experienced recipients after 6 months of HAART interruption, compared with IL-2 along with HAART. Despite a baseline IL-2 cycle administered in the setting of moderate to high CD4 T cell counts (range: 538–1390 cells/μl) and largely suppressed HIV viremia, this immune intervention could not sufficiently overcome the CD4 T cell declines associated with HAART interruption, as compared with patients who received IL-2 and remained on HAART.
Regarding its use with HAART interruption, the results of Agence Nationale de Recerche sur le Sida (ANRS) 095  and ACTG 5102  suggested IL-2 conferred no benefit to HIV-infected persons, regardless of whether ARV were initiated during primary infection or later in the disease. Nonetheless, earlier data from the ICARUS cohort comparing preenrollment and baseline IL-2 cycling indicated CD4 T cell increases were achievable with IL-2 followed by HAART interruption .
The recently published TILT trial demonstrated IL-2 could reduce the probability of restarting ARV by 50% following 2 years of HAART interruption . The different conclusions in ICARUS and TILT may be explained by the stricter criterion for treatment success used in the former. Whereas we sought to maintain CD4 T cells within 10% of baseline levels (947 cells/μl), in TILT, IL-2 cycles were triggered by CD4 T cell counts less than 350 cells/μl, and HAART was restarted for CD4 T cell counts less than 200 cells/μl . In fact, CD4 T cell increases following IL-2 with HAART were similar in these studies, with half the HAART interrupters in ICARUS qualifying as treatment successes at month 6. This occurred despite the potential for self-referral bias within the ICARUS cohort of patients who tolerated IL-2 well and had high baseline CD4 T cell counts.
Six months of HAART interruption in our study also provided little benefit to HAART interrupters, with only small decreases in total cholesterol (similar to ACTG 5102 ) and apolipoprotein A1. Although HgbA1c was lower in the continuous HAART group at month 6, the clinical relevance of this is unclear, as values in both groups remained within normal range. This may reflect the expected increase in erythrocyte life span after stopping nucleoside reverse transcriptase inhibitors and reducing subclinical hemolysis . A small (10% median group difference) though significant increase in energy level from baseline to month 6, as measured by the MOS-HIV Health Survey, was also observed in interrupted compared with continuous HAART participants, indicating IL-2 cycling (which was more frequent in HAART interrupters) did not adversely affect this quality of life measurement.
The findings of the ICARUS trial showed that IL-2 alone was inferior in maintaining baseline CD4 T cell counts after 6 months of HAART interruption, compared with IL-2 along with HAART. In the post-SMART era , HAART interruptions are of limited scope and conducted under close supervision in clinical trials. However, adjunctive therapies to limit HAART exposure and abrogate the chronic inflammation of HIV infection (presumed to be a major cause of non-HIV-related complications [12,60]) merit exploration. Studies are underway to evaluate the capacity of IL-2 to delay HAART initiation in early HIV infection (STALWART) , and preliminary data from ANRS 119 suggest IL-2 can delay CD4 T cell decline and prolong time to an AIDS-defining event or HAART initiation in ARV-naive individuals . Although unlikely to be of value as part of a HAART interruption strategy, the clinical impact of IL-2 in HIV disease will become clearer with the availability of data from the ESPRIT and SILCAAT trials.
The authors would like to thank all study participants and the staff of outpatient clinic 8 at NIAID for their help in completing this trial, Christine Salaita for collecting anthropometric measurements, and Francine Thomas for reading the CT scans. B.P. contributed to data organization, analysis, and interpretation, and wrote the article. K.A., B.H., C.L., J.K., and R.D. contributed to the development and implementation of the protocol, and review of the article. J.S. contributed to the implementation of the protocol, data organization and analysis, and review of the article. C.K. and F.M. contributed to data organization, analysis, and interpretation, and review of the article. W.B. contributed to development of the protocol, data organization, analysis, and interpretation, and review of the article. I.S. contributed to the development and implementation of the protocol, data organization, analysis, and interpretation, and editing of the article. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy & Infectious Diseases, Clinical and Molecular Retrovirology Section (Bethesda, Maryland).
The US Government has been granted a patent for the use of intermittent subcutaneous IL-2 as therapy in HIV infection, listing H.C. Lane and J.A. Kovacs as coinventors.
This work was funded through the National Institute of Allergy & Infectious Diseases Clinical and Molecular Retrovirology Section of the National Institutes of Health (Bethesda, Maryland, USA). Human recombinant IL-2 was provided by Novartis (Emeryville, California, USA).
These findings have not been published previously in their present form. However, preliminary data from this study were presented at the 2008 Conference on Retroviruses and Opportunistic Infections (CROI) and were published in abstract form (Abstract #706) in the 2008 CROI Proceedings (Boston, Massachusetts; February 3-6, 2008).
1. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.
2. Ledergerber B, Egger M, Telenti A. AIDS-related opportunistic illness and potent antiretroviral therapy. JAMA 2000; 283:2653–2654.
3. Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al
. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998; 352:1725–1730.
4. Ofotokun I, Smithson SE, Lu C, Easley KA, Lennox JL. Liver enzymes elevation and immune reconstitution among treatment-naive HIV-infected patients instituting antiretroviral therapy. Am J Med Sci 2007; 334:334–341.
5. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352:48–62.
6. Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med 2005; 118(Suppl 2):23S–28S.
7. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS 2004; 18:439–446.
8. Ananworanich J, Gayet-Ageron A, Le Braz M, Prasithsirikul W, Chetchotisakd P, Kiertiburanakul S, et al
. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet 2006; 368:459–465.
9. Ananworanich J, Nuesch R, Le Braz M, Chetchotisakd P, Vibhagool A, Wicharuk S, et al
. Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial. AIDS 2003; 17:F33–F37.
10. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al
. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367:1981–1989.
11. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al
. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
12. Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, et al
. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS 2007; 21:1957–1963.
13. Arduino RC, Nannini EC, Rodriguez-Barradas M, Schrader S, Losso M, Ruxrungtham K, et al
. CD4 cell response to 3 doses of subcutaneous interleukin 2: meta-analysis of 3 Vanguard studies. Clin Infect Dis 2004; 39:115–122.
14. Farel CE, Chaitt DG, Hahn BK, Tavel JA, Kovacs JA, Polis MA, et al
. Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection. Blood 2004; 103:3282–3286.
15. Natarajan V, Lempicki RA, Sereti I, Badralmaa Y, Adelsberger JW, Metcalf JA, et al
. Increased peripheral expansion of naive CD4+ T cells in vivo after IL-2 treatment of patients with HIV infection. Proc Natl Acad Sci USA 2002; 99:10712–10717.
16. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Sereti I, Sachau W, et al
. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J Clin Invest 2005; 115:2139–2148.
17. Sereti I, Anthony KB, Martinez-Wilson H, Lempicki R, Adelsberger J, Metcalf JA, et al
. IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Blood 2004; 104:775–780.
18. Kovacs JA, Vogel S, Metcalf JA, Baseler M, Stevens R, Adelsberger J, et al
. Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy. Eur J Immunol 2001; 31:1351–1360.
19. Sereti I, Imamichi H, Natarajan V, Imamichi T, Ramchandani MS, Badralmaa Y, et al
. In vivo expansion of CD4(+)CD45RO(−)CD25(+) T cells expressing foxP3 in IL-2-treated HIV-infected patients. J Clin Invest 2005; 115:1839–1847.
20. Sereti I, Martinez-Wilson H, Metcalf JA, Baseler MW, Hallahan CW, Hahn B, et al
. Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4(+)/CD25(+) T cells. Blood 2002; 100:2159–2167.
21. Pett SL, Wand H, Law MG, Arduino R, Lopez JC, Knysz B, et al
. Evaluation of Subcutaneous Proleukin (interleukin-2) in a Randomized International Trial (ESPRIT): geographical and gender differences in the baseline characteristics of participants. HIV Clin Trials 2006; 7:70–85.
22. Emery S, Abrams DI, Cooper DA, Darbyshire JH, Lane HC, Lundgren JD, Neaton JD. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials 2002; 23:198–220.
23. Durier C, Capitant C, Lascaux AS, Goujard C, Oksenhendler E, Poizot-Martin I, et al
. Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials). AIDS 2007; 21:1887–1897.
24. Levy Y, Durier C, Krzysiek R, Rabian C, Capitant C, Lascaux AS, 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; 17:343–351.
25. Davey RT Jr, Murphy RL, Graziano FM, Boswell SL, Pavia AT, Cancio M, et al
. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: a randomized controlled trial. JAMA 2000; 284:183–189.
26. Levy Y, Gahery-Segard H, Durier C, Lascaux AS, Goujard C, Meiffredy V, et al
. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 2005; 19:279–286.
27. Kilby JM, Bucy RP, Mildvan D, Fischl M, Santana-Bagur J, Lennox J, et al
. A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024). J Infect Dis 2006; 194:1672–1676.
28. Henry K, Katzenstein D, Cherng DW, Valdez H, Powderly W, Vargas MB, et al
. A pilot study evaluating time to CD4 T-cell count <350 cells/mm(3) after treatment interruption following antiretroviral therapy ± interleukin 2: results of ACTG A5102. J Acquir Immune Defic Syndr 2006; 42:140–148.
29. Keh CE, Shen JM, Hahn B, Hallahan CW, Rehm CA, Thaker V, et al
. Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients. AIDS 2006; 20:361–369.
30. Youle M, Emery S, Fisher M, Nelson M, Fosdick L, Janossy G, et al
. A Randomised Trial of Subcutaneous Intermittent Interleukin-2 without Antiretroviral Therapy in HIV-Infected Patients: the UK-Vanguard Study. PLoS Clin Trials 2006; 1:e3.
31. Kovacs JA, Baseler M, Dewar RJ, Vogel S, Davey RT Jr, Falloon J, et al
. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N Engl J Med 1995; 332:567–575.
32. Davey RT Jr, Chaitt DG, Piscitelli SC, Wells M, Kovacs JA, Walker RE, et al
. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis 1997; 175:781–789.
33. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, et al
. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 2005; 11:1238–1243.
34. Stevens R, Lempicki R, Natarajan V, Higgins J, Adelsberger J, Metcalfe J. General immunologic evaluation of patients with human immunodeficiency virus infection. In: Detrick B, Folds RHJ, editors. Manual of molecular and clinical laboratory immunology. 7th ed. Washington, DC: ASM Press; 2006. pp. 847–861.
35. Ellis KJ, Grund B, Visnegarwala F, Thackeray L, Miller CG, Chesson CE, et al
. Visceral and subcutaneous adiposity measurements in adults: influence of measurement site. Obesity (Silver Spring) 2007; 15:1441–1447.
36. Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, et al
. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. N Engl J Med 1990; 322:941–949.
37. Wu AW, Revicki DA, Jacobson D, Malitz FE. Evidence for reliability, validity and usefulness of the Medical Outcomes Study HIV Health Survey (MOS-HIV). Qual Life Res 1997; 6:481–493.
38. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, et al
. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med 1996; 124:792–802.
39. Gart JJ, Nam JM. Approximate interval estimation of the difference in binomial parameters: correction for skewness and extension to multiple tables. Biometrics 1990; 46:637–643.
40. Davey RT Jr, Chaitt DG, Albert JM, Piscitelli SC, Kovacs JA, Walker RE, et al
. A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis 1999; 179:849–858.
42. Mitsuyasu R, Gelman R, Cherng DW, Landay A, Fahey J, Reichman R, 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; 167:597–605.
43. Di Mascio M, Sereti I, Matthews LT, Natarajan V, Adelsberger J, Lempicki R, et al
. Naive T-cell dynamics in human immunodeficiency virus type 1 infection: effects of highly active antiretroviral therapy provide insights into the mechanisms of naive T-cell depletion. J Virol 2006; 80:2665–2674.
44. Anthony KB, Yoder C, Metcalf JA, DerSimonian R, Orenstein JM, Stevens RA, et al
. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr 2003; 33:125–133.
45. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al
. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197:126–133.
46. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al
. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med 2001; 194:1731–1741.
47. Sereti I, Lane HC. Immunopathogenesis of human immunodeficiency virus: implications for immune-based therapies. Clin Infect Dis 2001; 32:1738–1755.
48. Rodriguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, et al
. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 2006; 296:1498–1506.
49. Mellors JW, Margolick JB, Phair JP, Rinaldo CR, Detels R, Jacobson LP, Munoz A. Prognostic value of HIV-1 RNA, CD4 cell count, and CD4 cell count slope for progression to AIDS and death in untreated HIV-1 infection. JAMA 2007; 297:2349–2350.
50. Goujard C, Marcellin F, Hendel-Chavez H, Burgard M, Meiffredy V, Venet A, et al
. Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study. AIDS Res Hum Retroviruses 2007; 23:1105–1113.
51. Angus B, Lampe F, Tambussi G, Duvivier C, Katlama C, Youle M, et al
. TILT: a randomized controlled trial of interruption of antiretroviral therapy with or without interleukin-2 in HIV-1 infected individuals. AIDS 2008; 22:737–740.
52. Fox Z, Antunes F, Davey R, Gazzard B, Klimas N, Labriola A, et al
. Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with a CD4 count > or =300 cells/microL who were assigned to 7.5 MIU interleukin-2. HIV Med 2007; 8:112–123.
53. Markowitz N, Bebchuk JD, Abrams DI. Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2. Clin Infect Dis 2003; 37:e115–e120.
54. Read SW, Lempicki RA, Mascio MD, Srinivasula S, Burke R, Sachau W, et al
. CD4 T cell survival after intermittent interleukin-2 therapy is predictive of an increase in the CD4 T cell count of HIV-infected patients. J Infect Dis 2008; 198:843–850.
55. Davey RT Jr, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al
. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 1999; 96:15109–15114.
56. Ruiz L, Paredes R, Gomez G, Romeu J, Domingo P, Perez-Alvarez N, et al
. Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS 2007; 21:169–178.
57. Tarwater PM, Parish M, Gallant JE. Prolonged treatment interruption after immunologic response to highly active antiretroviral therapy. Clin Infect Dis 2003; 37:1541–1548.
58. Tebas P, Henry WK, Matining R, Weng-Cherng D, Schmitz J, Valdez H, et al
. Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk. PLoS ONE 2008; 3:e2021.
59. Diop ME, Bastard JP, Meunier N, Thevenet S, Maachi M, Capeau J, et al
. Inappropriately low glycated hemoglobin values and hemolysis in HIV-infected patients. AIDS Res Hum Retroviruses 2006; 22:1242–1247.
60. Emery S, Neuhaus J, Phillips A, Babiker A, Cohen CJ, Gatell J, et al
. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008; 197:000–10.
62. Molina J LY, Fournier I, Boulet T, Bentata M, Beck-Wirth G, Sereni D, et al
. Predictors of slow disease progression in antiretroviral (ART) naive HIV-1 infected patients treated with IL-2: three-year extended follow-up of the Interstart ANRS 119 trial.
In: 15th Conference on Retroviruses and Opportunistic Infections
; Boston, Massachusetts; 2008.