Induction-Maintenance

DEFINITION

  • Initiation of intensive ART regimen followed by simplification or de-intensification after virologic suppression to improve convenience and tolerability and to decrease toxicity. Switches from 4-drug to 3-drug regimens and from standard 3-drug to 1- or 2-drug regimens studied.

INDICATIONS

Indications

  • Aggressive induction regimens have been used to achieve more rapid initial suppression with PIs and RTIs, but without supporting evidence. InSTIs have rapid intial suppression and now prefered as intial therapy.
  • Switch to maintenance regimens to minimize long-term toxicity and optimize tolerability/adherence; fewer ADRs and drug-drug interactions with fewer drugs, fewer side effects and better adherence
  • Induction-maintenance not current standard-of-care.

CLINICAL RECOMMENDATION

Clinical Recommendation

  • Induction-maintenance approach not recommended based on available evidence: variability in drug regimens, duration of time for induction, variable baseline VL and CD4, inconsistent results.
    • Approach 1: 3-drug induction with 2 NRTIs + 1 PI; 2-drug maintenance with 2 NRTIs or 1 NRTI + 1 PI. Not effective.
    • Approach 2: 3-drug induction with 3TC/TDF/EFV; then 2-drug maintenance with TDF/EFV. No clear advantage to maintenance arm, and less effective.
    • Approach 3: 4-drug induction; 3-drug maintenance with 3 NRTIs. Some evidence of efficacy as maintenance after 4-drug induction in pts without prior NRTI resistance; however high rate of AEs with induction; AZT/3TC/ABC + EFV induction associated with higher VL failure than AZT/3TC/ABC + LPV/r induction
    • Approach 4: 4-drug induction with 2 NRTIs + 1 NNRTI + 1 PI; 3-drug maintenance with 2NRTIs + 1 NNRTI. 4 drugs no better than standard 3-drug regimen over 3 years in ARV-naive (see ACTG 5095, ref.). 4-drug induction better at 48 wks in another trial.
    • Approach 5: 3-drug induction with boosted PI+2 NRTIS, then PI/r monotherapy. Switching from DRV/r+2 NRTIs to DRV/r monotherapy was non-inferior at 144 wks by ITT but not TLOVR analysis (MONET study). Switching from DRV/r+2 NRTIs to DRV/r monotherapy excluded noninferioriority at 48 wks (MONOI-ANRS study). ATV/r+ 2NRTIS to ATV/r monotherapy associated with greater viral rebound at 48 wks (MODAT study). LPV/r + 2 NRTIs to LPV/r had higher viral rebound (81% vs. 95% on LPV/r +2NRTIs) (OK study). LPV/r + 2 NRTIs to LPV/r monotherapy (with reintroduction of NRTIs as needed) noninferior at 96 weeks (OK04 study). Switching from triple-therapy (PI and NNRTI based) to DRV/r or LPV/r compared to continuing triple therapy not inferior for development of new resistance that limited future options, but monitoring of VL every 12 wks and 27% switched back for VL rebound (PIVOT study). Not recommended currently.
    • Approach 6: 3-drug induction with boosted ATV+2NRTIs then unboosted ATV+2NRTIs: ATV/r+ABC/3TC, then unboosted ATV + ABC/3TC non-inferior to continuing ATV/r + 2NRTIs at 144 wks (ARIES study). ATV+2 NRTIs non-inferior to ATV/r+2NRTIs at 48 wks (InduMa study). Not guideline recommended. Simplification for fewer pills may not be as relevant with licensing of ATV/cobicistat combination. May be relevant to remove pharmacokinetic drug-drug interactions with either RBV or cobicistat.
    • Approach 7: 3-drug induction with boosted PI+2NRTIs, then PI+3TC non-inferior to PI/r+2 NRTIs at 48 wks with LPV/r+3TC (OLE study), ATV/r+3TC at 48 wks (SALT study) and ATV/r+3TC at 144 wks (ATLAS study). Not guideline recommended currently.
    • Approach 8: 3-drug induction with boosted PI+2NRTIs, then PI+InSTI. Higher viral rebound at 24 wks with ATVr/+RAL than maintaining ATV/r+TDF/FTC (HARNESS study). Induction with boosted PI or NNRTI + 2 NRTIs and non-inferior at 48 wks with LPV/r+RAL (KITE study). Not recommended currently.

References

  1. Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24(2):223-30.  [PMID:20010070]

    Comment: DRV/r monotherapy non-inferior to continuing 2 NRTI+PI after 24 wks of VL < 50.

  2. Arribas JR, Delgado R, Arranz A, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr. 2009;51(2):147-52.  [PMID:19349870]

    Comment: OK04 study. Pts on PI+NRTIs randomized to LPV/r montherapy (with reintroduction of NRTIs if needed) or continued 3-ARV therapy. At 96-wk, 87% on LPV/r monotherapy and 78% on 3-ARVs had VL < 50 (NS) AEs lower with monotherapy.

  3. Cameron DW, da Silva BA, Arribas JR, et al. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis. 2008;198(2):234-40.  [PMID:18540803]

    Comment: LPV/r monotherapy after LPV/r+ZDV+3TC vs EFV+ZDV+3TC in ARV-naive. At 96 wks, 48% of LPV/r and 61% of EFV with VL < 50 (NS)

  4. Mallolas J, Pich J, Peñaranda M, et al. Induction therapy with trizivir plus efavirenz or lopinavir/ritonavir followed by trizivir alone in naive HIV-1-infected adults. AIDS. 2008;22(3):377-84.  [PMID:18195564]

    Comment: AZT/3TC/ABC + EFV or LPV/r induction, followed by AZT/3TC/ABC alone as maintenance. HIgh rate of adverse events during induction, relatively low rate of viral suppression during maintenance.

  5. Asboe D, Williams IG, Goodall RL, et al. A virological benefit from an induction/maintenance strategy: the Forte trial. Antivir Ther. 2007;12(1):47-54.  [PMID:17503747]

    Comment: Virological benefit found with induction with 2 NRTIs + NNRTI + PI/r followed by 2 NRTIs + NNRTI compared to initial and continued therapy with 2 NRTIs + NNRTI

  6. INITIO Trial International Co-ordinating Committee, Yeni P, Cooper DA, et al. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial. Lancet. 2006;368(9532):287-98.  [PMID:16860698]

    Comment: EFV + 2 NRTIs superior to NFV + 2 NRTIs and EF + /NFV + 2 NRTIs for VL suppression and CD4 response at 3 yrs.

  7. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006;296(7):769-81.  [PMID:16905783]

    Comment: RCT in ARV-naive, no differences between 3- and 4-drug regimen (AZT/3TC/ABC + EFV vs. AZT/3TC + EFV) in VL suppression

  8. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr. 2005;40(3):280-7.  [PMID:16249701]

    Comment: Small pilot study (n=42). Increased risk of virologic rebound on LPV/r alone (81%) after 3-ARV induction then those remaining on 3-ARV (95%). Failures of monotherapy not associated with significant PI resistance.

  9. Markowitz M, Hill-Zabala C, Lang J, et al. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2005;39(3):257-64.  [PMID:15980684]

    Comment: AZT/3TC/ABC/EFV for 48 weeks, then AZT/3TC/ABC for 48 weeks: better adherence, equivalent VL suppression and better lipid profiles compared to continued 4 drugs. 56% had baseline VL > 100,000 c/ml. High drop-out rate before randomization step limits applicability of findings.

  10. Michelmore H, Jeganathan S, Chan D, et al. Sustained HIV-1 suppression in treatment-naive patients undergoing 4- to 3-drug induction maintenance therapy (INDUMAIN). J Acquir Immune Defic Syndr. 2003;33(4):543-4.  [PMID:12869845]

    Comment: Retrospective analysis of clinical cohort. 2 NRTI + 2 PI induction until VL <50 for > 6 mos, then 2 NRTI + NNRTI (EFV or NVP) maintenance. 1/43 had VL recound > 50 with mean 3.7 yr follow-up/

  11. Rutherford GW, Sangani PR, Kennedy GE. Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Cochrane Database Syst Rev. 2003.  [PMID:14583945]

    Comment: Synthesis of data from the above and earlier studies indicates that induction-maintenance with 2 drugs not good strategy, with up to 5-fold risk of viral rebound.

  12. Flandre P, Raffi F, Descamps D, et al. Final analysis of the Trilège induction-maintenance trial: results at 18 months. AIDS. 2002;16(4):561-8.  [PMID:11872999]

    Comment: After AZT/3TC/IDV 3-month induction, AZT/IDV or AZT/3TC associated with high rebound rate compared to continuing induction regimen.

  13. Girard PM, Cabie A, Michelet C, et al.; EFV/TDF vs EFV/3TC/TDF as maintenance regimen in virologically controlled patients under HAART: a 6-month analysis of the COOL trial.; Program and Abstracts of the 15th International AIDS Conference. July 11-16, 2004. Bangkok, Thailand. Abstract TuPeB4493;

    Comment: Short (6-month) follow-up suggests that EFV/TDF as effective as EFV/3TC/TDF, but insufficient follow-up to recommend currently. May make no sense to do this since TDF/FTC now coformulated, 3TC and FTC are safe and well tolerated, and both increase genetic barrier to resistance for TDF.

  14. Burgos J, Crespo M, Falco V, et al. Simplification to dual antiretroviral therapy including a ritonavir-boosted protease inhibitor in treatment-experienced HIV-1-infected patients. J Antimicrob Chemother. 2012; 67:2479-2486
  15. Di Giambenedetto S, Fabbiani M, Colafigli M, et al. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study). J Antimicrob Chemother. 2013; 68:1364-1372

    Comment: After viral suppression on ATV/r + 2 NRTIs, ATV/r + 1 NRTI (3TC) non-inferior to continuing ATV/r + 2 NRTIs.

  16. J.A. Perez-Molina, R. Rubio, A. Rivero, J. Pasquau, I. Suárez, M. Riera, M. Estébanez, J. Santos, J. Sanz, J. Troya, A. Mariño, A. Antela, J. Navarro, H. Esteban, GESIDA 7011 Study Group. Switching to dual therapy (atazanavir/ritonavir+lamivudine) vs. standard triple therapy (atazanavir/ritonavir+2 nucleos[t]ides) is safe and effective in virologically suppressed patients: 48-week results of a randomized clinical trial (SALT study). Abstract LBPE18 10th IAS, Melbourne, Australia July 20-15, 2014.

    Comment: After viral suppression on ATV/r + 2NRTIs, ATV/r + 1 NRTI (3TC) non-inferior to continuing ATV/r + 2 NRTIs.

  17. van Lunzen J, Pozniak A, J. Gatell, Antinori A, Klauck I, Serrano O, Baakili A, Yu M, Girard PM. HARNESS study: ritonavir-boosted atazanavir (ATV/r)+raltegravir (RAL) switch study in virologically suppressed, HIV-1-infected patients. Abstract LBPE19 10th IAS, Melbourne, Australia July 20-15, 2014

    Comment: After viral suppression on ATV/r+ 2 NRTIs, ATV/r + RAL was well-tolerated but resulted in more viral rebound than maintaining ATV/r+TDF/FTC at 24 weeks (ITT analysis: 80.6% vs. 94.6%). InSTI reistance in one patient.

  18. Wohl D. Simplification to abacavir/lamivudine (ABC/3TC) + atazanavir (ATV) from tenofovir/emtricitabine (TDF/FTC) + ATV/Ritonavir (RTV, /r) maintains viral suppression and improves bone biomarkers. Abstract H-556c. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; 2012

    Comment: Meta-analysis of RCTs - 5 trials included of induction-maintenance. After viral suppression on a boosted PI + 2 NRTI, unboosted ATV + 2 NRTI maintains viral suppression (varying follow-up from 24 to 144 weeks).

  19. Squires KE, Young B, DeJesus E, et al. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine. HIV Clin Trials. 2012; 13(5):233-244

    Comment: After viral suppression (< 50 copies/ml for 30 weeks) with ATV/r + 2 NRTIs (ABC+3TC), unboosted ATV + 2 NRTIs non-inferor to continued ATV/r + 2NRTIs out to 144 weeks of follow-up.

  20. Perez-Molina JA, Rubio R, Rivero A, Pasquau J, Suárez-Lozano I, Riera M, Estébanez M, Santos J, Sanz-Moreno J, Troya J, Mariño A, Antela A, Navarro J, Esteban H, Moreno S; GESIDA 7011 Study Group. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015; 15(7):775-84.

    Comment: In patients with VL < 50 copies/ml for 6 months on ATV/r + 2 NRTIs, switching to ATV/r + 3TC non-inferior to maintaining ATV/r + 2 NRTIs at 48 weeks of follow-up.

  21. Ofotokun I, Sheth AN, Sanford SE, et al. A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses. 2012; 28:1196-1206

    Comment: Pilot study (n=60) of patients with VL < 50 copies/ml on PI/r (65%) or NNRTI (35%) + 2 NRTIs switched to LPV/r+ RAL or continue baseline regimen. LPR/r + RAL non-inferior to baseline regimen at 48 weeks.

  22. Mondi A, Fabbiani M, Ciccarelli N, Colafigli M, D’Avino A, Borghetti A, Gagliardini R, Cauda R, De Luca A, Di Giambenedetto S. Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study. J Antimicrob Chemother. 2015; 70(6):1843-9.

    Comment: Small pilot study (n=40). After viral suppression (VL < 50 cpies/ml) with ATV/r + 2 NRTIs, ATV/r + 3TC non-inferior to maintaining ATV/r + 2 NRTI out to 144 weeks.

  23. Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010; 24(15):2365-2374

    Comment: In patients with baseline VL < 50 (n=242), DRV/r noninferior to DRV/r + 2 NRTIs at 48 weeks of follow-up per protocol analysis (99% DRV/r+2 NRTIs vs. 94.1% DRV/r) but difference excluded noninferiority by ITT analysis (92% (DRV/r+ 2NRTIs vs 87.5% DRV/r).

  24. Castagna A1, Spagnuolo V, Galli L, Vinci C, Nozza S, Carini E, D’Arminio Monforte A, Montella F, Antinori A, Di Biagio A, Rusconi S, Lazzarin A; MODAt Study Group. Simplification to atazanavir/ritonavir monotherapy for HIV-1 treated individuals on virological suppression: 48-week efficacy and safety results. AIDS. 2014; 28(15):2269-79.

    Comment: In patients with VL suppression on ATV/r + 2 NRTIs (n=103), ATV/r monotherapy showed lower virological efficacy compared to maintaining ATV/r + 2 NRTIs at 48 weeks.

  25. Arribas JR, Clumeck N, Nelson M, Hill A, van Delft Y, Moecklinghoff C. The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline. HIV Med. 2012;13(7):398-405.

    Comment: For patients with baseline VL < 50 for at least 6 months (n=256), DRV/r monotherapy non-inferior to DRV/r + 2 NRTIs to maintain viral suppression in ITT analysis (84% vs. 83%) out to 144 weeks, but not in TLOVR switch equals failure analysis (69% DVR/r vs 75% DVr/r+2NRTIs).

  26. Arribas JR, Girard PM, Landman R, Pich J, Mallolas J, Martínez-Rebollar M, Zamora FX, Estrada V, Crespo M, Podzamczer D, Portilla J, Dronda F, Iribarren JA, Domingo P, Pulido F, Montero M, Knobel H, Cabié A, Weiss L, Gatell JM; OLE/RIS-EST13 Study Group. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015; 15(7):785-92.

    Comment: After viral suppression on LPV/r + 2 NRTIs for at least 6 months(n=250), maintenance on LPV/r + 1 NRTI (3TC) non-inferior to continuing LPV/r + 2 NRTIs at 48 weeks.

  27. Ghosn J, Carosi G, Moreno S, Pokrovsky V, Lazzarin A, Pialoux G, Sanz-Moreno J, Balogh A, Vandeloise E, Biguenet S, Leleu G, Delfraissy JF. Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen. Antivir Ther. 2010;15(7):993-1002

    Comment: InduMa Study: After viral suppression on ATZ/r + 2 NRTIS for 26-30 weeks (n=172), unboosted ATZ + 2NRTIS non-inferior to continuing ATZ/r + 2 NRTIs at 48 weeks.

  28. Baril J1, Conway B, Giguère P, Ferko N, Hollmann S, Angel JB. A meta-analysis of the efficacy and safety of unboosted atazanavir compared with ritonavir-boosted protease inhibitor maintenance therapy in HIV-infected adults with established virological suppression after induction. HIV Med. 2014 May;15(5):301-10.

    Comment: Meta-analysis of 5 studies showing that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy

  29. Paton NI, Stohr W, Arenas-Pinto A, Fisher M, Williams I, Johnson M, Orkin C, Chen F, Lee V, Winston A, Gompels M, Fox J, Scott K, Dunn DT, for the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) team. Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV 2015; 2:e417-26.

    Comment: PIVOT trial: 587 patients with VL < 50 copies/ml for at least 24 weeks and CD4 > 100 on triple-combination therapy randomized to DRV+RTV QD or LPV+RTV BID or remain on triple therapy. Outcome of new intermediate or high-level resistance to 1 or more drugs originally sensitive. Non-inferiority of PI monotherapy at 3 years. Notably, monitoring of VL every 12 weeks throughout study.

  30. Paton NI, Stohr W, Arenas-Pinto A, Fisher M, Williams I, Johnson M, Orkin C, Chen F, Lee V, Winston A, Gompels M, Fox J, Scott K, Dunn DT, for the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) team. Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV 2015; 2:e417-26.

    Comment: PIVOT trial: 587 patients with VL < 50 copies/ml for at least 24 weeks and CD4 > 100 on triple-combination therapy randomized to DRV+RTV QD or LPV+RTV BID or remain on triple therapy. Primary outcome of new intermediate or high-level resistance to 1 or more drugs originally sensitive. Non-inferiority of PI monotherapy at 3 years with 58% able to stay on PI monotherapy; 27% had VL rebound and triple therapy restarted. 0.7% in triple therapy and 1.4% in PI mono had primary outcome. Notably, monitoring of VL every 12 weeks throughout study.

Induction-Maintenanceis the Johns Hopkins Guides Word of the day!

Last updated: October 31, 2015