Treatment durability and virological response in treatment-experienced HIV-positive patients on an integrase inhibitor-based regimen: an Australian cohort study
Nicole L. De La Mata A K , David A. Cooper A , Darren Russell B C D , Don Smith E F , Ian Woolley G H I , Maree O. Sullivan A J , Stephen Wright A and Matthew Law A
+ Author Affiliations
- Author Affiliations
A Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, NSW 2052, Australia.
B School of Medicine and Dentistry, James Cook University, Townsville, Qld 4811, Australia.
C University of Melbourne, Parkville, Vic. 3010, Australia.
D Cairns Sexual Health Service, Cairns, Qld 4870, Australia.
E The Albion Centre, Sydney, NSW 2010, Australia.
F School of Public Health and Community Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
G Monash Health, Infectious Disease, Melbourne, Vic. 3168, Australia.
H Monash Health, Australia Department of Medicine, Melbourne, Vic. 3168, Australia.
I Monash University, Australia Department of Infectious Diseases, Melbourne, Vic. 3800, Australia.
J Gold Coast Sexual Health Clinic, Miami, Qld 4215, Australia.
K Corresponding author. Email: ndelamata@kirby.unsw.edu.au
Sexual Health 13(4) 335-344 https://doi.org/10.1071/SH15210
Submitted: 30 October 2015 Accepted: 8 March 2016 Published: 21 April 2016
Abstract
Background: Integrase inhibitors (INSTI) are a newer class of antiretroviral (ARV) drugs that offer additional treatment options for experienced patients. Our aim is to describe treatment durability and virological outcomes in treatment-experienced HIV-positive patients using INSTI-based regimens. Methods: All patients in the Australian HIV Observational Database who had received an INSTI-based regimen ≥ 14 days as well as previous therapy were included in the study. We defined two groups of treatment-experienced patients: (1) those starting a second-line regimen with INSTI; and (2) highly experienced patients, defined as having prior exposure to all three main ARV classes, nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors and protease inhibitors, before commencing INSTI. Survival methods were used to determine time to viral suppression and treatment switch, stratified by patient treatment experience. Covariates of interest included age, gender, hepatitis B and C co-infection, previous antiretroviral treatment time, patient treatment experience and baseline viral load. Results: Time to viral suppression and regimen switching from INSTI initiation was similar for second-line and highly experienced patients. The probability of achieving viral suppression at 6 months was 77.7% for second-line patients and 68.4% for highly experienced patients. There were 60 occurrences of regimen switching away from INSTI observed over 1274.0 person-years, a crude rate of 4.71 (95% CI: 3.66–6.07) per 100 person-years. Patient treatment experience was not a significant factor for regimen switch according to multivariate analysis, adjusting for relevant covariates. Conclusions: We found that INSTI-based regimens were potent and durable in experienced HIV-positive patients receiving treatment outside clinical trials. These results confirm that INSTI-based regimens are a robust treatment option.
Additional keywords: regimen switch, viral load, time to treatment switch.
References
[1] Daniel V, Susal C, Melk A, Weimer R, Kropelin M, Zimmermann R, et al Reduction of viral load and immune complex load on CD4+ lymphocytes as a consequence of highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patients. Immunol Lett 1999; 69 283–9.| Reduction of viral load and immune complex load on CD4+ lymphocytes as a consequence of highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patients.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXltVCls7c%3D&md5=054930669a549b0c34555f03b2eb2740CAS | 10482364PubMed |
[2] Hejdeman B, Lenkei R, Leandersson AC, Hultstrom AL, Wahren B, Sandstrom E, et al Clinical and immunological benefits from highly active antiretroviral therapy in spite of limited viral load reduction in HIV type 1 infection. AIDS Res Hum Retroviruses 2001; 17 277–86.
| Clinical and immunological benefits from highly active antiretroviral therapy in spite of limited viral load reduction in HIV type 1 infection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXitVKntr8%3D&md5=79a97dac7c08f21bd78f34338cca310dCAS | 11242515PubMed |
[3] World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: WHO; 2013.
[4] Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, et al Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000; 287 646–50.
| Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXovVyjtQ%3D%3D&md5=9e7004bd58ca1b2c1c807976c5298dc5CAS | 10649997PubMed |
[5] Kumarasamy N, Madhavan V, Venkatesh KK, Saravanan S, Kantor R, Balakrishnan P, et al High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings. Clin Infect Dis 2009; 49 306–9.
| High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXpt12qsb4%3D&md5=6dbe40d1d78123de75f2d7308cb6bb02CAS | 19522657PubMed |
[6] Jansson J, Wilson DP, Carr A, Petoumenos K, Boyd MA. Currently available medications in resource-rich settings may not be sufficient for lifelong treatment of HIV. AIDS 2013; 27 1245–51.
| Currently available medications in resource-rich settings may not be sufficient for lifelong treatment of HIV.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXpsFaiurc%3D&md5=479cfcb8c694de5eb6e1ad54986229dbCAS | 23276809PubMed |
[7] Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359 339–54.
| Raltegravir with optimized background therapy for resistant HIV-1 infection.Crossref | GoogleScholarGoogle Scholar | 18650512PubMed |
[8] Sabin CA, Hill T, Lampe F, Matthias R, Bhagani S, Gilson R, et al Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study. BMJ 2005; 330 695–8.
| Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study.Crossref | GoogleScholarGoogle Scholar | 15749728PubMed |
[9] Eron JJ, Cooper DA, Steigbigel RT, Clotet B, Gatell JM, Kumar PN, et al Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis 2013; 13 587–96.
| Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXnt1alu7o%3D&md5=670346504d5157c7b144a27209833554CAS | 23664333PubMed |
[10] Caby F, Valin N, Marcelin AG, Schneider L, Andrade R, Guiguet M, et al Raltegravir as functional monotherapy leads to virological failure and drug resistance in highly treatment-experienced HIV-infected patients. Scand J Infect Dis 2010; 42 527–32.
| Raltegravir as functional monotherapy leads to virological failure and drug resistance in highly treatment-experienced HIV-infected patients.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXntVansrk%3D&md5=af4aa78eb8f33eddbd138047657ec12fCAS | 20222846PubMed |
[11] Marcelin AG, Delaugerre C, Beaudoux C, Descamps D, Morand-Joubert L, Amiel C, et al A cohort study of treatment-experienced HIV-1-infected patients treated with raltegravir: factors associated with virological response and mutations selected at failure. Int J Antimicrob Agents 2013; 42 42–7.
| A cohort study of treatment-experienced HIV-1-infected patients treated with raltegravir: factors associated with virological response and mutations selected at failure.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXlsVGrtLg%3D&md5=f1cf4ee444271a4d6faff0ced1b3c715CAS | 23562640PubMed |
[12] Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, et al Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382 700–8.
| Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtVKrur7I&md5=a6305d2cba712061efb1ab6d0ea75265CAS | 23830355PubMed |
[13] Wirden M, Simon A, Schneider L, Tubiana R, Malet I, Ait-Mohand H, et al Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother 2009; 64 1087–90.
| Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXht1OqtLvK&md5=c4a15f3d58bf2826bd8aeac7ab3d5a98CAS | 19717396PubMed |
[14] Shah BM, Schafer JJ, Desimone JA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014; 34 506–20.
| Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXmvF2ktLg%3D&md5=6fbe50632804a6f40582e5a560e5fa44CAS | 24347095PubMed |
[15] Lampiris HW. Elvitegravir: a once-daily, boosted, HIV-1 integrase inhibitor. Expert Rev Anti Infect Ther 2012; 10 13–20.
| Elvitegravir: a once-daily, boosted, HIV-1 integrase inhibitor.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhs1Shtb7E&md5=cdd46b48756994f95fefdbc5e9ed141aCAS | 22149610PubMed |
[16] Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs 2012; 21 395–401.
| Elvitegravir: a once-daily inhibitor of HIV-1 integrase.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XitFSrtLo%3D&md5=0babad86dd4f5ec437a41852c5412250CAS | 22321026PubMed |
[17] Patel DA, Snedecor SJ, Tang WY, Sudharshan L, Lim JW, Cuffe R, et al 48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. PLoS One 2014; 9 e105653
| 48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis.Crossref | GoogleScholarGoogle Scholar | 25188312PubMed |
[18] Fantauzzi A, Turriziani O, Mezzaroma I. Potential benefit of dolutegravir once daily: efficacy and safety. HIV AIDS 2013; 5 29–40.
| 1:CAS:528:DC%2BC3sXjtlCqsro%3D&md5=3fc48c2a2f7953906aaf09c9f4b53da0CAS |
[19] Osterholzer DA, Goldman M. Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection. Clin Infect Dis 2014; 59 265–71.
| Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection.Crossref | GoogleScholarGoogle Scholar | 24723281PubMed |
[20] The Australian HIV Observational Database Rates of combination antiretroviral treatment change in Australia, 1997–2000. HIV Med 2002; 3 28–36.
| Rates of combination antiretroviral treatment change in Australia, 1997–2000.Crossref | GoogleScholarGoogle Scholar | 12059948PubMed |
[21] Squires KE, Bekker LG, Eron JJ, Cheng B, Rockstroh JK, Marquez F, et al Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study. AIDS Res Hum Retroviruses 2013; 29 859–70.
| Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXns1antrY%3D&md5=ac3c5091e6816956d38c21de48bdbfc6CAS | 23351187PubMed |
[22] Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, et al Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis 2011; 53 807–16.
| Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXht1SitbnO&md5=f8fa7d1c335e15bc505b976b6f933ae9CAS | 21921224PubMed |
[23] Capetti A, Landonio S, Meraviglia P, Di Biagio A, Lo Caputo S, Sterrantino G, et al 96-week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience. PLoS One 2012; 7 e39222
| 96-week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtVKrsrnP&md5=ebdd55cd012ae64afea41a5a9bb151e3CAS | 22808029PubMed |
[24] Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, et al Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 2007; 369 1261–9.
| Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXktF2hu7c%3D&md5=3c093abbf0b8b71828efaccae4eae6ceCAS | 17434401PubMed |
[25] Wittkop L, Breilh D, Da Silva D, Duffau P, Mercie P, Raymond I, et al Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort. J Antimicrob Chemother 2009; 63 1251–5.
| Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXmtFSgtro%3D&md5=2fc9b4ac0b6581dfec71ada34eafae05CAS | 19336453PubMed |
[26] Palmisano L. Role of integrase inhibitors in the treatment of HIV disease. Expert Rev Anti Infect Ther 2007; 5 67–75.
| Role of integrase inhibitors in the treatment of HIV disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXjtF2jsLo%3D&md5=67cc764401c86982c7f0fc6d0562846fCAS | 17266455PubMed |
[27] Hughes A, Barber T, Nelson M. New treatment options for HIV salvage patients: an overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists. J Infect 2008; 57 1–10.
| New treatment options for HIV salvage patients: an overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists.Crossref | GoogleScholarGoogle Scholar | 18556070PubMed |
[28] Capetti A, Meraviglia P, Landonio S, Sterrantino G, Di Biagio A, Lo Caputo S, et al Four years data of raltegravir-based salvage therapy in HIV-1-infected, treatment-experienced patients: the SALIR-E Study. Int J Antimicrob Agents 2014; 43 189–94.
| Four years data of raltegravir-based salvage therapy in HIV-1-infected, treatment-experienced patients: the SALIR-E Study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhvFOhtbzJ&md5=eb523785eda9dc8b77c11d2f6faa0265CAS | 24315315PubMed |
[29] Australian HIVOD Rates of combination antiretroviral treatment change in Australia, 1997–2000. HIV Med 2002; 3 28–36.
| Rates of combination antiretroviral treatment change in Australia, 1997–2000.Crossref | GoogleScholarGoogle Scholar | 12059948PubMed |
[30] Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46 125–33.
| Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhtVOktbfL&md5=02585129837d635ce0896f0443d8879bCAS | 17721395PubMed |
[31] Elion R, Molina JM, Ramon Arribas Lopez J, Cooper D, Maggiolo F, Wilkins E, et al A randomized phase-3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results. J Acquir Immune Defic Syndr 2013; 63 494–7.
| A randomized phase-3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtVegur3P&md5=12cce3b7db92d96aba37e055568ce29dCAS | 23807156PubMed |
[32] Nkoa Onana DF, Mewoli B, Ouattara DA. Excitability in the host–pathogen interactions of HIV infection and emergence of viral load blips. J Theor Biol 2013; 317 407–17.
| Excitability in the host–pathogen interactions of HIV infection and emergence of viral load blips.Crossref | GoogleScholarGoogle Scholar | 23108210PubMed |
[33] Kanapathipillai R, McManus H, Kamarulzaman A, Lim PL, Templeton DJ, Law M, et al The Significance of HIV ‘blips’ in resource-limited settings: is it the same? Analysis of the Treat Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD). PLoS One 2014; 9 e86122
| 24516527PubMed |
[34] Verhofstede C, Van Wanzeele F, Reynaerts J, Mangelschots M, Plum J, Fransen K. Viral load assay sensitivity and low level viremia in HAART treated HIV patients. J Clin Virol 2010; 47 335–9.
| Viral load assay sensitivity and low level viremia in HAART treated HIV patients.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjslSqsbw%3D&md5=c174a77c32f15e1c737d38e1b8ec3eefCAS | 20138803PubMed |
[35] Vrijens B, Goetghebeur E, de Klerk E, Rode R, Mayer S, Urquhart J. Modelling the association between adherence and viral load in HIV-infected patients. Stat Med 2005; 24 2719–31.
| Modelling the association between adherence and viral load in HIV-infected patients.Crossref | GoogleScholarGoogle Scholar | 16118813PubMed |
[36] McManus H, Petoumenos K, Brown K, Baker D, Russell D, Read T, et al Loss to follow-up in the Australian HIV Observational Database. Antivir Ther 2014; 20 731–41.
| Loss to follow-up in the Australian HIV Observational Database.Crossref | GoogleScholarGoogle Scholar | 25377928PubMed |
[37] Lagnese M, Daar ES. Antiretroviral regimens for treatment-experienced patients with HIV-1 infection. Expert Opin Pharmacother 2008; 9 687–700.
| Antiretroviral regimens for treatment-experienced patients with HIV-1 infection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjtlWis7s%3D&md5=0a7d8bc090e3cc98ad707291ddd82bdbCAS | 18345948PubMed |
[38] Katlama C, Murphy R. Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection. Ther Clin Risk Manag 2009; 5 331–40.
| Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXpt1yltL0%3D&md5=c4f09b134ce8077144d151418661a457CAS | 19536321PubMed |
[39] Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, et al Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis 2010; 50 605–12.
| Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjtVSksLk%3D&md5=53b98f2218e945a511fbec60bf317639CAS | 20085491PubMed |
[40] Correll T, Klibanov OM. Integrase inhibitors: a new treatment option for patients with human immunodeficiency virus infection. Pharmacotherapy 2008; 28 90–101.
| Integrase inhibitors: a new treatment option for patients with human immunodeficiency virus infection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtlegsro%3D&md5=ef38894974a2592c6ae4526aa0b0c2a9CAS | 18154479PubMed |
