Artículo

Boyd, M.A.; Moore, C.L.; Molina, J.-M.; Wood, R.; Madero, J.S.; Wolff, M.; Ruxrungtham, K.; Losso, M.; Renjifo, B.; Teppler, H.; Kelleher, A.D.; Amin, J.; Emery, S.; Cooper, D.A. "Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis" (2015) The Lancet HIV. 2(2):e42-e51
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Abstract:

Background: WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study. Methods: As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance. Findings: From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3·0 (1·3-4·3) in the NtRTI group and 3·0 (1·0-4·3) in the raltegravir group. The median sGSS in the NtRTI group was 1·0 (0·5-1·8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2·18, 95%CI 1·07-4·47; p=0·03) and week 48 (2·49, 1·09-5·69; p=0·03), baseline plasma viral load greater than 100 000 copies per mL (3·43, 1·70-6·94; p=0·0006), baseline gGSS >4·25 (4·73, 1·94-11·6; p=0·0007), and being Hispanic (3·13, 1·21-8·13; p=0·02) or African (3·49, 1·68-7·28; p=0·0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2·47, 95% CI 1·02-5·99; p=0·05), baseline log10 viral load (1·83, 1·12-2·97; p=0·02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3·18, 1·12-9·02; p=0·03). Interpretation: Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable. Funding: University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research. © 2015 Elsevier Ltd.

Registro:

Documento: Artículo
Título:Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis
Autor:Boyd, M.A.; Moore, C.L.; Molina, J.-M.; Wood, R.; Madero, J.S.; Wolff, M.; Ruxrungtham, K.; Losso, M.; Renjifo, B.; Teppler, H.; Kelleher, A.D.; Amin, J.; Emery, S.; Cooper, D.A.
Filiación:The Kirby Institute for Infection and Immunity in Society, UNSW Medicine, University of New South Wales Australia, Sydney, NSW, Australia
Hospital Saint-Louis, Department of Clinical Infectious Diseases, Paris, France
Desmond Tutu HIV Foundation, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Instituto Nacional de Ciencias Medicas y Nutricion (Salvador Zubirán), Department of Infectious Diseases, Mexico DF, Mexico
Hospital San Borja-Arriaran, University of Chile, Santiago, Chile
Chulalongkorn University; HIV-NAT, Thai Red Cross AIDS Research Center, Bangkok, 10330, Thailand
Hospital J M Ramos Mejía, Servicio de Immunocompromatidos, Pabellon de Clinica, Buenos Aires, Argentina
Global Medical Affairs, Virology, Global Pharmaceutical Research and oDevelopment, AbbVie Inc, Chicago, IL, United States
Merck Clinical Research-Infectious Diseases, Merck, Whitehouse Station, NJ, United States
Palabras clave:abacavir; didanosine; emtricitabine; lamivudine; lopinavir; raltegravir; ritonavir; RNA directed DNA polymerase; RNA directed DNA polymerase inhibitor; stavudine; tenofovir; zidovudine; 2',3' dideoxynucleoside derivative; abacavir; anti human immunodeficiency virus agent; lamivudine; lopinavir; ritonavir; tenofovir; adult; aged; antiviral resistance; Article; female; gene mutation; genetic algorithm; genotype; genotypic sensitivity score; highly active antiretroviral therapy; human; Human immunodeficiency virus 1 infection; major clinical study; male; multicenter study; priority journal; randomized controlled trial; scoring system; sequence analysis; virus load; antiviral resistance; Australia; clinical trial; controlled study; drug combination; drug effects; genetics; HIV Infections; Human immunodeficiency virus 1; isolation and purification; medication compliance; middle aged; physiology; psychology; treatment outcome; virology; young adult; Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Ritonavir; South Australia; Tenofovir; Treatment Outcome; Viral Load; Young Adult
Año:2015
Volumen:2
Número:2
Página de inicio:e42
Página de fin:e51
DOI: http://dx.doi.org/10.1016/S2352-3018(14)00061-7
Título revista:The Lancet HIV
Título revista abreviado:Lancet HIV
ISSN:23523018
CAS:abacavir, 136470-78-5, 188062-50-2; didanosine, 69655-05-6; emtricitabine, 137530-41-7, 143491-54-7, 143491-57-0; lamivudine, 134678-17-4, 134680-32-3; lopinavir, 192725-17-0; raltegravir, 518048-05-0, 871038-72-1, 889131-29-7; ritonavir, 155213-67-5; RNA directed DNA polymerase, 37213-50-6, 9068-38-6; stavudine, 3056-17-5; tenofovir, 147127-19-3, 147127-20-6; zidovudine, 30516-87-1; abacavir; Anti-HIV Agents; Dideoxynucleosides; Lamivudine; Lopinavir; Ritonavir; Tenofovir
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_23523018_v2_n2_pe42_Boyd

Referencias:

  • Guidelines for the use of antiretroviral agents in adults and adolescents, , http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0, Department of Human and Health Services, USAUSA, (accessed March 10, 2014)
  • Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia (2003) N Engl J Med, 348, pp. 2186-2195. , TORO 2 Study Group
  • Hicks, C.B., Cahn, P., Cooper, D.A., Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials (2006) Lancet, 368, pp. 466-475. , for the RESIST investigator group
  • Clotet, B., Bellos, N., Mollina, J.-M., Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials (2007) Lancet, 369, pp. 1169-1178. , for the POWER 1 and 2 study groups
  • Raltegravir with optimized background therapy for resistant HIV-1 infection (2008) N Engl J Med, 359, pp. 339-354. , BENCHMRK Study Teams
  • Maraviroc for previously treated patients with R5 HIV-1 infection (2008) N Engl J Med, 359, pp. 1429-1441. , MOTIVATE Study Teams
  • Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study (2013) Lancet, 381, pp. 2091-2099. , SECOND-LINE Study Group
  • Paton, N.I., Kityo, C., Hoppe, A., A pragmatic randomised controlled strategy trial of three second-line treatment options for use in public health rollout programme settings: the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial (2014) N Engl J Med, 371, pp. 234-247. , for the EARNEST Trial Group
  • Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, , http://www.who.int/hiv/pub/guidelines/arv2013/download/en/, WHO, (accessed March 15, 2014)
  • Harries, A.D., Zachariah, R., van Oosterhout, J.J., Diagnosis and management of antiretroviral-therapy failure in resource-limited settings in sub-Saharan Africa: challenges and perspectives (2010) Lancet Infect Dis, 10, pp. 60-65
  • Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings (2009) J Infect Dis, 200, pp. 687-697. , EuroSIDA Study Group
  • Hosseinipour, M.C., van Oosterhout, J.J., Weigel, R., The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy (2009) AIDS, 23, pp. 1127-1134
  • Amin, J., Boyd, M.A., Kumarasamy, N., for the SECOND-LINE study group. Raltegravir non-inferior to nuleos(t)ide-based regimens in SECOND-LINE therapy with lopinavir/ritonavir over 96 weeks: a randomised (2014), open label study. Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, March 3-6, Abstr 237; Genotypic Resistance Interpretation Algorithm version 6.3.1, , http://sierra2.stanford.edu/sierra/servlet/JSierra, Stanford University HIV Drug Resistance Database, (accessed March 10, 2014)
  • Chesney, M.A., Ickovics, J.R., Chambers, D.B., Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG) (2000) AIDS Care, 12, pp. 255-266
  • Deeks, S.G., Wrin, T., Liegler, T., Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia (2001) N Engl J Med, 344, pp. 472-480
  • Nijhuis, M., Deeks, S., Boucher, C., Implications of antiretroviral resistance on viral fitness (2001) Curr Opin Infect Dis, 14, pp. 23-28
  • Deeks, S.G., Hoh, R., Neilands, T.B., Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection (2005) J Infect Dis, 192, pp. 1537-1544
  • Thirumurthy, H., Siripong, N., Vreeman, R.C., Differences between self-reported and electronically monitored adherence among patients receiving antiretroviral therapy in a resource-limited setting (2012) AIDS, 26, pp. 2399-2403
  • Hosseinipour, M.C., Kumwenda, J.J., Weigel, R., Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline (2010) HIV Med, 11, pp. 510-518
  • Johnston, V., Cohen, K., Wiesner, L., Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch (2014) J Infect Dis, 209, pp. 711-720
  • Molina, J.M., Lamarca, A., Andrade-Villanueva, J., Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study (2012) Lancet Infect Dis, 12, pp. 27-35
  • Cahn, P., Andrade-Villanueva, J., Arribas, J.R., Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial (2014) Lancet Infect Dis, 14, pp. 572-580
  • Katzenstein, D.A., HIV RNA and genotype in resource-limited settings: can we do better? (2014) Clin Infect Dis, 58, pp. 110-112
  • Panidou, E.T., Trikalinos, T.A., Ioannidis, J.P., Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analysis (2004) AIDS, 18, pp. 2153-2161
  • Eron, J.S., Young, B., Cooper, D.A., Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials (2010) Lancet, 375, pp. 396-407. , for the SWITCHMRK 1 and 2 investigators
  • Hurt, C.B., Sebastian, J., Hicks, C.B., Eron, J.J., Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012 (2014) Clin Infect Dis, 58, pp. 423-431
  • Raffi, F., Babiker, A.G., Richert, L., Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial (2014) Lancet, 384, pp. 1942-1951. , for the NEAT001/ANRS143 study group
  • Hosseinipour, M.C., Gupta, R.K., Van Zyl, G., Eron, J.J., Nachega, J.B., Emergence of HIV drug resistance during first- and second-line antiretroviral therapy in resource-limited settings (2013) J Infect Dis, 207, pp. S49-S56
  • Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant hiv-1: 24-week results of the phase III VIKING-3 study (2014) J Infect Dis, 210, pp. 354-362. , VIKING-3 Study Group
  • Johnson, V.A., Calvez, V., Gunthard, H.F., Update on the drug resistance mutations in HIV-1: March 2013 (2013) Top Antivir Med, 21, pp. 6-14

Citas:

---------- APA ----------
Boyd, M.A., Moore, C.L., Molina, J.-M., Wood, R., Madero, J.S., Wolff, M., Ruxrungtham, K.,..., Cooper, D.A. (2015) . Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis. The Lancet HIV, 2(2), e42-e51.
http://dx.doi.org/10.1016/S2352-3018(14)00061-7
---------- CHICAGO ----------
Boyd, M.A., Moore, C.L., Molina, J.-M., Wood, R., Madero, J.S., Wolff, M., et al. "Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis" . The Lancet HIV 2, no. 2 (2015) : e42-e51.
http://dx.doi.org/10.1016/S2352-3018(14)00061-7
---------- MLA ----------
Boyd, M.A., Moore, C.L., Molina, J.-M., Wood, R., Madero, J.S., Wolff, M., et al. "Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis" . The Lancet HIV, vol. 2, no. 2, 2015, pp. e42-e51.
http://dx.doi.org/10.1016/S2352-3018(14)00061-7
---------- VANCOUVER ----------
Boyd, M.A., Moore, C.L., Molina, J.-M., Wood, R., Madero, J.S., Wolff, M., et al. Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: An exploratory analysis. Lancet HIV. 2015;2(2):e42-e51.
http://dx.doi.org/10.1016/S2352-3018(14)00061-7