Comment
Since combination antiretroviral therapy (ART) for HIV became standard of care in the mid-1990s, all recommended initial treatments contain three active drugs: two drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class plus a third active drug with a different mechanism of action—a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor (typically boosted with ritonavir to improve pharmacokinetics), or an integrase inhibitor. This three-drug approach strikes the right balance between efficacy (as measured by rates of virological suppression) and the issues of toxicity and affordability (more drugs means more side-effects and higher costs). Importantly, this triple-therapy initial regimen has never been convincingly challenged in a comparative clinical trial, with strategies consisting of one, two, or four active drugs consistently falling short of the three-drug paradigm in efficacy or tolerability, or both.1–4 In The Lancet Infectious Diseases, Pedro Cahn and colleagues5 report the surprising results of the GARDEL (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) study. Done predominantly in middle-income countries, the study randomly assigned 426 treatment-naive patients with HIV to receive open-label lopinavir (400 mg) and ritonavir (100 mg) twice daily plus two NRTIs (triple therapy) or an experimental dual therapy regimen of lopinavir (400 mg) boosted with ritonavir (100 mg) plus lamivudine (150 mg) twice daily. The rationale behind selection of these two drugs was clear: many resistance mutations are needed for substantial resistance to ritonavir-boosted protease inhibitors (a high resistance barrier), making this class of antiviral drugs ideal for less intensive concomitant treatment. Additionally, the NRTIs lamivudine and the closely related emtricitabine have a favourable safety profile that distinguishes them from other drugs in this class.6 After 48 weeks of treatment, the virological response rate in both study arms was excellent. 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI –2·2 to 11·8; p=0·171), meeting the study’s primary non-inferiority endpoint. Even more impressive, non-inferiority was maintained for dual therapy even for those patients who entered with HIV RNA greater than
100 000 copies per mL at baseline (dual therapy 87·2% vs triple therapy 77·9%; difference 9·3%, 95% CI –2·8 to 21·5; p=0·145). These patients are typically the hardest to treat and, for both biological and psychosocial reasons, are at greatest risk for treatment failure. By contrast, in a recently presented study of another dual-therapy regimen—darunavir and ritonavir plus raltegravir—an excess of virological failure was noted for two active drugs compared with three in patients with high viral load.7 Since the dual-therapy approach obviated the use of several NRTIs with well-known and sometimes serious side-effects that are not reported with lamivudine alone, significantly fewer patients in the dual therapy group experienced drug-related adverse events. Zidovudine causes myelosuppression, gastrointestinal symptoms, headaches, and mitochondrial toxicity that can lead to lipoatrophy, hepatic steatosis, and lactic acidosis. Abacavir can induce a potentially life-threatening hypersensitivity syndrome, and hence should be given only to patients who are negative for the HLA-B*5701 allele; furthermore, it has been associated with an increased risk of cardiovascular disease.8 Tenofovir lowers bone density more than other NRTIs9 and can be nephrotoxic.10 Although none of these serious adverse events were reported in the GARDEL study, there were more NRTIrelated side-effects in the standard-of-care triple therapy arm than in the dual therapy arm. The results of GARDEL are important, and the investigators and study sponsor should be credited for doing a fully powered randomised trial of this new approach to treatment. However, there are several limitations to the study that make widespread adaptation of this particular strategy of lopinavir with ritonavir plus lamivudine unlikely. First, the regimen consists of three pills taken twice daily, which is cumbersome by current standards of HIV treatment. There are already three (and soon to be four) approved options for initial HIV treatment that consist of one pill once daily as a coformulation of three active drugs. Such simplified regimens are enormously popular with patients, reduce prescribing errors, and can improve both adherence and treatment outcomes.11 Second, once-daily atazanavir with ritonavir and darunavir with ritonavir, induce lower rates of hyperlipidaemia and gastrointestinal side-effects
www.thelancet.com/infection Published online April 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70753-4
Laguna Design/Science Photo Library
Initial therapy for HIV: can less be more?
Lancet Infect Dis 2014 Published Online April 28, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70753-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70736-4
1
Comment
and have supplanted lopinavir with ritonavir12,13 both in some treatment guidelines14,15 and in clinical practice. Can we assume that use of boosted atazanavir or darunavir with once-daily lamivudine would provide comparable results? Other details of the study raise some concerns about the validity of the results. Selection of the NRTI pair was at the discretion of the investigators, and the NRTIs were not provided by the study sponsors. Perhaps because zidovudine and lamivudine was the least expensive option for many participants, this NRTI combination was used by 54% of the control group, no doubt increasing the rate of adverse events for the triple therapy strategy. The study was done open label, which could lead to reporting bias for adverse events that disadvantaged the study group who received more active drugs. HIV RNA measurements were done in several different laboratories and with different assays (a very unusual practice for a contemporary HIV clinical trial). These caveats notwithstanding, the results of the GARDEL study support the testing of other novel twodrug strategies. Such regimens could be used either as initial therapy or as a deintensification option for virologically suppressed patients on triple therapy, which would be particularly useful for those experiencing toxicity to zidovudine, abacavir, or tenofovir. The availability of generic formulations of lamivudine might facilitate the testing of new coformulations, reducing pill burden and making these dual-therapy options more viable. If the promising results of GARDEL can be confirmed with other antiretroviral drugs—not just lopinavir with ritonavir and perhaps not just for boosted protease inhibitors—one could easily envision scenarios in which, for HIV treatment, less can certainly be more.
2
PES has received personal fees from AbbVie, BMS, Gilead, GlaxoSmithKline, Janssen, and Merck, and grants from BMS, Gilead, GlaxoSmithKline, the US National Institutes of Health (UM1AI069412), New England AIDS Education and Training Center (NEAETC; 6H4AHA00050-12-00), and Cost-Effectiveness of Preventing AIDS Complications (CEPAC; R37AI042006). 1
2 3
4
5
6
7
8
9
10
11
12
13
Paul E Sax
14
Division of Infectious Diseases and Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA [email protected]
15
Delfraissy JF, Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS 2008; 22: 385–93. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358: 2095–106. Kozal MJ, Lupo S, DeJesus E, et al. A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN study results. HIV Clin Trials 2012; 13: 119–30. 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: 769–81. Cahn P, Andrade-Villanueva J, Arribas JR, on behalf of the GARDEL Study Group. 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. Lancet Infect Dis 2014; published online April 28. http://dx.doi. org/10.1016/S1473-3099(14)70736-4 Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 1995; 333: 1662–69. Raffi F, Babiker AG, Richert L, et al. First-line RAL + DRV/r is non-inferior to TDF/FTC + DRV/r: the NEAT001/ANRS143 randomised trial. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014); Boston, MA, USA; March 3–6, 2014. Abstract 84LB. Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–26. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011; 203: 1791–801. Kalayjian RC, Lau B, Mechekano RN, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS 2012; 26: 1907–15. Bangsberg DR, Ragland K, Monk A, Deeks SG. A single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in HIV+ homeless and marginally housed people. AIDS 2010; 24: 2835–40. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008; 372: 646–55. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–97. US Department of Health and Human Services. Adult and adolescent ARV guidelines. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescentarv-guidelines/0 (accessed April 22, 2014). Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society–USA panel. JAMA 2012; 308: 387–402.
www.thelancet.com/infection Published online April 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70753-4
Since combination antiretroviral therapy (ART) for HIV became standard of care in the mid-1990s, all recommended initial treatments contain three active drugs: two drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class plus a third active drug with a different mechanism of action—a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor (typically boosted with ritonavir to improve pharmacokinetics), or an integrase inhibitor. This three-drug approach strikes the right balance between efficacy (as measured by rates of virological suppression) and the issues of toxicity and affordability (more drugs means more side-effects and higher costs). Importantly, this triple-therapy initial regimen has never been convincingly challenged in a comparative clinical trial, with strategies consisting of one, two, or four active drugs consistently falling short of the three-drug paradigm in efficacy or tolerability, or both.1–4 In The Lancet Infectious Diseases, Pedro Cahn and colleagues5 report the surprising results of the GARDEL (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) study. Done predominantly in middle-income countries, the study randomly assigned 426 treatment-naive patients with HIV to receive open-label lopinavir (400 mg) and ritonavir (100 mg) twice daily plus two NRTIs (triple therapy) or an experimental dual therapy regimen of lopinavir (400 mg) boosted with ritonavir (100 mg) plus lamivudine (150 mg) twice daily. The rationale behind selection of these two drugs was clear: many resistance mutations are needed for substantial resistance to ritonavir-boosted protease inhibitors (a high resistance barrier), making this class of antiviral drugs ideal for less intensive concomitant treatment. Additionally, the NRTIs lamivudine and the closely related emtricitabine have a favourable safety profile that distinguishes them from other drugs in this class.6 After 48 weeks of treatment, the virological response rate in both study arms was excellent. 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI –2·2 to 11·8; p=0·171), meeting the study’s primary non-inferiority endpoint. Even more impressive, non-inferiority was maintained for dual therapy even for those patients who entered with HIV RNA greater than
100 000 copies per mL at baseline (dual therapy 87·2% vs triple therapy 77·9%; difference 9·3%, 95% CI –2·8 to 21·5; p=0·145). These patients are typically the hardest to treat and, for both biological and psychosocial reasons, are at greatest risk for treatment failure. By contrast, in a recently presented study of another dual-therapy regimen—darunavir and ritonavir plus raltegravir—an excess of virological failure was noted for two active drugs compared with three in patients with high viral load.7 Since the dual-therapy approach obviated the use of several NRTIs with well-known and sometimes serious side-effects that are not reported with lamivudine alone, significantly fewer patients in the dual therapy group experienced drug-related adverse events. Zidovudine causes myelosuppression, gastrointestinal symptoms, headaches, and mitochondrial toxicity that can lead to lipoatrophy, hepatic steatosis, and lactic acidosis. Abacavir can induce a potentially life-threatening hypersensitivity syndrome, and hence should be given only to patients who are negative for the HLA-B*5701 allele; furthermore, it has been associated with an increased risk of cardiovascular disease.8 Tenofovir lowers bone density more than other NRTIs9 and can be nephrotoxic.10 Although none of these serious adverse events were reported in the GARDEL study, there were more NRTIrelated side-effects in the standard-of-care triple therapy arm than in the dual therapy arm. The results of GARDEL are important, and the investigators and study sponsor should be credited for doing a fully powered randomised trial of this new approach to treatment. However, there are several limitations to the study that make widespread adaptation of this particular strategy of lopinavir with ritonavir plus lamivudine unlikely. First, the regimen consists of three pills taken twice daily, which is cumbersome by current standards of HIV treatment. There are already three (and soon to be four) approved options for initial HIV treatment that consist of one pill once daily as a coformulation of three active drugs. Such simplified regimens are enormously popular with patients, reduce prescribing errors, and can improve both adherence and treatment outcomes.11 Second, once-daily atazanavir with ritonavir and darunavir with ritonavir, induce lower rates of hyperlipidaemia and gastrointestinal side-effects
www.thelancet.com/infection Published online April 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70753-4
Laguna Design/Science Photo Library
Initial therapy for HIV: can less be more?
Lancet Infect Dis 2014 Published Online April 28, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70753-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70736-4
1
Comment
and have supplanted lopinavir with ritonavir12,13 both in some treatment guidelines14,15 and in clinical practice. Can we assume that use of boosted atazanavir or darunavir with once-daily lamivudine would provide comparable results? Other details of the study raise some concerns about the validity of the results. Selection of the NRTI pair was at the discretion of the investigators, and the NRTIs were not provided by the study sponsors. Perhaps because zidovudine and lamivudine was the least expensive option for many participants, this NRTI combination was used by 54% of the control group, no doubt increasing the rate of adverse events for the triple therapy strategy. The study was done open label, which could lead to reporting bias for adverse events that disadvantaged the study group who received more active drugs. HIV RNA measurements were done in several different laboratories and with different assays (a very unusual practice for a contemporary HIV clinical trial). These caveats notwithstanding, the results of the GARDEL study support the testing of other novel twodrug strategies. Such regimens could be used either as initial therapy or as a deintensification option for virologically suppressed patients on triple therapy, which would be particularly useful for those experiencing toxicity to zidovudine, abacavir, or tenofovir. The availability of generic formulations of lamivudine might facilitate the testing of new coformulations, reducing pill burden and making these dual-therapy options more viable. If the promising results of GARDEL can be confirmed with other antiretroviral drugs—not just lopinavir with ritonavir and perhaps not just for boosted protease inhibitors—one could easily envision scenarios in which, for HIV treatment, less can certainly be more.
2
PES has received personal fees from AbbVie, BMS, Gilead, GlaxoSmithKline, Janssen, and Merck, and grants from BMS, Gilead, GlaxoSmithKline, the US National Institutes of Health (UM1AI069412), New England AIDS Education and Training Center (NEAETC; 6H4AHA00050-12-00), and Cost-Effectiveness of Preventing AIDS Complications (CEPAC; R37AI042006). 1
2 3
4
5
6
7
8
9
10
11
12
13
Paul E Sax
14
Division of Infectious Diseases and Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA [email protected]
15
Delfraissy JF, Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS 2008; 22: 385–93. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358: 2095–106. Kozal MJ, Lupo S, DeJesus E, et al. A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN study results. HIV Clin Trials 2012; 13: 119–30. 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: 769–81. Cahn P, Andrade-Villanueva J, Arribas JR, on behalf of the GARDEL Study Group. 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. Lancet Infect Dis 2014; published online April 28. http://dx.doi. org/10.1016/S1473-3099(14)70736-4 Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 1995; 333: 1662–69. Raffi F, Babiker AG, Richert L, et al. First-line RAL + DRV/r is non-inferior to TDF/FTC + DRV/r: the NEAT001/ANRS143 randomised trial. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014); Boston, MA, USA; March 3–6, 2014. Abstract 84LB. Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–26. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011; 203: 1791–801. Kalayjian RC, Lau B, Mechekano RN, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS 2012; 26: 1907–15. Bangsberg DR, Ragland K, Monk A, Deeks SG. A single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in HIV+ homeless and marginally housed people. AIDS 2010; 24: 2835–40. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008; 372: 646–55. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–97. US Department of Health and Human Services. Adult and adolescent ARV guidelines. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescentarv-guidelines/0 (accessed April 22, 2014). Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society–USA panel. JAMA 2012; 308: 387–402.
www.thelancet.com/infection Published online April 28, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70753-4
