Comment
of the Met184Val mutation, have residual antiviral drug activity despite resistance or maintain a viral population with reduced replicative capacity, as suggested by the results of the EARNEST study.11 Investigators of this study noted that lopinavir–ritonavir with a dual NRTI backbone was better than was lopinavir–ritonavir monotherapy, even in the subset of patients with resistance to both NRTIs. The boosted protease inhibitor and lamivudine combination might thus have more relevance in this population, although present data do not yet support this practice.1,2
3
4
5
6 7
*Catherine Orrell, Richard Kaplan Desmond Tutu HIV Foundation, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa [email protected] We declare no competing interests. 1
2
Arribas JR, Girard PM, Landman R, et al. Dual treatment with lopinavir and ritonavir plus lamivudine versus triple treatment with lopinavir and ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis 2015; published online June 1, 2015. http://dx.doi.org/10.1016/S14733099(15)00096-1. Perez-Molina JA, Rubio R, Rivero A. Dual treatment with atazanavir and ritonavir plus lamivudine versus triple treatment with atazanavir and ritonavir plus two nucleos[t]ides in patients who are HIV1 infected, on antiretroviral treatment, and virologically stable (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis 2015; published online June 1, 2015. http://dx.doi.org/10.1016/S14733099(15)00097-3.
8
9
10
11
Cahn P, Andrade-Villanueva J, Arribas JR, et al. 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; 14: 572–80. Di Giambenedetto S, Fabbiani M, Colafigli M, et al. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIVinfected 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: 1364–72. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection—recommendations for a public health approach. Geneva: World Health Organization, 2013. European AIDS Clinical Society. Guidelines. Version 7.1. November 2014. Brussels: European AIDS Clinical Society, 2014. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington, DC: Department of Health and Human Services USA, 2014. Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in the first protease inhibitor-based single tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2015; published online Apr 10. DOI:10.1097/ QAI.0000000000000618. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014; 67: 52–58. Orrell C, Walensky RP, Losina E, Pitt J, Freedberg KA, Wood R. HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme. Antiviral Ther 2009; 14: 523–31. Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 2014; 371: 234–47.
Lower-dose efavirenz: what is needed before implementation? Efavirenz has become one of the most commonly used antiretroviral agents worldwide and is a component of WHO’s recommended first-line antiretroviral therapy regimen. Recently, questions have been raised about whether the dose of efavirenz could be reduced to lessen toxic effects and cost while preserving effectiveness. The 96-week results of the ENCORE1 trial published in The Lancet Infectious Diseases1 show that efavirenz 400 mg is non-inferior to the standard dose of 600 mg daily (together with tenofovir and emtricitabine) at 96 weeks, which extends the findings of the previously published 48 week results.2 In this trial, 636 adult participants with HIV infection were enrolled and randomly assigned 1:1 to receive efavirenz 600 mg or 400 mg. The latest results show that at www.thelancet.com/infection Vol 15 July 2015
96 weeks’ follow-up, the percentage of participants with plasma HIV RNA load lower than 200 copies per mL was 90·0% (289/321) with efavirenz 400 mg versus 90·6% (280/309) with efavirenz 600 mg (difference –0·6% [95% CI –5·2 to 4·0]; p=0·72).1 Additionally, the number of patients reporting an adverse event that was definitely or probably related to efavirenz was significantly lower in the efavirenz 400 mg group (121/321 [38%]) than in the 600 mg group (148/309 [48%]; p=0·01). Treatment adherence, quality-oflife measures, and depression and anxiety scores did not differ between the two groups. However, rather than this modest reduction in toxic effects, the more compelling argument for reducing the efavirenz dose in international guidelines, as the ENCORE1
Published Online April 13, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70108-8 See Articles page 793
749
Comment
investigators and others3 have argued, is the potential cost savings that would result from a 33% reduction in the active pharmaceutical ingredient. 11·7 million of the 32·6 million people with HIV infection living in low-income and middle-income countries were on antiretroviral therapy by the end of 2013.4 Therefore, around 20 million people will need to start antiretroviral therapy now or in the near future at a time when donor funding has plateaued. A one-third saving in the active pharmaceutical ingredient of efavirenz could allow more patients to access antiretroviral therapy and free up funds to spend on other components of antiretroviral therapy programmes. The ENCORE1 study group investigators argue that their findings are sufficient to lower the treatment dose of efavirenz in first-line antiretroviral therapy. However, a few key pharmacokinetic concerns need to be addressed and several practical issues need to be resolved before widespread implementation of the lower dose of efavirenz. The therapeutic concentrations of efavirenz have not been clearly defined. An efavirenz trough concentration of lower than 1·1 mg per L has quite poor sensitivity but high negative predictive value for virological failure.5 Trough concentrations are not practical for therapeutic drug monitoring because efavirenz is taken at night, so mid-dosing interval concentrations of 1–4 mg per L are used as the therapeutic range following the results of a population pharmacokinetic study.6 Substantial interindividual variability exists in the pharmacokinetics of efavirenz, and some groups of patients might be at increased risk of virological failure with reduced doses of efavirenz. Efavirenz is metabolised by the cytochrome P450 enzyme CYP2B6. Three lossof-function polymorphisms in the CYP2B6 gene (at positions rs4803419 [15582C>T], rs3745274 [516G>T], and rs28399499 [983T>C]) are associated with impaired metabolism, resulting in higher plasma concentrations of efavirenz.7 The median estimated trough concentration in extensive metabolisers (who do not have any of the loss-of-function CYP2B6 polymorphisms) is lower than the recommended trough cutoff of 1 mg per L in people on the standard 600 mg dose of efavirenz.7 CYP2B6 metaboliser genotype does not predict virological outcome in patients on efavirenz-based antiretroviral therapy,8 which illustrates the poor sensitivity of the recommended cutoff for efavirenz trough con750
centrations.5 However, a dose reduction of efavirenz could increase the risk of virological failure in people with the extensive metaboliser genotype, the frequency of which ranges from around 23% of people of African or European descent to roughly 13% of people with Asian or Hispanic ancestry (Haas D, Vanderbilt University School of Medicine, personal communication). The results of the ENCORE1 pharmacogenetic substudy are awaited, but they are unlikely to have sufficient power to assess whether or not virological failure is higher in extensive metabolisers who were randomly assigned to the reduced dose (400 mg) of efavirenz than in those given the standard 600 mg dose of efavirenz. Two situations exist in which lower doses of efavirenz could result in an increased risk of virological failure, and especially in extensive metabolisers: first, during pregnancy; and second, in patients who are on rifampicin-based treatment for tuberculosis. Importantly, both these patient groups were excluded from the ENCORE1 trial. The physiological changes of pregnancy reduce the concentrations of many drugs, including efavirenz.9 In a pharmacokinetic study of the effect of pregnancy on efavirenz concentrations, concentrations of efavirenz were reduced by a greater extent in Nigerian pregnant women who were CYP2B6 516 GG homozygotes (the wild-type of the most important polymorphism impairing CYP2B6 activity) than in 516 GT heterozygotes or 516 TT homozygotes, and trough concentrations were lower than 1 mg per L in all the pregnant CYP2B6 516 GG homozygotes.10 Rifampicin-based antituberculosis therapy does not reduce the concentrations of efavirenz when efavirenz is dosed at 600 mg11,12 because rifampicin does not seem to have a substantial additive effect on the autoinduction of CYP2B6 by efavirenz.13 However, the extent of induction of CYP2B6 rises with increasing concentrations of efavirenz.14 Therefore, lower doses of efavirenz might fail to adequately autoinduce CYP2B6, and concomitant rifampicin could therefore further induce CYP2B6 when efavirenz is dosed at 400 mg, resulting in a further reduction in efavirenz concentrations. Pharmacokinetic studies of lower doses of efavirenz need to be undertaken in pregnant women and in patients with tuberculosis with known CYP2B6 genotypes, including sufficient numbers of extensive metabolisers, before broad implementation of the 400 mg efavirenz dose in high-burden countries. www.thelancet.com/infection Vol 15 July 2015
Comment
A practical challenge is that the fixed-dose combinations used in first-line antiretroviral therapy currently contain efavirenz 600 mg daily (together with tenofovir and emtricitabine or lamivudine). Manufacturers need to agree to make a new fixed-dose combination with 400 mg efavirenz, which will include obtaining the necessary regulatory approvals. The ENCORE1 study has shown that 400 mg efavirenz can replace the standard 600 mg dose in most patients with HIV infection, but the standard dose of efavirenz should continue to be used in pregnant patients and in those with tuberculosis until sufficient evidence is obtained regarding the efficacy of 400 mg of efavirenz in these important patient populations. Gary Maartens, *Graeme Meintjes Division of Clinical Pharmacology (GaM) and Division of Infectious Diseases and HIV Medicine (GrM), Department of Medicine, University of Cape Town, Cape Town, South Africa; and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Cape Town, 7925, South Africa (GrM) [email protected] GrM is funded by the Wellcome Trust (grant 098316). We declare no competing interests. 1
2
ENCORE1 Study Group. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebocontrolled, non-inferiority ENCORE1 study. Lancet Infect Dis 2015; published online April 13. http://dx.oi.org/10.1016/S1473-3099(15)70060-5. ENCORE1 Study Group, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet 2014; 383: 1474–82.
3 4
5
6
7
8
9
10
11
12
13
14
Lundgren JD, Phillips A. Antiretroviral dose reduction: good for patients and rollout. Lancet 2014; 383: 1442–43. WHO. Global update on the health sector response to HIV, 2014. Geneva: World Health Organization. July, 2014. http://apps.who.int/iris/ bitstream/10665/128494/1/9789241507585_eng.pdf?ua=1 (accessed March 10, 2015). Leth FV, Kappelhoff BS, Johnson D, et al. Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy. AIDS Res Hum Retroviruses 2006; 22: 232–39. Csajka C, Marzolini C, Fattinger K, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 2003; 73: 20–30. Holzinger ER, Grady B, Ritchie MD, et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet Genomics 2012; 22: 858–67. Lehmann DS, Ribaudo HJ, Daar ES, et al. Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols. Pharmacogenet Genomics 2015; 25: 51–59. Dooley KE, Denti P, Martinson N, et al. Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. J Infect Dis 2015; 211: 197–205. Olagunju A, Bolaji O, Amara A, et al. Pharmacogenetics of pregnancyinduced changes in efavirenz pharmacokinetics. Clin Pharmacol Ther 2015; 97: 298–306. Maartens G, Decloedt E, Cohen K. Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries. Antivir Ther 2009; 14: 1039–43. Luetkemeyer AF, Rosenkranz SL, Lu D, et al. Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Clin Infect Dis 2013; 57: 586–93. Ngaimisi E, Mugusi S, Minzi O, et al. Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis. Clin Pharmacol Ther 2011; 90: 406–13. Faucette SR, Zhang TC, Moore R, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007; 320: 72–80.
The downside of success: confirmation of HIV infection in early treated children Helen Payne and colleagues1 report in The Lancet Infectious Diseases the loss of HIV-specific antibodies in early treated children participating in the Children with HIV Early Antiretroviral Therapy (CHER) study,2 a phase 3, randomised, controlled trial done in South Africa in which children infected with HIV were randomly assigned to receive either early or deferred antiretroviral therapy (ART). About half of children who received early ART were HIV seronegative by commercial enzyme immunoassays at 92 weeks of age, although anti-gp120 antibodies were detectable in all children and correlated with cumulative viral www.thelancet.com/infection Vol 15 July 2015
load exposure. HIV seronegativity has been previously described,3,4 but this study is the first to rigorously quantify the time course and frequency of HIV seronegativity in early treated infants. The finding that half of children initiating ART in the first 12 weeks of life were HIV seronegative has important implications for use of serological tests to confirm HIV infection in infants starting treatment in the first few months of life, particularly as efforts intensify to identify and treat infants with HIV infection at young ages. If we could diagnose infants with 100% accuracy, this finding would not
Published Online June 3, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00086-9 See Articles page 803
751
of the Met184Val mutation, have residual antiviral drug activity despite resistance or maintain a viral population with reduced replicative capacity, as suggested by the results of the EARNEST study.11 Investigators of this study noted that lopinavir–ritonavir with a dual NRTI backbone was better than was lopinavir–ritonavir monotherapy, even in the subset of patients with resistance to both NRTIs. The boosted protease inhibitor and lamivudine combination might thus have more relevance in this population, although present data do not yet support this practice.1,2
3
4
5
6 7
*Catherine Orrell, Richard Kaplan Desmond Tutu HIV Foundation, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa [email protected] We declare no competing interests. 1
2
Arribas JR, Girard PM, Landman R, et al. Dual treatment with lopinavir and ritonavir plus lamivudine versus triple treatment with lopinavir and ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis 2015; published online June 1, 2015. http://dx.doi.org/10.1016/S14733099(15)00096-1. Perez-Molina JA, Rubio R, Rivero A. Dual treatment with atazanavir and ritonavir plus lamivudine versus triple treatment with atazanavir and ritonavir plus two nucleos[t]ides in patients who are HIV1 infected, on antiretroviral treatment, and virologically stable (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis 2015; published online June 1, 2015. http://dx.doi.org/10.1016/S14733099(15)00097-3.
8
9
10
11
Cahn P, Andrade-Villanueva J, Arribas JR, et al. 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; 14: 572–80. Di Giambenedetto S, Fabbiani M, Colafigli M, et al. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIVinfected 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: 1364–72. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection—recommendations for a public health approach. Geneva: World Health Organization, 2013. European AIDS Clinical Society. Guidelines. Version 7.1. November 2014. Brussels: European AIDS Clinical Society, 2014. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington, DC: Department of Health and Human Services USA, 2014. Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in the first protease inhibitor-based single tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2015; published online Apr 10. DOI:10.1097/ QAI.0000000000000618. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014; 67: 52–58. Orrell C, Walensky RP, Losina E, Pitt J, Freedberg KA, Wood R. HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme. Antiviral Ther 2009; 14: 523–31. Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 2014; 371: 234–47.
Lower-dose efavirenz: what is needed before implementation? Efavirenz has become one of the most commonly used antiretroviral agents worldwide and is a component of WHO’s recommended first-line antiretroviral therapy regimen. Recently, questions have been raised about whether the dose of efavirenz could be reduced to lessen toxic effects and cost while preserving effectiveness. The 96-week results of the ENCORE1 trial published in The Lancet Infectious Diseases1 show that efavirenz 400 mg is non-inferior to the standard dose of 600 mg daily (together with tenofovir and emtricitabine) at 96 weeks, which extends the findings of the previously published 48 week results.2 In this trial, 636 adult participants with HIV infection were enrolled and randomly assigned 1:1 to receive efavirenz 600 mg or 400 mg. The latest results show that at www.thelancet.com/infection Vol 15 July 2015
96 weeks’ follow-up, the percentage of participants with plasma HIV RNA load lower than 200 copies per mL was 90·0% (289/321) with efavirenz 400 mg versus 90·6% (280/309) with efavirenz 600 mg (difference –0·6% [95% CI –5·2 to 4·0]; p=0·72).1 Additionally, the number of patients reporting an adverse event that was definitely or probably related to efavirenz was significantly lower in the efavirenz 400 mg group (121/321 [38%]) than in the 600 mg group (148/309 [48%]; p=0·01). Treatment adherence, quality-oflife measures, and depression and anxiety scores did not differ between the two groups. However, rather than this modest reduction in toxic effects, the more compelling argument for reducing the efavirenz dose in international guidelines, as the ENCORE1
Published Online April 13, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70108-8 See Articles page 793
749
Comment
investigators and others3 have argued, is the potential cost savings that would result from a 33% reduction in the active pharmaceutical ingredient. 11·7 million of the 32·6 million people with HIV infection living in low-income and middle-income countries were on antiretroviral therapy by the end of 2013.4 Therefore, around 20 million people will need to start antiretroviral therapy now or in the near future at a time when donor funding has plateaued. A one-third saving in the active pharmaceutical ingredient of efavirenz could allow more patients to access antiretroviral therapy and free up funds to spend on other components of antiretroviral therapy programmes. The ENCORE1 study group investigators argue that their findings are sufficient to lower the treatment dose of efavirenz in first-line antiretroviral therapy. However, a few key pharmacokinetic concerns need to be addressed and several practical issues need to be resolved before widespread implementation of the lower dose of efavirenz. The therapeutic concentrations of efavirenz have not been clearly defined. An efavirenz trough concentration of lower than 1·1 mg per L has quite poor sensitivity but high negative predictive value for virological failure.5 Trough concentrations are not practical for therapeutic drug monitoring because efavirenz is taken at night, so mid-dosing interval concentrations of 1–4 mg per L are used as the therapeutic range following the results of a population pharmacokinetic study.6 Substantial interindividual variability exists in the pharmacokinetics of efavirenz, and some groups of patients might be at increased risk of virological failure with reduced doses of efavirenz. Efavirenz is metabolised by the cytochrome P450 enzyme CYP2B6. Three lossof-function polymorphisms in the CYP2B6 gene (at positions rs4803419 [15582C>T], rs3745274 [516G>T], and rs28399499 [983T>C]) are associated with impaired metabolism, resulting in higher plasma concentrations of efavirenz.7 The median estimated trough concentration in extensive metabolisers (who do not have any of the loss-of-function CYP2B6 polymorphisms) is lower than the recommended trough cutoff of 1 mg per L in people on the standard 600 mg dose of efavirenz.7 CYP2B6 metaboliser genotype does not predict virological outcome in patients on efavirenz-based antiretroviral therapy,8 which illustrates the poor sensitivity of the recommended cutoff for efavirenz trough con750
centrations.5 However, a dose reduction of efavirenz could increase the risk of virological failure in people with the extensive metaboliser genotype, the frequency of which ranges from around 23% of people of African or European descent to roughly 13% of people with Asian or Hispanic ancestry (Haas D, Vanderbilt University School of Medicine, personal communication). The results of the ENCORE1 pharmacogenetic substudy are awaited, but they are unlikely to have sufficient power to assess whether or not virological failure is higher in extensive metabolisers who were randomly assigned to the reduced dose (400 mg) of efavirenz than in those given the standard 600 mg dose of efavirenz. Two situations exist in which lower doses of efavirenz could result in an increased risk of virological failure, and especially in extensive metabolisers: first, during pregnancy; and second, in patients who are on rifampicin-based treatment for tuberculosis. Importantly, both these patient groups were excluded from the ENCORE1 trial. The physiological changes of pregnancy reduce the concentrations of many drugs, including efavirenz.9 In a pharmacokinetic study of the effect of pregnancy on efavirenz concentrations, concentrations of efavirenz were reduced by a greater extent in Nigerian pregnant women who were CYP2B6 516 GG homozygotes (the wild-type of the most important polymorphism impairing CYP2B6 activity) than in 516 GT heterozygotes or 516 TT homozygotes, and trough concentrations were lower than 1 mg per L in all the pregnant CYP2B6 516 GG homozygotes.10 Rifampicin-based antituberculosis therapy does not reduce the concentrations of efavirenz when efavirenz is dosed at 600 mg11,12 because rifampicin does not seem to have a substantial additive effect on the autoinduction of CYP2B6 by efavirenz.13 However, the extent of induction of CYP2B6 rises with increasing concentrations of efavirenz.14 Therefore, lower doses of efavirenz might fail to adequately autoinduce CYP2B6, and concomitant rifampicin could therefore further induce CYP2B6 when efavirenz is dosed at 400 mg, resulting in a further reduction in efavirenz concentrations. Pharmacokinetic studies of lower doses of efavirenz need to be undertaken in pregnant women and in patients with tuberculosis with known CYP2B6 genotypes, including sufficient numbers of extensive metabolisers, before broad implementation of the 400 mg efavirenz dose in high-burden countries. www.thelancet.com/infection Vol 15 July 2015
Comment
A practical challenge is that the fixed-dose combinations used in first-line antiretroviral therapy currently contain efavirenz 600 mg daily (together with tenofovir and emtricitabine or lamivudine). Manufacturers need to agree to make a new fixed-dose combination with 400 mg efavirenz, which will include obtaining the necessary regulatory approvals. The ENCORE1 study has shown that 400 mg efavirenz can replace the standard 600 mg dose in most patients with HIV infection, but the standard dose of efavirenz should continue to be used in pregnant patients and in those with tuberculosis until sufficient evidence is obtained regarding the efficacy of 400 mg of efavirenz in these important patient populations. Gary Maartens, *Graeme Meintjes Division of Clinical Pharmacology (GaM) and Division of Infectious Diseases and HIV Medicine (GrM), Department of Medicine, University of Cape Town, Cape Town, South Africa; and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Cape Town, 7925, South Africa (GrM) [email protected] GrM is funded by the Wellcome Trust (grant 098316). We declare no competing interests. 1
2
ENCORE1 Study Group. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebocontrolled, non-inferiority ENCORE1 study. Lancet Infect Dis 2015; published online April 13. http://dx.oi.org/10.1016/S1473-3099(15)70060-5. ENCORE1 Study Group, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet 2014; 383: 1474–82.
3 4
5
6
7
8
9
10
11
12
13
14
Lundgren JD, Phillips A. Antiretroviral dose reduction: good for patients and rollout. Lancet 2014; 383: 1442–43. WHO. Global update on the health sector response to HIV, 2014. Geneva: World Health Organization. July, 2014. http://apps.who.int/iris/ bitstream/10665/128494/1/9789241507585_eng.pdf?ua=1 (accessed March 10, 2015). Leth FV, Kappelhoff BS, Johnson D, et al. Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy. AIDS Res Hum Retroviruses 2006; 22: 232–39. Csajka C, Marzolini C, Fattinger K, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 2003; 73: 20–30. Holzinger ER, Grady B, Ritchie MD, et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet Genomics 2012; 22: 858–67. Lehmann DS, Ribaudo HJ, Daar ES, et al. Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols. Pharmacogenet Genomics 2015; 25: 51–59. Dooley KE, Denti P, Martinson N, et al. Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. J Infect Dis 2015; 211: 197–205. Olagunju A, Bolaji O, Amara A, et al. Pharmacogenetics of pregnancyinduced changes in efavirenz pharmacokinetics. Clin Pharmacol Ther 2015; 97: 298–306. Maartens G, Decloedt E, Cohen K. Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries. Antivir Ther 2009; 14: 1039–43. Luetkemeyer AF, Rosenkranz SL, Lu D, et al. Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Clin Infect Dis 2013; 57: 586–93. Ngaimisi E, Mugusi S, Minzi O, et al. Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis. Clin Pharmacol Ther 2011; 90: 406–13. Faucette SR, Zhang TC, Moore R, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007; 320: 72–80.
The downside of success: confirmation of HIV infection in early treated children Helen Payne and colleagues1 report in The Lancet Infectious Diseases the loss of HIV-specific antibodies in early treated children participating in the Children with HIV Early Antiretroviral Therapy (CHER) study,2 a phase 3, randomised, controlled trial done in South Africa in which children infected with HIV were randomly assigned to receive either early or deferred antiretroviral therapy (ART). About half of children who received early ART were HIV seronegative by commercial enzyme immunoassays at 92 weeks of age, although anti-gp120 antibodies were detectable in all children and correlated with cumulative viral www.thelancet.com/infection Vol 15 July 2015
load exposure. HIV seronegativity has been previously described,3,4 but this study is the first to rigorously quantify the time course and frequency of HIV seronegativity in early treated infants. The finding that half of children initiating ART in the first 12 weeks of life were HIV seronegative has important implications for use of serological tests to confirm HIV infection in infants starting treatment in the first few months of life, particularly as efforts intensify to identify and treat infants with HIV infection at young ages. If we could diagnose infants with 100% accuracy, this finding would not
Published Online June 3, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00086-9 See Articles page 803
751
