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
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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
Comment
Chris Sattlberger/Science Photo Library
be problematic because a child would not need to be retested once treatment is started. The problem, however, arises for two reasons. First, virological testing for HIV DNA or RNA (needed for infant diagnosis because of the presence of maternal antibodies to HIV) might not be readily available in all settings and, when available, might not be 100% accurate, and, second, present treatment guidelines recommend immediate initiation of ART for all children with a positive test result.5 As a result, confirmation of HIV infection might be needed after a child starts ART, either because the caregiver or clinician suspects misdiagnosis or because of a discrepant, negative confirmatory test. In 2013, 1·3 million pregnant women were estimated to be living with HIV in sub-Saharan Africa,6 giving birth to about 1·3 million newborns that were exposed to HIV. These infants should undergo diagnostic testing, with the goal of identification and treatment of the estimated 210 000 newly infected infants in 2013.6 In an ideal world with universal early infant testing, 1·09 million infants that had been exposed to HIV but were not infected would be tested.6 Although virological tests are highly accurate, and false positive results are rare,7,8 misdiagnosis does occur and is likely to increase as programmes to prevent mother-tochild transmission reach more women and reduce the incidence of paediatric HIV infection. Even with a specificity of 99·9%, 1090 of these infants without a HIV infection would have been misdiagnosed and started on ART in 2013. Once a child is diagnosed and treated effectively, resulting in virological suppression, subsequent confirmation of HIV infection is difficult. As findings from the study by Payne and colleagues1 show, serological tests cannot be used because a negative test result cannot confirm absence of infection after effective ART. Virological tests can be problematic for confirming absence of infection for the same reasons,9 and stopping ART might be the only option to confirm presence or absence of infection. Present treatment guidelines do not address the issue of misdiagnosis and how healthcare providers currently manage children who need repeated confirmation of HIV infection status after early, effective treatment is unclear. In our cohort of more than 800 children infected with HIV in rural Zambia,10 seven were suspected of misdiagnosis. 752
For two, sufficient evidence existed to discontinue ART, which was done at the discretion of the treating physician.11 One child was subsequently lost to followup and the other was followed up for 7 months after stopping treatment and discharged from the clinic after two negative HIV serological tests off treatment. Comprehensive guidelines exist for diagnosis and treatment of children infected with HIV.5 What are needed are guidelines addressing management of children receiving ART but suspected of misdiagnosis. The possibility of misdiagnosis affects not only the child but also the family and community. After identification of a misdiagnosed child, counselling family members and other patients at the clinic, and community outreach, might be necessary to preserve trust between the clinic, their patients, and the community, and to maintain progress in prevention and treatment of children infected with HIV. Catherine G Sutcliffe, *William J Moss Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA [email protected] We declare no competing interests. 1
2 3
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6 7
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Payne H, Mkhize N, Otwombe K, et al. Poor reactivity of routine 1 HIV antibody tests in children who initiate ART in early infancy: a restrospective obervational study of the Children with HIV Early Antiretroviral Therapy (CHER) trial. Lancet Infect Dis 2015; published online June 2, 2015. http://dx.doi.org/10.1016/S14733099(15)00087-0. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359: 2233–44. Luzuriaga K, McManus M, Catalina M, et al. Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication and absence of persistent HIV-1-specific immune responses. J Virol 2000; 74: 6984–91. Hainaut M, Peltier CA, Goetghebuer T, et al. Seroreversion in children infected with HIV type 1 who are treated in the first months of life is not a rare event. Clin Infect Dis 2005; 41: 1820–21. 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. Joint UN Programme on HIV and AIDS. The gap report. Geneva: Joint UN Programme on HIV/AIDS, 2014. Feucht UD, Forsyth B, Kruger M. False-positive HIV DNA PCR testing of infants: implications in a changing epidemic. S Afr Med J 2012; 102: 149–52. Kageha S, Okoth V, Kadima S, et al. Discrepant test findings in early infant diagnosis of HIV in a national reference laboratory in Kenya: challenges and opportunities for programs. J Trop Pediatr 2012; 58: 247–52. Garcia-Prats AJ, Draper HR, Sanders JE, Agrawal AK, Mohapi EQ, Schutze GE. False-negative post-18-month confirmatory HIV tests in HIV DNA PCR-positive children: a retrospective analysis. AIDS 2012; 26: 1927–34. van Dijk JH, Sutcliffe CG, Munsanje B, et al. HIV-infected children in rural Zambia achieve good immunologic and virologic outcomes two years after initiating antiretroviral therapy. PLoS One 2011; 6: e19006. Sutcliffe CG, Moss WJ, Thuma PE. False-positive HIV test results in infancy and management of uninfected children receiving antiretroviral therapy. Pediatr Infect Dis J 2015; 34: 607–09.
www.thelancet.com/infection Vol 15 July 2015
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
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10
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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
Comment
Chris Sattlberger/Science Photo Library
be problematic because a child would not need to be retested once treatment is started. The problem, however, arises for two reasons. First, virological testing for HIV DNA or RNA (needed for infant diagnosis because of the presence of maternal antibodies to HIV) might not be readily available in all settings and, when available, might not be 100% accurate, and, second, present treatment guidelines recommend immediate initiation of ART for all children with a positive test result.5 As a result, confirmation of HIV infection might be needed after a child starts ART, either because the caregiver or clinician suspects misdiagnosis or because of a discrepant, negative confirmatory test. In 2013, 1·3 million pregnant women were estimated to be living with HIV in sub-Saharan Africa,6 giving birth to about 1·3 million newborns that were exposed to HIV. These infants should undergo diagnostic testing, with the goal of identification and treatment of the estimated 210 000 newly infected infants in 2013.6 In an ideal world with universal early infant testing, 1·09 million infants that had been exposed to HIV but were not infected would be tested.6 Although virological tests are highly accurate, and false positive results are rare,7,8 misdiagnosis does occur and is likely to increase as programmes to prevent mother-tochild transmission reach more women and reduce the incidence of paediatric HIV infection. Even with a specificity of 99·9%, 1090 of these infants without a HIV infection would have been misdiagnosed and started on ART in 2013. Once a child is diagnosed and treated effectively, resulting in virological suppression, subsequent confirmation of HIV infection is difficult. As findings from the study by Payne and colleagues1 show, serological tests cannot be used because a negative test result cannot confirm absence of infection after effective ART. Virological tests can be problematic for confirming absence of infection for the same reasons,9 and stopping ART might be the only option to confirm presence or absence of infection. Present treatment guidelines do not address the issue of misdiagnosis and how healthcare providers currently manage children who need repeated confirmation of HIV infection status after early, effective treatment is unclear. In our cohort of more than 800 children infected with HIV in rural Zambia,10 seven were suspected of misdiagnosis. 752
For two, sufficient evidence existed to discontinue ART, which was done at the discretion of the treating physician.11 One child was subsequently lost to followup and the other was followed up for 7 months after stopping treatment and discharged from the clinic after two negative HIV serological tests off treatment. Comprehensive guidelines exist for diagnosis and treatment of children infected with HIV.5 What are needed are guidelines addressing management of children receiving ART but suspected of misdiagnosis. The possibility of misdiagnosis affects not only the child but also the family and community. After identification of a misdiagnosed child, counselling family members and other patients at the clinic, and community outreach, might be necessary to preserve trust between the clinic, their patients, and the community, and to maintain progress in prevention and treatment of children infected with HIV. Catherine G Sutcliffe, *William J Moss Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA [email protected] We declare no competing interests. 1
2 3
4
5
6 7
8
9
10
11
Payne H, Mkhize N, Otwombe K, et al. Poor reactivity of routine 1 HIV antibody tests in children who initiate ART in early infancy: a restrospective obervational study of the Children with HIV Early Antiretroviral Therapy (CHER) trial. Lancet Infect Dis 2015; published online June 2, 2015. http://dx.doi.org/10.1016/S14733099(15)00087-0. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359: 2233–44. Luzuriaga K, McManus M, Catalina M, et al. Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication and absence of persistent HIV-1-specific immune responses. J Virol 2000; 74: 6984–91. Hainaut M, Peltier CA, Goetghebuer T, et al. Seroreversion in children infected with HIV type 1 who are treated in the first months of life is not a rare event. Clin Infect Dis 2005; 41: 1820–21. 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. Joint UN Programme on HIV and AIDS. The gap report. Geneva: Joint UN Programme on HIV/AIDS, 2014. Feucht UD, Forsyth B, Kruger M. False-positive HIV DNA PCR testing of infants: implications in a changing epidemic. S Afr Med J 2012; 102: 149–52. Kageha S, Okoth V, Kadima S, et al. Discrepant test findings in early infant diagnosis of HIV in a national reference laboratory in Kenya: challenges and opportunities for programs. J Trop Pediatr 2012; 58: 247–52. Garcia-Prats AJ, Draper HR, Sanders JE, Agrawal AK, Mohapi EQ, Schutze GE. False-negative post-18-month confirmatory HIV tests in HIV DNA PCR-positive children: a retrospective analysis. AIDS 2012; 26: 1927–34. van Dijk JH, Sutcliffe CG, Munsanje B, et al. HIV-infected children in rural Zambia achieve good immunologic and virologic outcomes two years after initiating antiretroviral therapy. PLoS One 2011; 6: e19006. Sutcliffe CG, Moss WJ, Thuma PE. False-positive HIV test results in infancy and management of uninfected children receiving antiretroviral therapy. Pediatr Infect Dis J 2015; 34: 607–09.
www.thelancet.com/infection Vol 15 July 2015
