Jean B. Nachega, MD, MPH; Michael Hislop, MSc; David W. Dowdy, ScM; Richard E. Chaisson, MD; Leon Regensberg, MBChB; Gary Maartens, MBChB
Note: This paper was given in part as an oral presentation at the 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado, 5–8 February 2006 (MonOrAb#62).
Acknowledgments: The authors thank Steven G. Deeks, MD, PhD; Marc Mendelson, MD, PhD; and Mark Van Natta, MHS, for critical reading of the manuscript. They also thank Joanna Downer, PhD, and Rod Graham, MA, for technical and administrative support.
Grant Support: Drs. Nachega, Chaisson, and Maartens received support from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (R01 AI 5535901 and R01 AI 016137). Dr. Nachega is the recipient of a National Institute of Allergy and Infectious Diseases, National Institutes of Health, Mentored Patient-Oriented Research Career Award (K23 AI068582-01). Mr. Dowdy is supported by the National Institutes of Health Medical Scientist Training Program Award (5 T32 GMO7309).
Potential Financial Conflicts of Interest: Consultancies: R.E. Chaisson (Bristol-Myers Squibb); Honoraria: J.B. Nachega (GlaxoSmithKline, Merck-Sharp-Dohme for continuing medical education lectures), G. Maartens (Merck-Sharp-Dohme); Grants received: G. Maartens (Merck-Sharp-Dohme); Other: J.B. Nachega (Aspen Pharmaceuticals for conferences and travel grants).
Requests for Single Reprints: Jean B. Nachega, MD, MPH, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Suite W5031, Baltimore, MD 21205; e-mail, email@example.com.
Current Author Addresses: Dr. Nachega: Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Suite W5031, Baltimore, MD 21205.
Mr. Hislop and Dr. Regensberg: Aid for AIDS Disease Management Programme (Pty) Ltd., PO Box 38597, Howard Place, 7450 Cape Town, South Africa.
Mr. Dowdy: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.
Dr. Chaisson: Johns Hopkins School of Medicine, 1550 Orleans Street, Baltimore, MD 21231.
Dr. Maartens: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Groote Schuur Hospital, K45 Old Main Building, Observatory, 7925 Cape Town, South Africa.
Author Contributions: Conception and design: J.B. Nachega, M. Hislop, R.E. Chaisson, L. Regensberg, G. Maartens.
Analysis and interpretation of the data: J.B. Nachega, M. Hislop, L. Regensberg, D.W. Dowdy, R.E. Chaisson.
Drafting of the article: J.B. Nachega, M. Hislop, D.W. Dowdy, G. Maartens.
Critical revision of the article for important intellectual content: J.B. Nachega, D.W. Dowdy, R.E. Chaisson, G. Maartens.
Final approval of the article: J.B. Nachega, D.W. Dowdy, R.E. Chaisson, L. Regensberg, G. Maartens.
Provision of study materials or patients: M. Hislop, L. Regensberg.
Statistical expertise: J.B. Nachega, D.W. Dowdy.
Administrative, technical, or logistic support: R.E. Chaisson, L. Regensberg.
Nachega J., Hislop M., Dowdy D., Chaisson R., Regensberg L., Maartens G.; Adherence to Nonnucleoside Reverse Transcriptase Inhibitor–Based HIV Therapy and Virologic Outcomes. Ann Intern Med. 2007;146:564-573. doi: 10.7326/0003-4819-146-8-200704170-00007
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Published: Ann Intern Med. 2007;146(8):564-573.
Researchers have shown that adherence to highly active antiretroviral therapy (HAART) is a major predictor of viral suppression of HIV replication (1–3), emergence of drug resistance (4–6), disease progression (7), and death (8–10). Nonnucleoside reverse transcriptase inhibitor (NNRTI)–based HAART has emerged as the preferred option for first-line treatment of HIV and AIDS worldwide (11, 12), including the increase of HAART programs in resource-limited settings (13). When patients receive unboosted protease inhibitor–based HAART regimens, nearly perfect adherence (≥95%) is required for sustained virologic suppression (2). Emergence of drug resistance is highest at intermediate levels (70% to 90%) of adherence (5, 14). Data from a prospective study conducted by Maggiolo and colleagues (15) in Italy suggest that, at intermediate levels of adherence, patients who receive NNRTI–based regimens may have higher rates of viral suppression than those who receive unboosted protease inhibitor–based regimens. Similarly, a study of homeless and indigent HIV-infected patients with antiretroviral therapy experience in San Francisco, California, found that, in contrast to patients who received unboosted protease inhibitors, approximately 70% of patients who received NNRTI–based HAART who had intermediate adherence (70% to 90%, as evaluated by pill count or electronic monitor) achieved undetectable viral load (<400 copies/mL) with lower levels of resistance compared with patients who had low adherence (0% to 50%) (16, 17). These studies were limited by small sample sizes and reduced generalizability to other populations. As a result, it remains unclear whether the relationship between adherence and viral suppression in patients receiving NNRTI–based HAART treatment resembles a linear dose–response relationship or whether there is a threshold adherence level below which virologic failure rapidly increases.
David J. Cennimo
UMDNJ-New Jersey Medical School
April 26, 2007
Prolonged efavirenz half-life as a protective factor in non-adherence?
In their article, Nachenga and colleagues describe the virologic response to NNRTI usage across a spectrum of adherence in a predominantly (96.9%) black South African patient cohort. (1) Their findings suggest a superiority of efavirenz (EFV) based regimens over nevirapine even when adjusted for adherence and other baseline variables. One potential confounding variable is the delayed hepatic clearance of efavirenz noted in some American patients of African descent. (2) This has been attributed to mutation in CPY2B6 gene (516Gâ†’T) which can prolong EFV half-life to 48 hours in TT homozygous mutants. In comparison, the half-lives in GG homozygotes and GT heterozygotes are 23 and 27 hours respectively. (3) This prolonged half-life, if present, could have ameliorated the effects of inconsistent adherence by maintaining effective levels until the next dose was taken. If this is the case, these effects may not be seen in alternate patient populations.
1. Nachega J, Hislop M, Dowdy D, Chaisson R, Regensberg L, Maartens G. Adherence to nonnucleoside reverse transcriptase inhibitor"“based HIV therapy and virologic outcomes. Ann Intern Med. 2007;146:564-573.
2. Pfister M, LabbeÂ´ L, Hammer S, Mellors J, Bennett K, Rosenkranz S, Sheiner L. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob. Agents Chemother. 2003;47:130-137.
3. Ribaudo H, Haas D, Tierney C, Kim R, Wilkinson G, Gulick R, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: An Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42:401-407.
D Cennimo reports receiving a BMS Virolgy Fellows Research Grant.
Jean B. Nachega
Johns Hopkins University, Dept. of International Health, Baltimore, Maryland, USA
May 18, 2007
Pharmacogenetics of efavirenz, adherence and virologic outcomes
We thank Dr. Cennimo for raising this interesting point. The primary aim of our analysis was to assess the relationship between adherence and virologic outcomes on nonnucleoside reverse transcriptase inhibitor regimens, and we caution that our finding of superior outcomes for efavirenz compared with nevirapine must be regarded as preliminary.
The homozygous CYP2B6 position 516 TT genotype was found in 3.4% of European-Americans and 20% of African-Americans in the AIDS Clinical Trials Group study A5097s(1), and in 13.1% of a recent South African study(2).The CYP2B6 TT genotype increases the efavirenz half-life, but, as pointed out in the article Dr. Cennimo cites(3), this would be expected to result in a higher risk for the selection of drug resistant mutations in poorly adherent patients as the interruption of their other antiretroviral drugs with shorter half lives will result in prolonged effective monotherapy with efavirenz.
The CYP2B6 TT genotype is also associated with an increased incidence of efavirenz-induced neuropsychiatric symptoms(1), which may reduce adherence. Therefore one could argue that in populations such as ours with a higher proportion of patients with the CYP2B6 TT genotype that efavirenz should be associated with poorer outcomes. Finally, efavirenz has also been shown to be more effective than nevirapine in a collaborative study of twelve cohorts from Europe and North America(4), populations in which the prevalence of the CYP2B6 TT mutation is low. This suggests that population pharmacogenetic differences are not the likely explanation for our preliminary finding that efavirenz is more effective than nevirapine.
1.Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18(18):2391-400.
2.Cohen K, Dandara C, McIlleron H, Pemba L, Churchyard G, Maartens G, et al. The effect of rifampicin and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval plasma concentrations in South African adults. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 16-18 April 2007; Budapest, Hungary.
3.Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group study. Clin Infect Dis 2006;42:401-7.
4.The Antiretroviral Therapy Cohort Collaboration. Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies. J Infect Dis 2006;194:612-22.
Conflict of Interest
R.E. Chaisson (Bristol-Myers Squibb); Honoraria: J.B. Nachega (GlaxoSmithKline, Merck-Sharp-Dohme for continuing medical education lectures), G. Maartens (Merck-Sharp-Dohme); Grants received: G. Maartens (Merck-Sharp-Dohme); Other: J.B. Nachega (Aspen Pharmaceuticals for conferences and travel grants).
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