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Adherence to Nonnucleoside Reverse Transcriptase Inhibitor–Based HIV Therapy and Virologic Outcomes

Jean B. Nachega, MD, MPH; Michael Hislop, MSc; David W. Dowdy, ScM; Richard E. Chaisson, MD; Leon Regensberg, MBChB; and Gary Maartens, MBChB
[+] Article and Author Information

From Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland, and Groote Schuur Hospital, University of Cape Town, and Aid for AIDS Disease Management Programme (Pty) Ltd., Cape Town, South Africa.


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, jnachega@jhsph.edu.

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.


Ann Intern Med. 2007;146(8):564-573. doi:10.7326/0003-4819-146-8-200704170-00007
Text Size: A A A

We identified 2821 patients who met all inclusion criteria; of whom, 1822 (64.6%) received efavirenz-based regimens and 999 (35.4%) received nevirapine-based regimens. The mean age at HAART initiation was 37.0 years (SD, 7.8), 1775 patients (62.9%) were women, and 2734 patients (96.9%) were black Africans (Table 1). The median follow-up period was 2.2 years (interquartile range, 1.7 to 2.7 years), and the median frequency of viral load measurement was 1.2 measurements per year (interquartile range, 0.7 to 1.7 measurements per year). For viral load measurements less than 400 copies/mL (5513 [75.6%] of 7290 total measurements), 65.9% were recorded as less than 50 copies/mL, 22.1% as less than 400 copies/mL, and 11.9% as between 50 and 400 copies/mL. The median CD4+ T-cell counts at HAART initiation for men and women were 0.130 × 109 cells/L (interquartile range, 0.56 to 0.211 × 109 cells/L) and 0.157 × 109 cells/L (interquartile range, 0.69 to 0.236 × 109 cells/L), respectively (P = 0.002). The median HIV-1 RNA levels at HAART initiation for men and women were 5.1 log10 copies/mL (interquartile range, 4.6 to 5.6 log10 copies/mL) and 5.2 log10 copies/mL (interquartile range, 4.7 to 5.6 log10 copies/mL), respectively (P = 0.184).

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Figures

Grahic Jump Location
Figure 1.
Proportion of patients at each level of pharmacy claim adherence to nonnucleoside reverse transcriptase inhibitor–based highly active antiretroviral therapy with sustained viral suppression less than 400 copies/mL.

The error bars represent 95% CIs around the estimate of the respective proportions based on a binomial probability distribution and using the sample sizes listed.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Pharmacy claim adherence to nonnucleoside reverse transcriptase inhibitor–based highly active antiretroviral therapy (HAART) and viral suppression less than 400 copies/mL within specified time strata after HAART initiation.

For patients with >1 viral load measurement within each time stratum, only the first qualifying measurement was included in this analysis. The error bars represent 95% CIs around the estimate of the respective proportions based on a binomial probability distribution and using the sample sizes listed.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Kaplan–Meier plots of patients with sustained HIV-1 RNA less than 400 copies/mL after initial viral suppression according to levels of pharmacy claim adherence.
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Tables

References

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Comments

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Prolonged efavirenz half-life as a protective factor in non-adherence?
Posted on April 26, 2007
David J. Cennimo
UMDNJ-New Jersey Medical School
Conflict of Interest: None Declared

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 (516G→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, Labbe´ 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.

Conflict of Interest:

D Cennimo reports receiving a BMS Virolgy Fellows Research Grant.

Pharmacogenetics of efavirenz, adherence and virologic outcomes
Posted on May 18, 2007
Jean B. Nachega
Johns Hopkins University, Dept. of International Health, Baltimore, Maryland, USA
Conflict of Interest: None Declared

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.

References

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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Summary for Patients

Adherence to Nonnucleoside Reverse Transcriptase Inhibitor–Based HIV Therapy and Patient Outcomes

The summary below is from the full report titled “Adherence to Nonnucleoside Reverse Transcriptase Inhibitor– Based HIV Therapy and Virologic Outcomes.” It is in the 17 April 2007 issue of Annals of Internal Medicine (volume 146, pages 564-573). The authors are J.B. Nachega, M. Hislop, D.W. Dowdy, R.E. Chaisson, L. Regensberg, and G. Maartens.

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