Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients

Sanjiv M Baxi, Ruth M Greenblatt, Peter Bacchetti, Chengshi Jin, Audrey L French, Marla J Keller, Michael H Augenbraun, Stephen J Gange, Chenglong Liu, Wendy J Mack, Monica Gandhi, Women’s Interagency HIV Study (WIHS), Kathryn Anastos, Howard Minkoff, Mary Young, Ruth Greenblatt, Phyllis Tien, Bradley Aouizerat, Alexandra Levine, Mardge Cohen, Stephen J Gange, Elizabeth Golub, Sanjiv M Baxi, Ruth M Greenblatt, Peter Bacchetti, Chengshi Jin, Audrey L French, Marla J Keller, Michael H Augenbraun, Stephen J Gange, Chenglong Liu, Wendy J Mack, Monica Gandhi, Women’s Interagency HIV Study (WIHS), Kathryn Anastos, Howard Minkoff, Mary Young, Ruth Greenblatt, Phyllis Tien, Bradley Aouizerat, Alexandra Levine, Mardge Cohen, Stephen J Gange, Elizabeth Golub

Abstract

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%-94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Bar graph of multivariate-adjusted odds…
Fig 1. Bar graph of multivariate-adjusted odds ratio of viral suppression by quartile of concentration of NVP in hair.

References

    1. Moore RD, Keruly JC, Bartlett JG. Improvement in the health of HIV-infected persons in care: reducing disparities. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;55(9):1242–51. 10.1093/cid/cis654
    1. Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PloS one. 2013;8(12):e81355 10.1371/journal.pone.0081355
    1. Bradley H, Hall HI, Wolitski RJ, Van Handel MM, Stone AE, LaFlam M, et al. Vital Signs: HIV diagnosis, care, and treatment among persons living with HIV—United States, 2011. MMWR Morbidity and mortality weekly report. 2014;63(47):1113–7. .
    1. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. The New England journal of medicine. 2011;365(6):493–505. 10.1056/NEJMoa1105243
    1. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y, et al. Common clinical conditions—age, low BMI, ritonavir use, mild renal impairment—affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. Aids. 2014;28(1):59–66. 10.1097/QAD.0000000000000033
    1. Gandhi M, Greenblatt RM, Bacchetti P, Jin C, Huang Y, Anastos K, et al. A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis. 2012;206(9):1453–61. 10.1093/infdis/jis508
    1. Loutfy MR, Walmsley SL, Klein MB, Raboud J, Tseng AL, Blitz SL, et al. Factors affecting antiretroviral pharmacokinetics in HIV-infected women with virologic suppression on combination antiretroviral therapy: a cross-sectional study. BMC infectious diseases. 2013;13:256 10.1186/1471-2334-13-256
    1. Pham PA. Antiretroviral adherence and pharmacokinetics: review of their roles in sustained virologic suppression. AIDS patient care and STDs. 2009;23(10):803–7. 10.1089/apc.2008.0269 .
    1. Berg KM, Arnsten JH. Practical and conceptual challenges in measuring antiretroviral adherence. Journal of acquired immune deficiency syndromes. 2006;43 Suppl 1:S79–87. 10.1097/01.qai.0000248337.97814.66
    1. Kagee A, Nel A. Assessing the association between self-report items for HIV pill adherence and biological measures. AIDS care. 2012;24(11):1448–52. 10.1080/09540121.2012.687816 .
    1. Blumenthal J, Haubrich R. Pre-exposure prophylaxis for HIV infection: how antiretroviral pharmacology helps to monitor and improve adherence. Expert opinion on pharmacotherapy. 2013;14(13):1777–85. 10.1517/14656566.2013.812072
    1. Baxi SM, Liu A, Bacchetti P, Mutua G, Sanders EJ, Kibengo FM, et al. Comparing the Novel Method of Assessing PrEP Adherence/Exposure using Hair Samples to other Pharmacologic and Traditional Measures. Journal of acquired immune deficiency syndromes. 2014. 10.1097/QAI.0000000000000386 .
    1. Gandhi M, Ameli N, Bacchetti P, Anastos K, Gange SJ, Minkoff H, et al. Atazanavir concentration in hair is the strongest predictor of outcomes on antiretroviral therapy. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2011;52(10):1267–75. Epub 2011/04/22. 10.1093/cid/cir131
    1. Gandhi M, Ameli N, Bacchetti P, Gange SJ, Anastos K, Levine A, et al. Protease inhibitor levels in hair strongly predict virologic response to treatment. Aids. 2009;23(4):471–8. Epub 2009/01/24. 10.1097/QAD.0b013e328325a4a9
    1. van Zyl GU, van Mens TE, McIlleron H, Zeier M, Nachega JB, Decloedt E, et al. Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting. J Acquir Immune Defic Syndr. 2011;56(4):333–9. 10.1097/QAI.0b013e31820dc0cc .
    1. Bernard L, Peytavin G, Vuagnat A, de Truchis P, Perronne C. Indinavir concentrations in hair from patients receiving highly active antiretroviral therapy. Lancet. 1998;352:1757–8.
    1. Bernard L, Vuagnat A, Peytavin G, Hallouin MC, Bouhour D, Nguyen TH, et al. Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy. Annals of Internal Medicine. 2002;137(8):656–9.
    1. Duval X, Peytavin G, Breton G, Ecobichon JL, Descamps D, Thabut G, et al. Hair versus plasma concentrations as indicator of indinavir exposure in HIV-1-infected patients treated with indinavir/ritonavir combination. Aids. 2007;21(1):106–8. 10.1097/QAD.0b013e3280118486 .
    1. Servais J, Peytavin G, Arendt V, Staub T, Schneider F, Hemmer R, et al. Indinavir hair concentration in highly active antiretroviral therapy-treated patients: association with viral load and drug resistance. Aids. 2001;15(7):941–3. .
    1. Gandhi M, Greenblatt RM. Hair it is: the long and short of monitoring antiretroviral treatment. Ann Intern Med. 2002;137(8):696–7. .
    1. Barkan SE, Melnick SL, Preston-Martin S, Weber K, Kalish LA, Miotti P, et al. The Women's Interagency HIV Study. Epidemiology. 1998;9(2):117–25.
    1. Huang Y, Gandhi M, Greenblatt RM, Gee W, Lin ET, Messenkoff N. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry. Rapid Commun Mass Spectrom. 2008;22(21):3401–9. 10.1002/rcm.3750
    1. Huang Y, Yang Q, Yoon K, Lei Y, Shi R, Gee W, et al. Microanalysis of the antiretroviral nevirapine in human hair from HIV-infected patients by liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2011;401(6):1923–33. Epub 2011/08/19. 10.1007/s00216-011-5278-7
    1. Liu AY, Yang Q, Huang Y, Bacchetti P, Anderson PL, Jin C, et al. Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP). PloS one. 2014;9(1):e83736 Epub 2014/01/15. 10.1371/journal.pone.0083736 PONE-D-13-32897 [pii].
    1. DiFrancesco R, Tooley K, Rosenkranz SL, Siminski S, Taylor CR, Pande P, et al. Clinical pharmacology quality assurance for HIV and related infectious diseases research. Clin Pharmacol Ther. 2013;93(6):479–82. Epub 2013/04/17. 10.1038/clpt.2013.62 clpt201362 [pii]. .
    1. Aziz M, Livak B, Burke-Miller J, French AL, Glesby MJ, Sharma A, et al. Vitamin D insufficiency may impair CD4 recovery among Women's Interagency HIV Study participants with advanced disease on HAART. Aids. 2013;27(4):573–8. 10.1097/QAD.0b013e32835b9ba1
    1. Gandhi M, Yang Q, Bacchetti P, Huang Y. Short communication: A low-cost method for analyzing nevirapine levels in hair as a marker of adherence in resource-limited settings. AIDS research and human retroviruses. 2014;30(1):25–8. 10.1089/AID.2013.0239
    1. McFall AM, Dowdy DW, Zelaya CE, Murphy K, Wilson TE, Young MA, et al. Understanding the disparity: predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity. Journal of acquired immune deficiency syndromes. 2013;64(3):289–98. Epub 2013/06/26. 10.1097/QAI.0b013e3182a095e9
    1. Levine RS, Briggs NC, Kilbourne BS, King WD, Fry-Johnson Y, Baltrus PT, et al. Black-White mortality from HIV in the United States before and after introduction of highly active antiretroviral therapy in 1996. Am J Public Health. 2007;97(10):1884–92. Epub 2007/09/01. doi: AJPH.2005.081489 [pii] 10.2105/AJPH.2005.081489
    1. Lemly DC, Shepherd BE, Hulgan T, Rebeiro P, Stinnette S, Blackwell RB, et al. Race and sex differences in antiretroviral therapy use and mortality among HIV-infected persons in care. J Infect Dis. 2009;199(7):991–8. Epub 2009/02/18. 10.1086/597124 [pii]. .
    1. Pence BW, Ostermann J, Kumar V, Whetten K, Thielman N, Mugavero MJ. The influence of psychosocial characteristics and race/ethnicity on the use, duration, and success of antiretroviral therapy. Journal of acquired immune deficiency syndromes. 2008;47(2):194–201. Epub 2007/11/01. 10.1097/QAI.0b013e31815ace7e .
    1. Ribaudo HJ, Smith KY, Robbins GK, Flexner C, Haubrich R, Chen Y, et al. Racial differences in response to antiretroviral therapy for HIV infection: an AIDS clinical trials group (ACTG) study analysis. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2013;57(11):1607–17. Epub 2013/09/21. 10.1093/cid/cit595 cit595 [pii].
    1. Murphy K, Hoover DR, Shi Q, Cohen M, Gandhi M, Golub ET, et al. Association of self-reported race with AIDS death in continuous HAART users in a cohort of HIV-infected women in the United States. Aids. 2013;27(15):2413–23. 10.1097/01.aids.0000432537.92958.73
    1. Bock P, Fatti G, Grimwood A. Comparing the effectiveness of efavirenz and nevirapine for first-line antiretroviral therapy in a South African multicentre cohort. International health. 2013;5(2):132–8. 10.1093/inthealth/iht002 .
    1. Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, et al. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. Aids. 2008;22(16):2117–25. 10.1097/QAD.0b013e328310407e
    1. Masebe TM, Bessong PO, Nwobegahay J, Ndip RN, Meyer D. Prevalence of MDR1 C3435T and CYP2B6 G516T polymorphisms among HIV-1 infected South African patients. Disease markers. 2012;32(1):43–50. 10.3233/DMA-2012-0859
    1. Chantarangsu S, Cressey TR, Mahasirimongkol S, Capparelli E, Tawon Y, Ngo-Giang-Huong N, et al. Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women. The Journal of antimicrobial chemotherapy. 2009;64(6):1265–73. 10.1093/jac/dkp351
    1. Vardhanabhuti S, Acosta EP, Ribaudo HJ, Severe P, Lalloo U, Kumarasamy N, et al. Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission. J Infect Dis. 2013;208(4):662–71. 10.1093/infdis/jit223
    1. Swaminathan S, Ramachandran G, Agibothu Kupparam HK, Mahalingam V, Soundararajan L, Perumal Kannabiran B, et al. Factors influencing plasma nevirapine levels: a study in HIV-infected children on generic antiretroviral treatment in India. The Journal of antimicrobial chemotherapy. 2011;66(6):1354–9. 10.1093/jac/dkr075

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner