20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND – TEL CENTRAL +41 22 791 2111 – FAX CENTRAL +41 22 791 3111 – WWW.WHO.INT Comments on EML application : cobicistat + elvitegravir + emtricitabine + tenofovir alfenamide The WHO HIV Department does not support the addition of the formulation cobicistat + elvitegravir + emtricitabine + tenofovir alfenamide in 2017 WHO Model List of Essential Medicines for treatment of HIV infection for the following reasons Cobicisitat( COBI), elvitegravir (EVG) and tenofovir alfenamide (TAF) are not included as options in 2016 WHO consolidated guidelines on use of antiretrovirals for treating and preventing of HIV infection 1. A recent WHO systematic review comparing the use of integrase inhibitors in 1st line showed that dolutegravir and raltegravir were superior to elvitegravir/cobicistat (EVG/COBI) in terms of viral suppression, CD4 recovery and risk of treatment discontinuation.2 There are important concerns with the use of TAF and EVG/COBI in TB co-infection. EGV/COBI has important and well documented drug interactions with rifampicin and must not be co-administrated, as will result in loss of its antiviral effect3 4 Regarding TAF, there are no published data available on the pharmacokinetics and real-world efficacy of TAF in TB- coinfected patients. While the current available tenofovir prodrug (tenofovir disoproxil fumarate or TDF) does not require dose-adjustment if co-administered with rifampicin, TAF is currently contraindicated by the originator in patients being treated with rifampicin, as significant drug interaction is predicted based on pK modelling 56. Data on the potential for TAF dose adjustment are awaited. There are very limited data available on the safety of EVG/COBI and TAF during pregnancy. Preliminary pK studies in pregnant women showed that EVG and COBI exposure are substantially lower during pregnancy compared to postpartum and standard doses may not be adequate for sustained viral suppression 7 8. Despite preclinical toxicity studies with TAF in pregnancy didn´t reveal concerns, preliminary pK data in humans showed a 5-fold higher intracellular tenofovir concentration with TAF when compared with TDF9. It might lower the risk of mother-to-child transmission of HIV, but it can also increase the risk of birth abnormalities. There is no data are available on placental or breast milk passage of EVG/COBI or TAF in 1 World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2nd Edition Geneva: WHO; 2016. 2 Kanters S, Vitoria M, Doherty M, Mills EJ. Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis. Lancet HIV, 2016; 3:e510-20. 3 Lee JSF, Calmy A, Andrieux-Meyer I, Ford N. Review of the safety, efficacy, and pharmacokinetics of elvitegravir with an emphasis on resource-limited settings. HIV/AIDS (Auckland, NZ). 2012;4:5-15. 4 Evitegravir [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/ drugsatfda_docs/label/2015/203093s002lbl.pdf. 5 Genvoya [package insert]. Food and Drug Administration. 2015. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2015/207561s000lbl.pdf 6 Ray AS, Fordyce MW, Hitchcock MJM.Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res, 2016, 125:63-70 7 Schalkwijk S, Colbers A, Konopnicki D, et al. First reported use of elvitegravir and cobicistat during pregnancy. AIDS. 2016;30(5):807-808. 8 Best BM, Capparelli EV, Stek A, Acosta EP, Smith E and IMPAACT 1026a Protocol Team. Elvitegravir/Cobicistat Pharmacokinetics in Pregnancy and Postpartum. Abstract #755. CROI 2017, Seattle; 2017 9 Vitoria M, Hill AM, Ford NP, Doherty M, Khoo SH, Pozniak AL. Choice of antiretroviral drugs for continued treatment scale-up in a public health approach: what more do we need to know? J Int AIDS Soc. 2016; 19(1): 20504. Page 2 humans. Until results from pK and large database of TAF- and EVG/COBI treated pregnant women have been analysed, it is not possible to evaluate the real safety risk of using these drugs in pregnant/breastfeed women. Despite lesser detrimental effects on bone and renal lab markers with TAF use, there is no difference in adverse event rates in major TAF and TDF comparative studies1011. An unpublished meta-analysis of 10 clinical trials compared TDF- and TAF-based regimens, which together comprised almost 7000 participants and more than 8000 patient-years of follow-up. This metanalysis did not reveal statistically significant differences in virological outcomes, adverse events, lab abnormalities, or deaths, and only showed differences when specific bone and renal laboratorial parameters were compared. 12 Data on the effectiveness of TAF in severely immunocompromised HIV patients is also missing: none of the available studies had mean/median baseline CD4 cell counts below 350 cells/mm3. Important to emphasize that the median CD4 cell count at ART initiation among PLHIV in all regions of the globe, including high income countries, are still below this threshold.13 14 15 16 17 18 19 Data on EVG/COBI and TAF use in adolescents (12-18 years old) are available only for a comparatively small sample (50 participants in total), and only for 48 weeks of study follow-up20. Clinical studies in children younger than 12 years old are still ongoing. In conclusion, the recommendation to use therapeutic regimens containing COBI, EVG and TAF as a standard options for low- and middle-income countries is viewed by WHO as premature and requires more data for tuberculosis, pregnancy, children and PLHIV with severe immunosuppression. 10 Sax P, Zolopa A, Brar I et al. 2014. Tenofovir alafenamide vs tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomised phase 2 study. J Acquire Immune Defic Syndr, 67(1), pp. 52-58 11 Sax P, Wohl D, Yin M et al. 2015. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for inititial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. The Lancet, 385, pp 2606-2615 12 Gotham D, Hill A, Pozniak A L. Candidates for inclusion in a Universal Antiretroviral Regimen: Tenofovir Alafenamide. Curr Opin HIV AIDS, 2017 (submitted for publication). 13 Mills A, Crofoot G, McDonald C, Shalit P, Flamm JA, Gathe J, et al. Tenofovir Alafenamide Versus 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;69(4):439–45. 14 Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, 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;67:52–8. 15 Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606–15. 16 Orkin C. Switching from rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) to rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF): safety and efficacy through 48 weeks. In: HIV Glasgow. Glasgow; 2016. 17 Gallant JE, Daar ES, Raffi F, Brinson C, Ruane P, DeJesus E, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, activ. 3(4):e158--e165. 18 Raffi F. Long-term (96-week) efficacy and safety after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in HIV-infected, virologically suppressed adults. In: HIV Glasgow. Glasgow; 2016 19 Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016 Nov;16(1):43–52. 20 Gaur AH, Kizito H, Prasitsueubsai W, Rakhmanina N, Rassool M, et al. Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial The Lancet HIV, Volume 3, Issue 12, December 2016, Pages e561-e568 .