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ART drug resistance mutations Implications for TDF use

ART drug resistance mutations Implications for TDF use. Phyllis Kanki and Beth Chaplin Harvard PEPFAR Harvard School of Public Health. Drug resistance to current d4t or ZDV based regimens? Implications for TDF in alternative or second line regimens

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ART drug resistance mutations Implications for TDF use

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  1. ART drug resistance mutations Implications for TDF use Phyllis Kanki and Beth Chaplin Harvard PEPFAR Harvard School of Public Health

  2. Drug resistance to current d4t or ZDV based regimens? • Implications for TDF in alternative or second line regimens • What do we know about drug resistance to TDF as first line regimens? • HIV subtype issues • Preliminary data on TDF resistance (K65R) transmission potential • Baseline and toxicity issues with TDF

  3. K65R Mutation of Lysine to Arginine in Codon 65 of the reverse transcriptase. It was first identified in response to TDF; only drug resistance mutation for TDF It confers resistance to TDF and also causes cross resistance to other NRTIs (ABC, ddI, FTC, 3TC) except zidovudine. In subtype B virus it is uncommon in patients who are not on a regimen containing TDF

  4. Drug resistance in d4t or AZT based first line regimens • “Options for 2nd line ART regimens whose initial regimen of d4T+3TC+NVP fails” • 92-95% of mulit-drug resistance to NRTIs and NNRTIs (89% M184V) • TAMs (37%), K65R (6%), Q151M (8%) • (Sungkanuparph et al, CID 2007:44-447)

  5. Preliminary data on drug resistance mutations in Nigerian patients on non-TDF regimens • 194 Nigerian patients on a regimen of d4T-3TC-NVP/EFV in virologic failure • Virologic failure defined as VL >2000 copies/ml with history of 6 month regular drug pickup. • 10/194 (5.2%) had the K65R mutation

  6. Possible Implications: • Drug resistance to TDF (K65R) observed in non-TDF based regimens was not predicted. • Coupled with M184V will effectively limit options for alternative or second line regimens.

  7. What do we know about drug resistance to TDF as first line regimens? No significant difference in efficacy measured by viral suppression

  8. What do we know about drug resistance to TDF as first line regimens? • Preliminary data from Nigeria: • Evaluated drug resistance in patients initiating TDF first line regimens in virologic failure • 4 of 10 TDF virologic failures had K65R • K65R was accompanied by multi-drug resistance mutations including M184V and TAMS

  9. What do we know about drug resistance to TDF as first line regimens?

  10. Which mutations are the first to appear? NNRTIs: NVP EFV # of patients with this mutation NRTIs: 3TC d4T ZDV Patients with only one mutation

  11. mutations that seem to appear later in the course of resistance “Early” and “Late” NNRTI Mutations early mutation

  12. Implications: Use of TDF in first line may lead to high rates of resistance (K65R) TDF resistance mutations would occur late Therefore, AZT could still be employed in alternative and second line regimens

  13. What do we know about drug resistance to TDF as first line regimens? • HIV subtype issues • Botswana : Increased In vitro resistance to TDF in subtype C virus (Wainburg et al) • Nigeria: Genotype data • Subtype CRF 02 increased development of resistance to TDF • Subtype 06 decreased development of resistance to TDF

  14. Emergence of Resistance to Tenofovir (TDF) in Subtype C Compared to Other Subtypes in Vitro 12-23 AIDS 20:F9-F13,2006

  15. JUTH Plateau State N = 123 UMTH Borno State N = 31 UCH Oyo State N = 39 REC REC CRF11 A REC D F2 CRF06 CRF13 A CRF02 A CRF06 CRF02 CRF02 CRF06 G G G LUTH Lagos State N = 47 NIMR Lagos State N = 58 68Military Lagos State N = 43 REC REC F2 REC CRF06 CRF06 A CRF06 CRF02 CRF02 CRF02 G G G

  16. K65R by subtype

  17. Tenofovir K65R M41L A62V 69ins K70R L210W T215YF K219QE A62V V75I F77L F116Y Q151M Frequency of Mutations Associated with NRTI Resistance Grouped by Subtype Subtype: G CRF02 CRF06 M41L14/87 6/76 4/9 E44D 3/87 1/76 0/9 K65R 3/87 7/76 0/9 D67N 18/87 10/76 5/9 K70R 25/87 11/76 4/9 L74V 2/87 0/76 0/9 Y115F 2/87 2/76 0/9 V118I 6/87 2/76 1/9 M184V 72/87 65/76 7/9 M184I 2/87 3/76 1/9 L210W 4/87 3/76 1/9 T215Y 13/87 14/76 0/9 T215F 11/87 13/76 3/9 K219Q 12/87 6/76 3/9 K219E 6/87 4/76 0/9 Multi-nRTI Resistance M41L E44D D67N K70R V118I L210W T215YF K219QE Zidovudine M41L E44D D67N K70R V118I L210W T215YF K219QE Stavudine M41L E44D K65R D67N K70R V118I L210W T215YF K219QE Didanosine K65R L74V Abacavir K65R Y115F M184V L74V Lamivudine K65R M184VI Emtricitabine K65R M184VI Subtype: G CRF02 CRF06 A62V 2/87 5/76 0/9 V75I 9/87 5/76 0/9 F77L 3/87 5/76 0/9 F116Y 2/87 3/76 0/9 Q151M 3/87 5/76 0/9 Multi-NRTI Resistance Ins. Complex Multi-NRTI Resistance 151 Complex

  18. Implications: HIV subtype may influence (increase) development of K65R More studies need to evaluate potential impact of geographic (subtype) implications for TDF use However, even with K65R subtype differences - AZT could still be employed in alternative and second line regimens

  19. Preliminary data on TDF resistance (K65R) transmission potential • Preliminary data from Nigeria: • Clustering of TDF resistance (K65R) • 3 possible cases of TDF resistance(K65R) - where resistance seen prior to ART

  20. Responsive to a regimen of Kaletra (LPV/r), AZT and TDF K65R T69del V75I F77L Q151M K219R -- NNRTIs K65R T69del V75I F77L Q151M K219R -- NNRTIs G d4T-3TC-NVP AZT-TDF-LPV/r

  21. This patient may represent a case of transmitted resistance. K65R V75I F77L Y115F F116Y Q151M -- NNRTIs K65R V75I F77L F116Y Q151M -- NNRTIs K65R Q151M -- NNRTIs CRF02 d4T-3TC-NVP AZT-TDF-LPV/r

  22. Another case of transmitted resistance? K65R T69I F77L F116Y Q151M M184V -- NNRTIs K65R F116Y Q151M M184V -- NNRTIs CRF02 AZT-3TC- NVP AZT-3TC- TDF-LPV/r Surveying for possible cases of transmitted resistance...

  23. Implications: • Surveillance is needed to evaluate possibility of transmission of drug resistant viruses • TDF-first line regimens might have reduced efficacy in the face of transmitted resistant virus (K65R) but we need much more data • In our small numbers patients still responded to TDF-second line even with the drugs resistance mutations (K65R)

  24. Baseline and toxicity issues with TDF • Reports of renal dysfunction in TDF-treated patients raise concerns about the potential for nephrotoxicity despite its excellent safety profile in clinical trials; particularly in patients with other risk factors for renal dysfunction, or deranged baseline renal function.

  25. Baseline and toxicity issues with TDF • Preliminary data from Nigeria: • Baseline chemistries suggest that abnormal renal function will be low -- TDF could be used in the majority of patients. • Serum CR and creatinine clearance compromised in patients on TDF- regimens

  26. Laboratory values at baseline (n= 25,747)

  27. TEMPORAL CHANGES IN RENAL FUNCTION ASSOCIATED WITH THE USE OF TENOFOVIR DISOPROXIL FUMARATE (TDF) IN HIV-INFECTED NIGERIAN ADULTSAgbaji O1, Agaba P1, Sule H1, Ojoh R1, Audu E1, Sani M1, Akintunde L1, Taiwo B2, Idoko J1, Murphy R² Kanki P31AIDS Prevention Initiative in Nigeria Plus, Jos University Teaching Hospital, Jos, Nigeria; 2Division of Infectious Diseases, Northwestern School of Medicine, Chicago, IL, USA; 3Harvard School of Public Health Boston, MA, USA. Clinical/laboratory data for 84 on TDF-regimen and 102 on other NRTI regimens evaluated at 12 months Creatinine clearance (CLcr) estimated using the Cockcroft-Gault equation. Changes in serum creatinine and CLcr from baseline for each patient were compared between the TDF-treated patients and those in the non-TDF NRTI group. Multivariate analysis to control for other factors.

  28. Results Serum creatinine increased by 23% (97.8 ± 25.9) and 3% (89.0 ± 26.2) in the TDF and non-TDF NRTI arms, at 48 weeks (p=0.02). Greater mean decrease in CLcr reduction from baseline in TDF (14.7 ± 44.4 ml/L) versus the non-TDF NRTI (10.4 ± 37.7 ml/L) arm at 48 weeks (p=0.001). In multivariate analyses, variables predictive of reduced CLcr were TDF use (p=0.005), age (p=0.002) and male gender (p=0.004).

  29. Implications: • TDF-regimens associated with a small, but statistically significant renal compromise compared with non-TDF- regimens. • CLcr however remained within normal range. • Assessment of renal function prior to initiation of tenofovir therapy is recommended for all patients. • Therefore, frequent monitoring of renal function may not be necessary in patients with baseline normal renal function.

  30. Future Directions • Are second line therapies containing tenofovir effective over the long-term for resistant (K65R) patients? • - How do failure rates compare to patients with other mutation patterns? • - Does TDF in a 2nd line regimen impact efficacy? • Testing partners where available and examining cases of transmitted resistance.

  31. Harvard PEPFAR P. Kanki B. Chaplin R. Murphy J-L Sankalé S. Meloni A-Dieng Sarr S. Calves J. Hosseini W. Odutolu P. Okonkwo E. Ekong T. Jolayemi J. Samuels S. Ochigbo P. Akande B. Aluko B. Taiwo K. Scarsi K. Hurt J. Idoko O. Idigbe I. Adewole D. OIaleye C. Okany S. Akanmu S. Ogunsola W. Gashau M. Garbati R. Nkado D. Owujekwe H. Muktar S. Garko J. Abah R. Marlink T. Gaolathe J. Mukhema N. Ndwapi P.J. Burns P. Mwala K. Mukendi J. Puvimanasinghe M. Mine C. Bussmann M. Essex V. Novitsky M. Wainburg

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