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This session featured a case-based panel discussion by Dr. Michael S. Saag on selecting antiretroviral therapy for specific patient profiles, including those coinfected with hepatitis B virus and HIV, pregnant partners of HIV-seropositive patients, and individuals experiencing chronic kidney disease. Key topics covered cost-effectiveness of different ARVs and the use of dolutegravir in pregnancy based on fetal toxicity studies and placental transfer data.

• Antiretroviral therapy
• Clinical cases
• Hepatitis B
• HIV
• Pregnancy

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1. Cases From the Clinic(ians): A Case-based, Panel Discussion Michael S. Saag, MD Professor of Medicine Associate Dean for Global Health University of Alabama at Birmingham Birmingham, Alabama FORMATTED: 03-28-16 Chicago, Illinois: May 9, 2016 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

2. Learning Objectives After attending this presentation, participants will be able to: Select antiretroviral therapy for patients who are: Coinfected with hepatitis B virus and HIV Pregnant Partners of HIV-seropositive patients Experiencing chronic kidney disease Slide 2 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

3. Cost Effectiveness of 5 ARVs (07-12) FTC/RPV/TDF EFV/FTC/TDF Slide 3 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

4. Minimum Costs of ARV treatments ______________________________________________________________ Combination Estimated price / year ______________________________________________________________ TDF/3TC/ATV/r $279 TDF/FTC/ELV/c $184 GREEN FULLY GENERIC ABC/3TC/DTG $179 WORLDWIDE IN 2017 TDF/FTC/EFV600 $144 RED STILL PATENTED TO 2025+ : TDF/3TC/EFV600 $130 VOLUNTARY LICENSES TDF/3TC/EFV400 $100 TAF/3TC/DTG $60 DTG/3TC $46 _______________________________________________________ Slide 4 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

5. Dolutegravir in pregnancy: Background No fetal toxicity or teratogenicity in animal studies described in manufacturer s submission for regulatory approval1 High placental transfer of DTG relative to other ARVs in an ex vivo study2 Unexpected placental transfer of DTG with fetal accumulation and then slow neonatal clearance 3 1. European Medicines Agency. Dolutegravir. Annex I: Summary of Product Characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/002753/WC500160680.pdf 2. Schalkwijk S, Greupink R, Colbers AP, Wouterse AC, Verweij VGM, van Drongelen J, et al. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model. J Antimicrob Chemother. 2015 Nov 3 pii: dkv358. [Epub ahead of print] Available from: http://www.jac.oxfordjournals.org/lookup/doi/10.1093/jac/dkv358 3. Pain JB, L MP, Caseris M, Amiel C, Lassel L, Charpentier C, et al. Pharmacokinetics of Dolutegravir in a Premature Neonate after HIV Treatment Intensification during Pregnancy: FIG 1. Antimicrob Agents Chemother [Internet]. 2015 Jun;59(6):3660 2. Available from: http://aac.asm.org/lookup/doi/10.1128/AAC.00173-15 Slide 5 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

6. Dolutegravir PK IMPAACT P1026s Mulligan N et al. CROI 2016. Poster abstract 398 DTG AUC 25-30% lower in 2nd/3rd trimester vs paired postpartum (PP) data. Differences not significant. DTG Cmax significantly lower in 3rd trimester vs postpartum. C24 41% lower in 2nd/3rd trimester not significant. 6/9 (67%) women in 2nd trimester, 12/15 (80%) in 3rd and 8/9 postpartum had AUC above 10th percentile (37.5 mcg*hr/mL) of non- pregnant adults. AUC and trough exposures appeared to be lower in pregnancy compared to postpartum. But antepartum AUC and trough values still similar to those seen in non-pregnant adults. Slide 6 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

7. Hunt, et al. CROI 2016 Abs 671 Slide 7 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

8. Slide 8 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

9. Slide 9 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

10. Change in eGFR (Cockcroft-Gault) with TAF vs TDF Studies 104 and 111: Week 48 Combined Analysis 20 E/C/F/TAF Mean (SD) change from baseline eGFR Cockroft-Gault (mL/min) E/C/F/TDF 10 from Baseline eGFR* Mean (SD) Change 0 -6.6 p <0.001 -10 -11.2 -20 0 12 24 36 48 Time (Weeks) Time (Weeks) *Cockcroft-Gault (mL/min). Slide 10 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.

11. Results: 235 patients from 28 cohorts 84% male, median age at CM 38 years. Death rate at 6 months: 42/235 (18%) Hazard Ratios (95% CI) for deferred vs early ART Crude 1.29 (0.68-2.43) Adjusted 1.30 (0.66-2.55) Kaplan-Meier survival estimates 1.00 0.90 0.80 % still alive 0.70 0.60 Regime A (early ART) Regime B (deferred ART) 0.50 0 2 4 6 Time (months) since CM diagnosis Number at risk Regime A 235 58 56 55 Regime B 235 66 63 60 Conclusions: Early ART does not seem to be associated with higher mortality in resource rich settings, in contrast to data from resource limited settings Underpowered to provide robust evidence Limitation: lack of data on CM treatment and disease management. We aim to obtain this in the future. Slide 11 of 11 From MS Saag, MD, at Chicago, IL: May 9, 2016, IAS-USA.