Cases from the Clinic(ians): Case-Based Panel Discussion Michael S. Saag, MD Professor of Medicine The University of Alabama at Birmingham EDITED: 03-12-14 Learning Objectives After attending this presentation, learners will be able to: Know when to initiate therapy for acute HIV infection Define the timing of discontinuation of primary prophylaxis Describe the biology of HIV in the setting of ARV therapy Slide 3 of 50 Slide 4 of 50 Should I treat patients with acute seroconversion syndrome, and if so, when and with what ARV therapy? Page 1 of 17
Case 1 Slide 5 of 50 24 yo man presents with mononucleosis-like illness Febrile, faint rash on chest, pharyngeal edema, diffuse lymphadenopathy Combo Ab/Ag Test: HIV Ab Negative P24 Ag Positive Slide 6 of 50 At this point you would order confirmatory HIV RNA, genotypic resistance test, and: 1. Hold ARV Rx until lab tests return 2. Start ARV Rx with 2 nucs and an NNRTI 3. Start ARV Rx with 2 nucs and a boosted PI 4. Start ARV Rx with 2 nucs and an STII (integrase inhibitor) 5. Not give ARV Rx until otherwise indicated Slide 7 of 50 Natural History and Laboratory Staging of HIV Infection Eclipse Phase I II III IV V VI v RNA+ (Fiebig, AIDS 2003) Western blot +/- Western blot + (p31-) Western + (p31+) Keele et al., PNAS 2008 Page 2 of 17
CROI 2014: Acute Infection Slide 8 of 50 Sigmoid Biopsies: Significantly lower frequency of Th17 cells was observed in FIII compared to FI/ II (Median 7.1% vs. 13.2%, p=0.03) (Schuetz Abstract 77) Initiation of ART at very early stages of infection (Fiebig I) impeded seroconversion to anti-hiv antibody. Initiation of ART at Fiebig II-V delayed evolution of serological markers (Manak Abst 395) Extremely Early Initiation of ART (~Day10) HIV RNA/DNA tests have been negative, including those performed in colorectal biopsy Samples enriched for total CD4+ T cells and CD4+ T cell subsets (Tn, Tcm, Ttm, Tem) from leukapheresis were also negative for HIV RNA and DNA (Cheret Abst 398) Slide 9 of 52 50 Slide 9 of 52 Slide 10 of 52 Slide 10 of 50 Page 3 of 17
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Slide 14 of 52 50 Viral Load 10 1 10 2 10 3 10 4 10 5 10 6 T 1/2 = 1.1 days Slide 14 of 52 0 2 4 6 8 10 12 Weeks Slide 15 of 50 What do I do for patients who have virologic success but a poor CD4 count response? Case 2 Slide 16 of 50 30 yo female started on TDF / FTC / ATZ / rit 3 years ago Initial: Now: HIV RNA 78,000 c/ml CD4 count 80 cells/ul HIV RNA < 50 c/ml (persistently) CD4 167 cells/ul She is tolerating the regimen well Page 5 of 17
At this point you would: Slide 17 of 50 1. Continue her current ARV Rx 2. Change her ARV Rx to 2 nucs and an NNRTI 3. Change her ARV Rx to 2 nucs and a different boosted PI 4. Change her ARV Rx to 2 nucs and an STII (integrase inhibitor) 5. Change her ARV Rx to an STII and a different boosted PI 6. Something else 300-200 - 100-0 -1.0 - -2.0 - -3.0 - What is Immunologic Failure? 6 weeks 3 months 2 years 3 years Slide 18 of 50 Slide 19 of 50 Can I stop PCP prophylaxis in a patient with a good virologic response but immunologic failure? Page 6 of 17
Case 3 Slide 20 of 50 30 yo female started on TDF / FTC /ATZ / rit 3 years ago Initial: Now: HIV RNA 78,000 c/ml CD4 count 80 cells/ul HIV RNA < 50 c/ml (persistently) CD4 167 cells/ul (CD4 % = 12%) She remains on TMP/ SMX primary prophylaxis, one DS tablet daily and tolerating it well At this point you would: Slide 21 of 50 1. Continue her current TMP/SMX Rx 2. Change her Rx to 1 DS tablet every other day 3. Stop all PCP prophylaxis 4. Call Dr. Friedland Slide 22 of 50 Page 7 of 17
Conclusions: The virus is Evil: Replication: Bad Suppression: Good CD4 count cutoffs for PCP prophylaxis established prior to effective ARV Rx Slide 23 of 50 In setting where VL < 50, PCP prophylaxis can be safely stopped when CD4 > 100 cells Slide 24 of 50 In a patient with elevated lipids, do I change the antiretroviral therapy or add lipid therapy? Case 4 56 yo male started on ARV Rx many years ago (unknown resistance history) Has been through multiple regimens; now on TDF / FTC / Lop / rit Non-Smoker / Neg PMH / Neg Fam Hx for CAD Now: Slide 25 of 50 HIV RNA < 50 c/ml (persistently) CD4 560 cells/ul Cholesterol 220 mg/dl (HDL 38 / LDL 122) Triglycerides 540 mg/dl Page 8 of 17
At this point you would: 1. Continue her current ARV Rx 2. Change her Lop/Rit to DRV/Rit 3. Change her Lop/Rit to an SSTI 4. Start a statin 5. 1 and 4 6. 2 and 4 7. 3 and 4 8. None of the above Slide 26 of 50 Case 5 56 yo male started on ARV Rx many years ago (unknown resistance history) Has been through multiple regimens; now on TDF / FTC / DRV / rit Non-Smoker / H/o DM / Neg Fam Hx for CAD Now: Slide 27 of 50 HIV RNA < 50 c/ml (persistently) CD4 560 cells/ul Cholesterol 220 mg/dl (HDL 38 / LDL 122) Slide 28 of 50 In addition to starting a statin, you would: 1. Continue her current ARV Rx 2. Change her DRV/Rit to NNRTI 3. Change her DRV/Rit to an SSTI 4. Some other option Page 9 of 17
Slide 29 of 50 What is the current status of use of abacavir in a patient with CV risk factors? Case 6 56 yo male started on ARV Rx many years ago (resistance history no known PI mutations) Has been through several regimens; now on ABC / 3TC / Dolutegravir Smoker / Diabetic / + Fam Hx for CAD Now: Slide 30 of 50 HIV RNA < 50 c/ml (persistently) CD4 560 cells/ul Cholesterol 220 mg/dl (HDL 38 / LDL 122) Slide 31 of 50 In addition to starting a statin, you would: 1. Continue her current ARV Rx 2. Change her ABC/3TC to TDF/FTC 3. Change her ABC/3TC to DRV/rit 4. Some other option Page 10 of 17
Clinical experience with DRV/r + DTG Slide 32 of 50 There is no effect of DTG on DRV/r PK DRV/r 600/100 BID lowers DTG Cmin by 38%. This is not considered clinically significant, given the 50mg OD dose of DTG used DRV/r + integrase proof of principle: NEAT (DRV/r + RAL vs DRV/r + TDF/FTC) (CROI 2014) DRV/r + DTG + 2 Nucs was the most common combination used in the SAILING Trial (Lancet 2013, 382, 700-708) Slide 33 of 50 What is the best initial ARV therapy for a patient with baseline CKD? Case 7 Slide 34 of 50 46 yo male newly diagnosed HIV resistance assay reveals wild type virus Smoker / H/o DM / Neg Fam Hx for CAD HIV RNA 128,000 c/ml CD4 count 280 cells/ul S-creatinine 2.1 mg/dl (ecrcl = 48 cc/min) Page 11 of 17
What ARV regimen would you start? 1. TDF every other day, FTC, EFV 2. TDF every other day, FTC, DRV/rit 3. ABC / 3TC / EFV 4. ABC / 3TC / DRV/rit 5. ABC / 3TC / DTG 6. TDF / FTC / ELV / cobi 7. ABC / FTC / DRV/rit 8. DRV/rit / RAL 9. DRV/rit / DTG 10. Some other option Slide 35 of 50 Slide 36 of 50 What is the best way to manage chronic HBV infection in a patient with CKD? Case 8 Slide 37 of 50 46 yo male newly diagnosed HIV resistance assay reveals wild type virus Smoker / H/o DM / Neg Fam Hx for CAD HIV RNA 128,000 c/ml CD4 count 280 cells/ul S-creatinine 2.1 mg/dl (ecrcl = 48 cc/min) HBsAb+ / HBsAg+ / HBeAg- Page 12 of 17
Slide 38 of 50 With regard to treating the HBV, what is the best approach? 1. TDF every other day in the regimen 2. FTC in the regimen (no other nuc) 3. 3TC in the regimen (no other nuc) 4. Entecavir in addition to the ARV Rx 5. Adefovir in addition to the ARV Rx 6. PEG-IFN weekly in addition to the ARV Rx for 48 weeks 7. No need to Rx for HBV in this setting 8. Some other option Slide 39 of 50 How do I best use resistance test results, especially in a patient with a baseline K65R? Case 9 56 yo male started on ARV Rx many years ago (resistance history no known PI mutations) Has been through several regimens; now on TDF / FTV / ETV Smoker / Diabetic / + Fam Hx for CAD VL Max: 240,000 c/ml / CD4 nadir 5 cells/ul Slide 40 of 50 Now: HIV RNA 1200 c/ml (confirmed) CD4 160 cells/ul Page 13 of 17
Slide 41 of 50 Which ARV regimen would you choose: 1. ABC / 3TC / EFV 2. ABC / 3TC / DTG 3. ABC / 3TC / DRV/ rit 4. TDF / FTC / ELV / cobi 5. TDF / FTC / EFV 6. TDF / FTC / DRV / rit 7. RAL / DRV/ rit +/- FTC 8. DTG / DRV/ rit +/- FTC 9. Another choice What ARV regimen would you use now? 1. TDF, FTC, ATZ/rit 2. TDF, FTC, DRV/rit 3. ABC / 3TC / DRV/rit 4. ABC / 3TC / DTG 5. TDF / FTC / ELV / cobi 6. TDF / ZDV / DRV/rit 7. ZDV / DRV/rit / DTG 8. DRV/rit / DTG / FTC 9. Some other option Slide 42 of 50 Slide 43 of 50 Can I simplify the ARV regimen of an ARV experienced patient who is now under virologic control? Page 14 of 17
Case 10 56 yo male started on ARV Rx many years ago (3 class resistance by history; 184V, K103N, Y181C, D30N) Slide 44 of 50 Has been through several regimens; has been on ZDV / TDF / FTC / DRV/rit / RTG VL Max: 240,000 c/ml / CD4 nadir 5 cells/ul Now: HIV RNA <50 c/ml (for 3 years) CD4 360 cells/ul Slide 45 of 50 With regard to simplifying the regimen, you would: 1. Continue her current ARV Rx (GHWB) 2. Stop the ZDV and cont TDF/ FTC / DRV/rit / RTG 3. Stop the ZDV and cont TDF/ FTC / DRV/rit 4. Stop the ZDV and cont TDF/ FTC / RTG 5. Stop the TDF and cont ZDV/ FTC / DRV/rit / RTG 6. Some other option Slide 46 of 50 What will be the right approach for selection of initial ARV Rx when more drugs become generic? Page 15 of 17
Case 11 Slide 47 of 50 46 yo male newly diagnosed HIV resistance assay reveals wild type virus Non-Smoker / Neg PMH/ Neg Fam Hx for CAD HIV RNA 128,000 c/ml CD4 count 280 cells/ul S-creatinine 0.9 mg/dl HBsAb+ / HBcAb- / HBsAg- What ARV regimen would you start? Slide 48 of 50 1. Generic ZDV, 3TC, EFV 2. Brand TDF + Generic 3TC, EFV 3. Generic ABC + 3TC + EFV 4. Brand TDF / FTC / EFV (FDC) 5. Brand TDF / FTC / ELV / cobi (FDC) 6. Brand ABC / 3TC / DTG (FDC) 7. Some other option Patent expiration dates for HIV drugs Slide 49 of 50 The original 20 year patents for most key antiretrovirals have already expired, or will expire in the next 3-4 years. Walensky, 49 et al, Ann Int Med 158, 2013 Page 16 of 17
Slide 50 of 50 Patent expiration dates for HIV drugs 2012: ZDV, 3TC, d4t, ddi, SQV, NVP generic 2013: ritonavir, efavirenz, ZDV/3TC generic 2016: abacavir, LPV/r (soft-gel) 2017: atazanavir, tenofovir, darunavir 2019: etravirine, ABC/3TC 2024: TDF/FTC 2025: raltegravir 2026: TDF/FTC/EFV, TDF/FTC/RPV, dolutegravir Ref: Medecins Sans Frontieres 2013: Untangling the web of ARV price reductions Page 17 of 17