2/10/2015. Switching from old regimens. HIV treatment revision: As simple as old versus new? What is an old regimen? What is an old regimen?

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1 Switching from old regimens David Nolan Department of Immunology, Royal Perth Hospital, Western Australia Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia What is an old regimen? What is an old regimen? Switching for dosing simplification? Switching for dosing simplification? Pre-HAART era Early HAART era Late HAART era Contemporary HAART: once-daily one-pill regimens High-level, multiple-doses per day regimens AZT (987) Initially 4-hourly, day + night onwards (developed world) Twice-daily co-formulated regimens AZT + TC (997) AZT + TC + ABC (000) (developed world) Once-daily co-formulated regimens ABC + TC (004) TDF + FTC (004) TDF + FTC + EFV = Atripla (006) Baseline VL <0 5 copies/ml Any viral load Any viral load (HLA-B*57 ve) Take with food No food requirement No food requirement Drug interaction: PPIs Drug interaction: CYPA4* Drug interaction: Metformin TDF + FTC + Rilpivirine (Eviplera) TDF + FTC + Elvitegravir + Cobicistat* (Stribild) ABC + TC + Dolutegravir (Triumeq)

2 CD4+ T cell count /0/05 Switching for toxicity? David Nolan Department of Immunology, Royal Perth Hospital, Western Australia Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia 8 No one, however smart, however well educated, however experienced, is the suppository of all wisdom. What do you do when you re asked to do nothing? I don t want to change my therapy What do you do when you re asked to do nothing? I don t want to change my therapy Pre-HAART era Early HAART era Late HAART era AZT (989-9) Pneumocystis Pneumonia AZT + ddi (99-96) CD4 + d4t + TC ( ) TDF + FTC ( ) IDV(996-98) HIV RNA <00 copies/ml EFV (998-00) HIV RNA (K0N) CMV retinitis ABC + TC (000) r/lpv (000-0) r/atz (00-07) HIV RNA <50 copies/ml NRTIs PIs Pre-HAART era Early HAART era Late HAART era AZT (989-9) Myopathy Mild anemia AZT + ddi (99-96) Neuropathy Weight loss d4t + TC ( ) Weight gain IDV(996-98) Renal calculi Dry skin, lips Fat loss (face + limbs) Metabolic syndrome Diabetes Sleep disturbance EFV (998-00) NNRTIs Vivid dreams Compliance ~90% ABC + TC (000) r/lpv (000-0) Diarrhea Hypersensitivity reaction day 9 TDF + FTC ( ) r/atz (00-07) Bilirubin (no jaundice)

3 . What do we know that we know? Plasma viral load <40 copies/ml on ART regimen X CD4 T cell count 50 cells/ L (from nadir <00 cells/ L. What do we know that we know? Plasma viral load <40 copies/ml on ART regimen X CD4 T cell count 50 cells/ L (from nadir <00 cells/ L TOXICITY? Cardiovascular risk calculation: % 5-yr risk (6 yrs old) Renal function and protein/creatinine ratio: egfr >90, urine PCR 6 mg/mmol FRAX score and BMD (+/- metabolic bone study): osteopenia Cardiovascular risk calculation: % 5-yr risk (6 yrs old) Renal function and protein/creatinine ratio: egfr >90, urine PCR 6 mg/mmol FRAX score and BMD (+/- metabolic bone study): osteopenia. What do we know that we do not know? Plasma VL below 40 copies/ml, CSF or seminal fluid VL Immune activation markers, esp innate (eg monocyte) markers Cognitive function and risk of cognitive decline in future Cancer risk? Transmissibility risk?. What do we know that we do not know? Plasma VL below 40 copies/ml, CSF or seminal fluid VL Immune activation markers, esp innate (eg monocyte) markers Cognitive function and risk of cognitive decline in future Cancer risk? Transmissibility risk?. What don t we know that we do not know? Do new drugs achieve better outcomes due to things that we can t measure? Do they penetrate different sites?... Brain (CPE), Monocytes (MES), genital tract?. What don t we know that we do not know? Does it matter that there are things we know we don t know? Do they do things beyond reduce viral load?... Reduce innate immune activation? Do they have additional benefits?... Reduce malignancy risk, or frailty ( inflammaging )

4 Treatment intensification, residual viremia and the latent reservoir a long tale. What do we know that we do not know? Plasma VL below 40 copies/ml, CSF or seminal fluid VL Immune activation markers, esp innate (eg monocyte) markers Cognitive function and risk of cognitive decline in future Cancer risk? Transmissibility risk? Genital tract ART penetration Genital tract ART penetration BUT... Study of TDF/FTC + Raltegravir (n=4) or Atazanavir (n=9) in HIV+ women ATZ Else LJ, et al. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antiviral Therapy 0; 6:49-67 Raltegravir CVL level 59% higher than Atazanavir (p<0.00) Genital tract VL <40 copies/ml in 90% of subjects, no difference by group No changes in cervical CD4+ or CD8+ cell activation markers by group Meditz A, et al. Relationship between Genital Drug Concentrations and Cervical Cellular Immune Activation and Reconstitution in HIV- Infected Women on a Raltegravir versus a Boosted Atazanavir Regimen. AIDS Res Hum Retroviruses. 05 May Central nervous system penetration scores 008 TDF/FTC/EFV = TDF/FTC/r-ATZ = ABC/TC/r-LPV=.5 ABC/TC/NVP =.5 00 TDF/FTC/EFV = 7 TDF/FTC/r-ATZ = 6 ABC/TC/r-LPV= 8 ABC/TC/NVP = 9 4

5 Immune activation and integrase inhibitors CPE score (00) 4 00 Stribild Vs 00 Atripla 4 Cancer risk and ART Lipids and integrase inhibitors vs EFV vs DRV n=,000 DTG pts over 4 studies HDL LDL TG Total cholesterol * Also noted in D:A:D study: J Acquir Immune Defic Syndr. 05;68: No one, however smart, however well educated, however experienced, is the suppository of all wisdom. No one, however smart, however well educated, however experienced, is the suppository of all wisdom.... But for the moment, knowing what you know is most likely enough 5

6 HIV treatment revision: Into the future? I would not say that the future is less predictable than the past. I think the past was not predictable when it started 6