Optimization of Antiretroviral Therapy - PowerPoint Presentation

1. Optimization of Antiretroviral TherapyWith Emergence of ComorbiditiesRoger J. Bedimo, MDProfessor of MedicineUniversity of Texas Southwestern Medical CenterDallas, TX

2. Learning ObjectivesOn completion of this presentation, learners will be able to:Describe general principles for antiretroviral optimization in the setting of virologic suppressionIdentify comorbid conditions that can impact the survival of people with HIV (PWH)Select antiretroviral regimens in PWH with increased cardiometabolic risk and renal dysfunction

3. Decreased Life Expectancy in Older Adults with HIV in Modern ART EraPopulation-based cohort study of survival in HIV-infected pts (n = 2440) and uninfected controls matched by age and sex (n = 14,588) in DenmarkHIV-Negative Controls1996-20142006-20142000-20051996-1999 PLWH1.000.750.500.250Probability of Survival50607080Age (Yrs)Legarth RA, et al. J Acquir Immune Defic Syndr. 2016;71:213-218.

4. Reasons for Regimen Optimization During Virologic Suppression: “STIFF Cost”Simplification: To reduce pill burden and/or dosing frequencyTo switch to long-acting injectable ARV drugsTolerability: To enhance tolerability and/or decrease toxicityCardiovascular, Bone, Renal, Weight GainInteractions: To prevent or mitigate drug-drug interactionsFood/Fluids: To eliminate food or fluid requirementsFertility: To allow for optimal use of ART during pregnancy or where pregnancy may occur Cost: To reduce costs

5. Improving Survival in PWH on ART  Increasing Burden of NCDsPredicted burden of non-communicable diseases (NCDs) in HIV patients modeled for 2010-2030Increasing proportion with more NCDs over timeNCDs includeCardiovascular disease (hypertension, hypercholesterolemia, myocardial infarction, stroke)DiabetesChronic kidney diseaseOsteoporosisNon-AIDS malignanciesSmit Lancet ID 2015.

6. General Principles for Optimizing ART in the Setting of Viral SuppressionFirst Goal is to Maintain Viral Suppression: First do no harm…Review the ARV History: Failures? Toxicities? Interactions?Assume resist. to EFV, 3TC/FTC, RAL, EVG if previous failure on themAssess Prior Resistance Before Switch: Once selected, resistance mutations are “archived”; With history of multiple failures or prior regimens, consider proviral DNA genotyping.Consider HBV co-Infection and other Co-morbidities:Maintain 2 HBV-active drugs in new regimen. 3TC or FTC as sole HBV-active drug NOT recommended. Important: HBV flares…Consider Other Comorbidities, DDIs and Potential for PregnancyCVD risk +++, CKD, weight gain risk

7. Chronic Complications of HIV Infection: Treatment is Just One of Three Groups of FactorsMetabolic Complications:Cardiovascular DiseaseRenal DiseaseOsteoporosisNon-AIDS Cancers#3: THE TREATMENTART and toxicity#1: THE PATIENTIndividual and social factorsHigher rate of traditional risk factors: smoking, dyslipidemia, HTN, diabetes, obesity#2: THE VIRUS(ES)HIV infection itselfInflammation and immune activationCoinfections: HCV

8. Simplification: Switching From Suppressive ART to an STR: Noninferior Efficacy Across Phase III Studies1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Sax. IAS 2019. Abstr MOAB0105. 4. Kityo. CROI 2018. Abstr 500. 5. Johnson. JAIDS. 2019;81:463. 6. Orkin. Lancet HIV. 2017;4:e195. 7. DeJesus. Lancet HIV. 2017;4:e205. 8. Trottier. Antivir Ther. 2017;22:295. 9. Mills. Lancet Infect Dis. 2016;16:43. 10. Orkin. Lancet HIV. 2018;5:e23 11. van Wyk. Clin Infect Dis. 2020;[Epub]. 12. Llibre. Lancet. 2018;391:839. Slide credit: clinicaloptions.comKey Studies*Switch to†Switch From380-1878,[1] 380-1844,[2] 380-4030,[3] and 380-1961‡[4]BIC/FTC/TAF Boosted PI + 2 NRTIs, DTG/ABC/3TC, DTG + FTC/(TAF or TDF), or EVG/COBI/FTC/(TAF or TDF)DRIVE-SHIFT[5]DOR/3TC/TDFBoosted PI, EVG/COBI, or NNRTI + 2 NRTIsGS-1216[6] and GS-1160[7]RPV/FTC/TAFRPV/FTC/TDF or EFV/FTC/TDFSTRIIVING[8]DTG/ABC/3TCThird agent + 2 NRTIsGS-109[9]EVG/COBI/FTC/TAFTDF-based regimenEMERALD‡[10]DRV/COBI/FTC/TAFBoosted PI + FTC/TDFTANGO[11]DTG/3TC3-drug or 4-drug TAF-based ARTSWORD-1/2[12]DTG + RPVThird agent + 2 NRTIs*Listed studies not head to head. †Most recent FDA approvals: for BIC/FTC/TAF, DTG/RPV, DOR/3TC/TDF, and DTG/3TC must have no history of treatment failure and no resistance to regimen components; for DRV/COBI/FTC/TAF, must have no resistance to DRV, TFV ‡Patients with resistance permitted.

9. Simplification: What are the Options for 2-drug therapy in PWH Who are Already Virologically Suppressed?TreatmentStudies Boosted PI + 3TCMultiple studies1-3Dolutegravir/rilpivirineSWORD trials4Dolutegravir + darunavir/rDUALIS5DTG/3TCTANGO6; SALSA7DTG + FTCSIMPL’HIV8Cabotegravir/rilpivirine LA injectionATLAS9; FLAIR10; ATLAS-2M11Remember not to use these two drug regimens in people with HIV/HBV; need to continue tenofovir

10. Tolerability: Increased Fracture Risk in PWHMeta-analysis: HIV-positive patients had 6.4-fold increased risk of low BMD and 3.7-fold increased risk of osteoporosis[1]8525 HIV-infected patients compared with 2,208,792 uninfected patients in Partners HealthCare System, 1996-2008[2]Slide 10 of 721. Brown TT, et al. AIDS. 2006;20:2165-2174. 2. Triant V,A et al. J Clin Endocrinol Metab. 2008;93:3499-3504.WomenMenAge (Yrs)7.06.05.04.03.02.01.00Fracture Prevalence/ 100 Persons30-3940-4950-5960-6970-79P = .002(overall comparison)Age (Yrs)7.06.05.04.03.02.01.00Fracture Prevalence/100 Persons20-2930-3940-4950-5960-69P < .0001(overall comparison)HIVNon-HIV

11. Tolerability: Look for Ways to Enhance Tolerability and Limit ToxicityDTG + 2 NRTIsPI/RTV + 2 NRTIs0.7-8.7-11.30.54.22.01.12.50.4-18.4-7.7-7.0TCNon–HDL-CTGLDL-CHDL-CTC/HDL RatioP < .001P < .001P < .001P < .001P < .001P = .286Mean Change From BL to Wk 48 (%)5-5-15100-10-20-25Gatell JM, et al. AIDS. 2017;31:2503-2514. Additional Considerations:- inflamm markers (good) but also  adiponectin (bad)-Potential for weight gain.Martinez. Glasgow. 2018; Lake. CROI 2019Additional Considerations:- LDL; Potential for weight gain.Gomez. Infection. 2019 Feb;47(1):95-102.

12. MenWomenWeight Gain with Antiretroviral TherapyVenter WF, et al. J Int AIDS Soc. 2019;22(suppl 5):103-104. Abstract WEAB0405LB. Venter WF, et al. N Engl J Med. 2019;July 24, 2019. [Epub ahead of print]. Hill A, et al. J Int AIDS Soc. 2019;22(suppl 5):92. Abstract MOAX0102LBEstimated BMI increase @ 1 year: ≈ 1.5 in males, ≈ 2 in femalesDTG + F/TAFDTG + F/TDFEFV/F/TDF≥10% change in body weight (%) 25*†13*11Treatment-emergent obesity (BMI ≥30 kg/m2; %)19*†8*4MenWomen

13. -4-1-2-3Tolerability: DEFINE: Results of Switch to PI-Based ART Following Weight Gain on INSTI-Based ART (Surprised?)No significant difference between arms in weight change from baseline to Week 24Most participants in each arm had body weight changes of ≤3%Changes in body weight were consistent among key subgroupsBody composition by DXA remained stable for both study armsVirologic efficacy of ART maintained across both study armsPrimary Endpoint: % Change From BL in Body Weight Over Time in ITT PopulationLeast Square Means % Change From BL (95% CI)Wk 4Wk 12Wk 24P = .23940.19(-0.91 to +1.28)0.05(-1.07 to +1.17)-0.24(-1.35 to +0.87)0.63(-0.44 to +1.70)-0.12(-1.12 to +0.94)-0.17(-1.21 to +0.88)DRV/COBI/FTC/TAFINSTI + FTC/TAFShort. IAS 2023. Abstr OALBB0502.43210

14. -4-1-2-3Tolerability: Switch to PI-Based ART Did Not Reverse Weight Gain on INSTI-Based ART (Surprised?)No significant difference between arms in weight change from baseline to Week 24Most participants in each arm had body weight changes of ≤3%Changes in body weight were consistent among key subgroupsBody composition by DXA remained stable for both study armsVirologic efficacy of ART maintained across both study armsPrimary Endpoint: % Change From BL in Body Weight Over Time in ITT PopulationLeast Square Means % Change From BL (95% CI)Wk 4Wk 12Wk 24P = .23940.19(-0.91 to +1.28)0.05(-1.07 to +1.17)-0.24(-1.35 to +0.87)0.63(-0.44 to +1.70)-0.12(-1.12 to +0.94)-0.17(-1.21 to +0.88)DRV/COBI/FTC/TAFINSTI + FTC/TAFShort. IAS 2023. Abstr OALBB0502.43210

15. Tolerability: Maybe More Attention Should be Paid to PIsNA-ACCORD. Bourgi. J Int AIDS Soc. 2020 Apr;23(4):e25484. doi: 10.1002/jia2.25484. Koethe. CROI 2020; Abstract 668

16. Tolerability: Weight Change by Sex After Switch From ADVANCE Trial Regimens to DTG/3TC/TDF Bosch. CROI 2023. Abstr 167.FemaleMaleMedian Change in Weight (kg)DTG + FTC/TAF (n = 29)DTG + FTC/TDF (n = 30)EFV/FTC/TDF (n = 7)DTG/3TC/TDF-1.6 kg+2.9 kgMedian Change in Weight (kg)WkDTG + FTC/TAF (n = 41)DTG + FTC/TDF (n = 41)EFV/FTC/TDF (n = 24)DTG/3TC/TDF121086420-250100150200250ADVANCECHARACTERISEWk121086420-250100150200250ADVANCECHARACTERISEFemale patients switched from DTG + FTC/TAF to DTG/3TC/TDF lost a median of 1.6 kg

17. INSTI-based regimens associated with numerically higher changes in BP compared with other regimen typesTolerability: INSTI ART and Risk of HypertensionStudy NameSettingRegimens StudiedFindingsNAMSAL*1*HTN not routinely treated in this trial. Sub-Saharan Africa(N = 613)DTG + 3TC/TDF vs EFV/3TC/TDFMean SBP significantly greater in INSTI arm by Wk 60 Significant differences between arms in all grades of HTN at Wk 192ADVANCE†1†HTN routinely treated in this trial. Sub-Saharan Africa(N = 1053; 11% HTN at BL)DTG + FTC/TAF vsDTG + FTC/TDF vsEFV/FTC/TDFTreatment-emergent grade 1 HTN (140-159/90-99 mmHg) significantly higher for DTG + FTC/TAF vs EFV/FTC/TDF (P = .038) at Wk 192D2EFT2International (N = 621; HTN at BL excluded in primary analysis)DRV/RTV + 2 NRTIs vs DTG + DRV vs DTG + XTC/TDF as second-line ARTAt Wk 48, significantly greater mean change in SBP and DBP with DTG + DRV/RTV vs DRV/RTV + 2 NRTIs, even after adjustment for BMI change1. Venter. IAS 2023. Abstr OALBB0504. 2. Petoumenos. IAS 2023. Abstr LBPEB01

18. Tolerability: Are INSTIs Associated with Increased CVD Risk?INSTI exposure associated with a 2.5-fold greater incidence of CVD within first 6 months of exposure compared to no exposure in adjusted analysesNeesgaard et al. vCROI 2021, abstract 488; Lancet HIV 2022 Jul;9(7):e474-e485.International collaboration of 17 cohortsComposite endpoint of MI, stroke and invasive cardiovascular procedure; adjudicated eventsN=21267 (46% exposed to INSTI)517 CVD events, 4.9/1000 PYCould not specifically examine ART-naive

19. Incident CVD Rates Similar with ART Initiation with INSTIs vs. Non-INSTI.Surial et al. CROI 2023. Abstract #149Adjusted for calendar year, demographic & HIV variables, co-morbidities, use of antiplatelet and lipid-lowering drugs, current use of ABC and TAF

20. Tolerability: Look for Ways to Enhance Tolerability and Limit ToxicitySpecial attention to older patients, polypharmacy.Low BMD / History of Fractures:TDF  TAF, ABC: Increases in BMD; Clinical significance unclearHigh CVD RiskABC  TAF, TDF: High CVD risk with ABC; Impact of switch?RTV or COBI-boosted PI  INSTI: High CVD risk with DRV; Improved lipids with switch; impact on CVD risk unclear.CKD / Proximal TubulopathyTDF  TAF, ABCATV/RTV  DTG, BIC, RAL, or NNRTIWeight Gain: Unclear benefit of switchbalance with other potential benefits (virologic, lipids, CVD, renal, bone)

21. US PWH ≥ 65 yrs of age from Jan 2015 – Aug 2018 (N = 112)87% with HIV-1 RNA < 20 copies/mLPolypharmacy: ≥ 5 medications 95% considering all drugs; 84% considering only non-HIV drugsAverage number of medications: 12.3, including 9.0 non-HIV medications Inappropriate prescribing defined by 2012 Beers, 2011 STOPP, and 2011 START criteriaDDIs assessed using University of Liverpool HIV Drug Interactions databaseRisk of serious DDI correlated with polypharmacy (P < .01) and inappropriate prescribing (P < .01) Interactions: Avoid Creating Drug-Drug Interactions, Polypharmacy and Inappropriate Prescribing in Older PWHPrescribing Errors and DDIsPatients With ≥ 1 Error/DDI (%)Cabanilla. IAS 2019. Abstr WEPEB314. 020406080100Beers CriteriaSTOPP CriteriaSTART CriteriaDDIIncorrect Dose4654796321Inappropriate Prescribing

22. Interactions with Drugs and Food: Selected Concomitant Drugs to Watch for with Switching to INSTI-based RegimenPolyvalent cations (Al, Mg, Ca): ↓ INSTI exposure – space dosing; Do not co-administer Al/Mg w/ RAL:Direct-acting anticoagulants: Exposure  by EVG/c. Caution…Anti-seizure: Carbamazepine & Phenytoin ↓INSTI exposure: Can use DTG BID with CarbamazepineMetformin: Increases BIC and DTG exposure. Caution with DTG BIDRifamycins: ↓INSTI exposure. Can use Rifabutin with DTGSteroids: Exposure increased by EVG/c (Beclomethasone inh OK)PPIs: They decrease exposure to Atazanavir (ATV) and RPV. HMG CoA reductase inhibitors (statins): Their metabolism can be impaired by PIs leading to significantly increased serum levelsConsult DHHS Guidelines: https://aidsinfo.nih.gov/guidelinesLiverpool HIV Drug Interactions Website: https://www.hiv-druginteractions.org/

23. Fertility (Pregnancy): DHHS Recommendations: Initial ART During PregnancyGuideline StatusNRTIsINSTIsPIsNNRTIsPreferred3TC/ABC*FTC/TDF or 3TC + TDFFTC/TAF or 3TC + TAFDTGRAL† ATV/RTVDRV/RTV†Alternative3TC/ZDVEFV RPV (PO)‡ Insufficient data to recommendBICDORNot recommendedEVG/COBICABATV/COBIDRV/COBILPV/RTV‡ETRNVPRPV (IM)*Only if HLA-B*5701 negative. †Must be used twice daily in pregnancy. ‡ Only if pretreatment HIV-1 RNA ≤100,000 c/mL and CD4+ cell count ≥200 cells/mm3. DHHS. clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines. March 2022.Long-acting injectable (LAI) cabotegravir (CAB) with rilpivirine (RPV) has not been studied in pregnancy and currently is not recommended in individuals who are trying to conceive.

24. Fertility (Pregnancy): Safety and Efficacy of DTG vs EFV and TDF vs TAF Through 50 Wk PostpartumChinula. Lancet HIV. 2023 May 8:S2352-3018(23)00061-9DTG + FTC/TAF Vs. .vsDTG + FTC/TDFDTG + FTC/TDF Vs. vsEFV/FTC/TDFDTG + FTC/TAF Vs. vsEFV/FTC/TDF

25. Female and Fertility: Considerations for Women and PregnancyConsider DDIs with hormonal contraceptives, gender-affirming care, and pharmacokinetics in pregnancy:EFV might decrease progestin exposure:  possible risk of oral contraceptive failure; no significant impact on injectable contraceptives (depot medroxyprogesterone).Boosted PIs or EVG/Cobi ↓ estradiol exposure:  possible spottingDuring pregnancy, an additional goal of ART is to reduce the risk of HIV transmission to the fetus and newbornImPrEPT: No Interaction Between FTC/TDF and Hormone Therapy in Transgender IndividualsTsepamo: Initial concerns of NTD with DTG not confirmed in final analysisSlide 25 of 76DHHS Guidelines on Antiretroviral Therapy; Zash. AIDS 2020. Abstr OAXLB0102.

26. Cost: Less is More…Two-drug therapy:Potential savings: >$500 million in ART costs in the US over 5 y