Disclosures Research grant support from Gilead Sciences Lipids, - PDF document

Disclosures • Research grant support from Gilead Sciences Lipids, Statins and HIV: for work in East Africa related to antiretroviral delivery strategies Topics in Clinical Management • Research grant support from NIH,CDC, Medical Management of AIDS & Hepatitis PEPFAR December 8, 2018 • Work not related to this presentation Vivek Jain, M.D., M.A.S. Associate Professor of Medicine Division of HIV, Infectious Diseases & Global Medicine San Francisco General Hospital University of California, San Francisco Outline Outline • Who should be on statins? Recent guidance • Who should be on statins? Recent guidance • Practical use of statins in patients with HIV • Practical use of statins in patients with HIV – specific drug interactions with ARV’s – specific drug interactions with ARV’s • What can statins achieve? • What can statins achieve? – Lipid lowering, CV risk mitigation, malignancy reduction – Lipid lowering, CV risk mitigation, malignancy reduction • What downside risks do statins pose? • What downside risks do statins pose? – Myopathy, diabetes?, cognitive changes? – Myopathy, diabetes?, cognitive changes? • If statins don’t achieve their goals, or can’t be used, • If statins don’t achieve their goals, or can’t be used, what can ARV switching do to improve lipids? what can ARV switching do to improve lipids? • New drug class: PCSK9 inhibitors • New drug class: PCSK9 inhibitors

Older System: LDL-based goals New statin guidelines in 2013 LDL (mg/dL) Non-HDL (mg/dL) LDL to Consider • AHA/ACC guidelines Nov. 2013: Risk Category Primary target Secondary target Drug Therapy – assess risk of “hard” CV events Very High < 70 < 100 > 100 – used a new “global risk prediction score” High – recommend statins when 10-year risk is >7.5 % ³ 100 CHD or CHD Risk Equiv. < 100 < 130 (10-year risk > 20%) – consider statins when 10-year risk is 5 - 7.5% • Controversies: Moderately High ³ 130 < 130 < 160 ³ 2 Risk Factors < 100: optional < 130: optional 100–129: optional – do new guidelines mean there are many patients on (10-year risk 10-20%) statins who do not need to be? Moderate – do new guidelines mean many low risk patients not on ³ 2 Risk Factors ³ 160 < 130 < 160 statins should be initiated? (10-year risk < 10%) – Huge resource questions involving millions of patients Low ³ 190 < 160 < 190 0–1 Risk Factor 3 rd Report, National Cholesterol Education Program (NCEP), 2002 event rate Controversy over new guidelines predicted by November 2018: New Cholesterol Guidelines algorithm observed event rate Ridker & Cook (Lancet, 2013): 3 primary • Key Changes to new 2018 guidelines: • New calculator can overestimate risk …and prevention therefore recommend statins for too many people cohorts – Amplifies patient-clinician discussion on patient • No statin RCT used a ‘global risk prediction score’ specific risks, and risks/benefits of statin as an entry criterion… • Smoking and HTN are major drivers of risk… but – Emphasis on early lifestyle modifications could end up being addressed by a statin rather • Diet: high vegetable, fruit, lean protein, whole grains, limit than by habit reduction… sweets & processed fats • Can have odd individual situations where statin • Exercise: 40 minutes, vigorous, 3-4 times per week unexpectedly is or isn’t recommended… • Heavily influenced by age: 41% of men and 27% of – Understand high/moderate/low intensity statin women age 60-69 have risk>10%, and many options age>65 with no risk factors will meet risk criteria... however, no statin trials ever enrolled persons of – Use new updated risk calculator (“risk plus”) these ages with zero risk factors… • Still based on pooled population based risk equations, but • However, new risk calculator is widely now more of a “launch point” for discussion and decision recognized; use as a starting point to foster making individual discussions Grundy SM et al., 2018 JACC: 2018 AHA/ACC Guideline on the Management of Blood Cholesterol Ridker & Cook, Lancet , 2013

New Cholesterol Guidelines: Overview of New 2018 Guidelines Primary Prevention Consider many factors simultaneously • Focus on ASCVD risk, as well as certain numeric LDL targets • Differentiate who needs statin for ASCVD (secondary prevention) vs. who needs it for primary prevention • Differentiate high-intensity statin from moderate intensity statin •Screen for LDL>190 and diabetes •Calculate patient 10-year risk: is it >7.5%? •Consider several “risk enhancers” •Consider coronary artery calcium score Also include in discussion •Smoking cessation • Diet • HTN control • Exercise Grundy SM et al., 2018 JACC: 2018 AHA/ACC Grundy SM et al., 2018 JACC: 2018 AHA/ACC Guideline on the Management of Blood Cholesterol Guideline on the Management of Blood Cholesterol New Cholesterol Guidelines: Strength of Recommendations Secondary Prevention • Colors correspond to strength of recommendations Grundy SM et al., 2018 JACC: 2018 AHA/ACC Guideline on the Management of Blood Cholesterol

“Risk-Plus Calculator” November 2018: New Cholesterol Guidelines Updated Web-based Calculator http://tools.acc.org/ASCVD-Risk-Estimator-Plus Enter variables: • Initiate statin to achieve goals • Then add ezetimibe if not achieving goals • Then consider adding PCSK-9 inhibitor • Consider coronary artery calcium score in patients >40 with uncertain risk status: if ≥100 Agatson units= ASCVD risk ≥7.5% = start statin Read out 10-year and life- And how this risk can time risk: be optimized/lowered with therapies: http://tools.acc.org/ASCVD-Risk-Estimator-Plus Outline “Risk-Plus Calculator” Updated Web-based Calculator http://tools.acc.org/ASCVD-Risk-Estimator-Plus • Who should be on statins? Recent guidance Treatment Impact of therapy: Recommendations, • Practical use of statins in patients with HIV including statin: – specific drug interactions with ARV’s • What can statins achieve? – Lipid lowering, CV risk mitigation, malignancy reduction • What downside risks do statins pose? – Myopathy, diabetes?, cognitive changes? • If statins don’t achieve their goals, or can’t be used, what can ARV switching do to improve lipids? • New drug class: PCSK9 inhibitors http://tools.acc.org/ASCVD-Risk-Estimator-Plus

Statin Choices: a review Outline When using PI’s: ß PI’s NNRTI’s INSTI • Who should be on statins? Recent guidance can use, just reduce Most statins are Atorvastatin to 10-20mg metabolized by CYP3A4 system; • Practical use of statins in patients with HIV Lovastatin Pravastatin, – specific drug interactions with ARV’s pitavastatinarenot less potent • What can statins achieve? Protease inhibitors EFV: raises CYP3A4 cobicistat: Pravastatin use at lower doses inhibit/ activity reduces (use lowest dose with DRV, downregulate CYP3A4 – Lipid lowering , CV risk mitigation, malignancy reduction or just give atorvastatin) CYP3A4 to different Simvastatin degrees • What downside risks do statins pose? Ritonavir and – Myopathy, diabetes?, cognitive changes? cobicistat: most Fluvastatin PI’s à thus can EFV à can reduce statin • If statins don’t achieve their goals, or can’t be used, boost some statins levels to dangerous levels Rosuvastatin can us at 5-10mg, what can ARV switching do to improve lipids? and trigger Etravirine reduces fewer data in HIV+ rhabdomyolysis atorvastatin, • New drug class: PCSK9 inhibitors increases fluvastatin, no Pitavastatin change on pravastatin can us at 4mg dose Grundy: Update to NCEP ATPIII Guidelines Circulation, 2004 Statin potency in HIV+ patients Pitavastatin vs. Pravastatin • Retrospective study: 700 HIV+ patients, 2 large US clinics initiating statin • INTREPID Study: First double blind RCT of 2 statins in • Both atorvastatin and rosuvastatin did better than pravastatin in HIV+ population; first trial of pitavastatin reducing total cholesterol, LDL, TGs and non-HDL cholesterol • Randomized trial: 4mg daily pitavastatin vs. pravastatin 40mg daily • Less accumulated data with rosuvastatin limits its use • Inclusions: Age 18-70, on ART≥6mo., CD4>200, VL<200, • 4-week diet stabilization lead in; then advised lipid restricted diet throughout study • After this period: dyslipidemia: LDL 130-220 mg/dL and triglycerides ≤400 mg/dL • Exclusions: darunavir (due to pravastatin interaction), homozygous familial hypercholesterolemia, other secondary cause for hyperlipidemia, statin intolerance, diabetes, high fasting glucose, coronary artery disease Singh et al., Clin. Infect. Dis. , 2011