Antiretroviral therapy and Primary Care Chris Boyle, MD 9/8/2011

Case 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. Do you a) Refer him to a HIV specialist b) Take care of him yourself.

Katz, MH. Human Immunodeficiency Virus Is (Once Again) a Primary Care Disease. Arch Intern Med. 2011;171(8):

HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care (2011) “Increased use of strategies such as task shifting, comanagement, and care coordination can help to maximize the ability of the current health care workforce to accommodate an increased number of HIV-positive individuals. In addition, these strategies may result in improved patient care and increased provider satisfaction, which, in turn, may increase the retention of HIV/AIDS care providers in the field.” “...the emergence of HIV as a chronic medical condition...infectious disease specialists and primary care providers who are HIV experts due to substantial patient care experiences, formal training, or both, are generally better-prepared to manage HIV disease than are primary care generalists....However, most HIV-positive patients can benefit greatly from the broader skills of primary care providers in addressing their other health care needs.” Committee on HIV Screening and Access to Care; Institute of Medicine. “HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care.” The National Academies Press, 2011.

Case 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You keep him!

Case 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You check HIV intake labs, including a CD4, viral load and resistance panel. Labs are significant for a CD4=496 and VL=6500, with wild type virus.

When to Start 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You check HIV intake labs, including a CD4, viral load and resistance panel. Labs are significant for a CD4=496 and VL=6500, with wild type virus. a) Initiate ARVs - everyone should be on treatment b) Initiate ARVs - His CD4 count is <500 c) Do not initiate ARVs until his CD4 is <350 d) Do not initiate ARVs until his CD4 count is <200 e) Do not initiate ARVs until he has an opportunistic infection

When to Start There are two major organizations that periodically make updates regarding when and what to start. The Department of Health and Human Services (DHHS) - last updated in 01/2011 and The International Antiviral Society - USA (IAS-USA) - last updated in 07/2010

When to Start Historical Perspective treat for a CD4<500, consider treatment in all Mantra “Hit Early, Hit Hard ”(N Engl J Med. 1995;333(7):450.) however drugs had multiple side effects, difficult to adhere to regimens, which led to treat for a CD4<200 and consider treatment if however regimens became better tolerated, easier to administer and there was increasing evidence that treating earlier improved mortality, which led to treat for a CD4<350, several caveats of when to treat earlier treat for a CD4<500, consider treatment in all.

When to Start Cohort study from using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients at Brigham and Women’s Hospital (BWH) or Massachusetts General Hospital (MGH) The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria J Clin Endocrinol Metab Jul;92(7):

When to Start J Clin Endocrinol Metab Jul;92(7): A, Myocardial infarction rates and corresponding adjusted RR. HIV Non-HIV

When to Start Patel P, et al. Incidence of Types of Cancer among HIV Infected Persons Compared with the General Population in the United States, 1992–2003. Ann Intern Med. 2008;148:

When to Start Randomized controlled study evaluating continuous use of antiretroviral therapy vs scheduled drug interruptions in management of HIV 5472 participants with 2720 assigned to drug conservation (scheduled interruptions) and 2752 to viral suppression arms (continuous therapy) Medial CD4 count at entry was 597. The primary end point was the development of an opportunistic disease or death from any cause. The secondary end point was major cardiovascular, renal, or hepatic disease. SMART El-Sadr WM, et al. CD4+ Count–Guided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:

Whn to Start El-Sadr WM, et al. CD4+ Count–Guided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:

When to Start N Engl J Med Apr 30;360(18): Lancet Apr 18;373(9672): Ann Intern Med Apr 19;154(8): The HIV-CAUSAL Collaboration NA-ACCORD Art-CC

When to Start Observational study of 17,517 asymptomatic HIV infected patients in the United States and Canada from1996 through All patients were ARV naive and were stratified according to the CD4, either >500 or at initiation or ARVs. Primary endpoint was relative risk of death for patients who initiated treatment with those that deferred. NA-ACCORD N Engl J Med Apr 30;360(18):

When to Start N Engl J Med 2009;360:

When to Start N Engl J Med Apr 30;360(18):

When to Start N Engl J Med Apr 30;360(18):

When to Start Multi-national randomized controlled trial which enrolled 1763 ART naïve HIV positive patients with CD4 counts of who were in sero-discordant couples. The primary end point was linked HIV transmission in HIV negative partners. Study halted early, and data analyzed found that early initiation of ART had a 96% relative reduction in linked HIV transmissions HPTN N Engl J Med 2011; 365:

DHHS guidelines ss Department of Health and Human Services, 2011

What to Start 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You check HIV intake labs, including a CD4, viral load and resistance panel. Labs are significant for a CD4=496 and VL=6500, with wild type virus. You review his HIV genotype and he has wild type virus. What do you want to start? a) Tenofovir + Emtricitabine (Truvada) + Lopinavir/Ritonavir (Kaletra) b) Abacavir + Lamivudine (Epzicom) + Atazanavir/Ritonavir c) Combination Tenofovir + Emtricitabine + Efavirenz (Atripla) d) Combination abacavir, zidovudine, lamivudine (Trizivir)

What to Start

+ Rilpivirine

What to Start Combination NRTIs NNRTIs Integrase Inhibitors Protease Inhibitors

What to Start Concepts in antiretroviral treatment Always have three active drugs Whenever possible those should include a “preferred” or “alternative” regimen which includes 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) AND 1 active protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor NOTE: Protease inhibitors should almost always be co- administered with ritonavir

What to Start DHHS graphic of the Preferred and alternative regimens Department of Health and Human Services, 2011

Thompson, M.A. et al. JAMA 2010;304:

with + or = HAART df

What to Start Choosing a regimen 1) Based on resistance profile 2) Prior ARV exposure 3) side effects 4) pill burden 5) potential drug-drug interactions 6) patient co-morbidities

What to Start 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You check HIV intake labs, including a CD4, viral load and resistance panel. Labs are significant for a CD4=496 and VL=6500, with wild type virus....you discuss his options as TDF/FTC/EFV (Atripla), TDF/FTC (Truvada) + Atazanavir/ritonavir, TDF/FTC (Truvada) + Darunavir/ritonavir, and TDF/FTC (Truvada) + Raltegravir. He prefers a once-a-day regimen, but doesn’t otherwise care if he has to take multiple pills. He is worried about that pill that makes you “go crazy”.

What to Start...you probe his PMH a bit more and find out that his GERD quite severe and is taking daily Omeprazole and he is on Simvastatin 40mg PO daily for an LDL of 160 with multiple CAD risk factors. What do you choose? a) Tenofovir + Emtricitabine (Truvada) + Atazanavir/Ritonavir b) Tenofovir + Emtricitabine (Truvada) + Darunavir/Ritonavir c) Combination Tenofovir + Emtricitabine + Efavirenz (Atripla) d) Tenofovir + Emtricitabine (Truvada) + Raltegravir

Side effects 58 yo woman with pancreatitis, neuropathy, lipodystrophy and lactic acidosis. What ARV is she on? Stavudine or didanosine (no longer used in the US, or most of the world)

Side effects 30 yo man on ARVs with an elevated creatinine seen on routine labs. What ARV is he on? Tenofovir renal insufficiency (0.5% of patients) fanconi syndrome

Side effects 23 yo woman who started ARVs two weeks ago and now feels “flu-ish”, along with diarrhea, nausea, vomiting and new dyspnea on exertion for the past week. Also for the past 2 days she has noticed a new rash. On exam she has a fever to 39.5 celsius and blood pressure of 95/50 (baseline is 120/75). What ARV is she on? Abacavir Abacavir hypersensitivity (3-5% of patients) screen with HLA-B*5701 testing prior to initiation also caution in patients with CAD or CAD risk factors

Side effects NRTIs lactic acidosis (very very very rare with current NRTIs …mostly from stavudine, didanosine and AZT) nausea/vomiting HBV flare if discontinued Abacavir Abacavir hypersensitivity (3-5% of patients) screen with HLA-B*5701 testing also caution in patients with CAD or CAD risk factors Tenofovir fanconi syndrome renal insufficiency (0.5% of patients) Stavudine and didanosine (no longer used in the US, or most of the world) pancreatitis lactic acidosis lipodystrophy neuropathy

Side effects 28 yo man whose skin looks like this. What ARV is he on? Atazanavir commonly causes an indirect hyperbilirubinemia rarely causes jaundice entirely harmless and goes away with discontinuation

Side effects 34 yo man started on ARVs 2 weeks ago who has been hanging out with this guy for the past 10 days.

Side effects What class of ARVs is he on?

Side effects PIs (all cause nausea, vomiting and diarrhea and dyslipidemia) Atazanavir jaundice (elevated indirect bilirubinemia) excellent lipid profile Darunavir caution in sulfa allergic patients excellent lipid profile Ritonavir reputation for bad nausea, vomiting, diarrhea

Side effects 56 yo man started on ARVs 6 months ago. Since starting ARVs he has had nightly vivid nightmares. Additionally he now feels kind of depressed. What ARV is he on? Efavirenz

Side effects NNRTIs Efavirenz headaches, nightmares, depression/mood disorders, feeling "hung over" or "disassociated" (23% will have some CNS effects; generally goes away with time) rash (up to 25%, usually goes away) dyslipidemia hepatotoxicity teratogenic (neural tube disorders), don’t use in the first trimester Nevirapine hepatic necrosis (idiosyncratic, and increased risk at higher CD4 counts)

Side effects 45 year old man recently started on ARVs and is experiencing no side effects, but is realizing that twice daily meds is harder than expected Raltegravir very well tolerated occasional nausea, vomiting, headache, diarrhea, but usually no side effects. BID dosing

Drug-Drug Interactions 1) Acid suppressants 2) Anticonvulsants 3) Statins 4) TB medications 5) Methadone 6) Antidepressants 7) Oral Contraceptives

Drug-Drug Interactions 1) Acid suppressants atazanavir requires a acidic environment and should not be coadministered with a PPI and should be separated from a H2 blocker by 12 hours

Drug-Drug Interactions Antidepressants – Interact with protease inhibitors, and NNRTIs and generally DECREASE antidepressant levels. Bupropion + Efavirenz (decreases bupropion) Sertraline + Efavirenz (decreases sertraline) Paroxetine + Darunavir/r (decreases paroxetine) Sertraline + Darunavir/r (decreases sertraline) Trazadone + all ritonavir boosted PIs (increases trazadone) TCAs + all ritonavir boosted PIs (increases TCA)

Drug-Drug Interactions Anticonvulsants Phenytoin - DO NOT use with PIs or NNRTIs (decreases ARV serum levels) Carbamezapine - DO NOT use with Pis (decreases ARV serum levels) Lamotrigine - Avoid with PIs (decreases lamotrigine drug levels)

Drug-Drug Interactions Statins NNRTIs (namely Efavirenz) will decrease the serum concentration of nearly all statins, adjust statin to meet LDL goal PIs Simvastatin CONTRAINDICATED with all PIs as it can increase serum concentrations up to 3000% Atorvastatin and Rosuvastatin, increased statin concentrations, but OK to use Pravastatin - very little interaction with most PIs

Drug-Drug Interactions TB medications Rifampin is CONTRAINDICATED with all PIs as it will decrease PI serum concentrations. Efavirenz should be dose adjusted.

Drug-Drug Interactions Methadone PIs and NNRTIs may decrease methadone serum concentrations

Drug-Drug Interactions interactionchecker

Case 56 yo man tests positive for HIV after you initiate routine HIV testing during your first clinic visit. He feels well. He has a PMH of hyperlipidemia, GERD and seasonal allergies. He is highly motivated to initiate ARVs. You check HIV intake labs, including a CD4, viral load and resistance panel. Labs are significant for a CD4=496 and VL=6500, with wild type virus. You discuss his options and he prefers a once-a-day regimen, but doesn’t otherwise care if he has to take multiple pills. He is worried about that pill that makes you “go crazy”. He is taking daily Omeprazole and Simvastatin 40mg PO daily for an LDL of 160 with multiple CAD risk factors. What do you choose? Darunavir/ritonavir + Tenofovir/Emtricitabine!!...and change his statin to Atorvastatin or Rosuvastatin.

Exciting New Directions New (possibly 1st line) ARVs Dolutegravir (next generation highly potent, mutation resistant, integrase inhibitor) Elvitegravir (once-a-day integrase inhibitor which is just around the corner) Will be coformulated with TDF/FTC and new boosting agent cobisistat into a once-a-day “quad pill” Rilpivirene (new FDA approved once-a-day NNRTI without the bad CNS side effects) Also, rilpivirene coformulated with Truvada (B- tripla!)...it’s actually called Complera Randomized trial of when to start Strategic Timing of Antiretroviral Treatment (START) trial…however becoming a moot point as we move towards treatment for all. Pre-exposure prophylaxis Not clear what role this will have, but likely more of an argument for earlier treatment

Summary 1) Why primary care doctors should care about HIV care 2) The important societies making the rules for ARV management 3) Historical context to “when to start” 4) Reviewed the studies which are pushing the field towards earlier treatment 5) Important drugs to know 6) Important concepts on “what to start” 6) major ARV side effects 7) major drug-drug interactions, and where to quickly trouble-shoot ARV interaction questions 8) Future directions

Thank you!