Antiretroviral therapy and Primary CareChris Boyle, MD 9/8/2011

Case56 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 youa) Refer him to a HIV specialistb) Take care of him yourself.

Katz, MH. Human Immunodeficiency Virus Is (Once Again) a Primary Care Disease. Arch Intern Med.2011;171(8):719-720.

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.

Case56 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!

Case56 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

When to StartThere 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 StartHistorical Perspective1996 - treat for a CD4

When to Start - 2011Cohort study from 1996-2004 using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients at Brigham and Womens Hospital (BWH) or Massachusetts General Hospital (MGH)The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteriaJ Clin Endocrinol Metab. 2007 Jul;92(7):2506-12

When to Start - 2011J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12

A, Myocardial infarction rates and corresponding adjusted RR.

HIV Non-HIV

When to Start - 2011Patel P, et al. Incidence of Types of Cancer among HIV Infected Persons Compared with the General Population in the United States, 19922003. Ann Intern Med. 2008;148:728-736.

When to Start - 2011Randomized controlled study evaluating continuous use of antiretroviral therapy vs scheduled drug interruptions in management of HIV5472 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. SMARTEl-Sadr WM, et al. CD4+ CountGuided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-96.

El-Sadr WM, et al. CD4+ CountGuided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-96.

Whn to Start - 2011El-Sadr WM, et al. CD4+ CountGuided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-96.

When to Start - 2011N Engl J Med. 2009 Apr 30;360(18):1815-26Lancet. 2009 Apr 18;373(9672):1352-63.Ann Intern Med. 2011 Apr 19;154(8):509-15.The HIV-CAUSAL CollaborationNA-ACCORDArt-CC

When to Start - 2011Observational study of 17,517 asymptomatic HIV infected patients in the United States and Canada from1996 through 2005. All patients were ARV naive and were stratified according to the CD4, either >500 or 351-499 at initiation or ARVs.Primary endpoint was relative risk of death for patients who initiated treatment with those that deferred.NA-ACCORDN Engl J Med. 2009 Apr 30;360(18):1815-26

When to Start - 2011N Engl J Med 2009;360:1815-26

When to Start - 2011N Engl J Med. 2009 Apr 30;360(18):1815-26

When to Start - 2011N Engl J Med. 2009 Apr 30;360(18):1815-26

When to Start - 2011Multi-national randomized controlled trial which enrolled 1763 ART nave HIV positive patients with CD4 counts of 350-500 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 transmissionsHPTN - 052N Engl J Med 2011; 365:493-505

DHHS guidelinesssDepartment of Health and Human Services, 2011

What to Start

What to Starthttp://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf

http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf

+ Rilpivirinehttp://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf

What to StartCombination NRTIsNNRTIsIntegrase InhibitorsProtease Inhibitorshttp://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf

What to StartConcepts in antiretroviral treatmentAlways have three active drugsWhenever possible those should include a preferred or alternative regimen which includes2 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 StartDHHS graphic of the Preferred and alternative regimensDepartment of Health and Human Services, 2011

Thompson, M.A. et al. JAMA 2010;304:321-333

with+oror=HAARThttp://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf

What to StartChoosing a regimen1) Based on resistance profile2) Prior ARV exposure3) side effects4) pill burden5) potential drug-drug interactions 6) patient co-morbidities

What to Start56 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 doesnt 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/Ritonavirb) Tenofovir + Emtricitabine (Truvada) + Darunavir/Ritonavirc) Combination Tenofovir + Emtricitabine + Efavirenz (Atripla)d) Tenofovir + Emtricitabine (Truvada) + Raltegravir

Side effects58 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 effects30 yo man on ARVs with an elevated creatinine seen on routine labs. What ARV is he on?Tenofovirrenal insufficiency (0.5% of patients)fanconi syndrome

Side effects23 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 initiationalso caution in patients with CAD or CAD risk factors

Side effectsNRTIslactic acidosis (very very very rare with current NRTIs mostly from stavudine, didanosine and AZT)nausea/vomitingHBV flare if discontinuedAbacavir Abacavir hypersensitivity (3-5% of patients)screen with HLA-B*5701 testingalso caution in patients with CAD or CAD risk factorsTenofovirfanconi syndromerenal insufficiency (0.5% of patients)Stavudine and didanosine (no longer used in the US, or most of the world) pancreatitislactic acidosislipodystrophyneuropathy

Side effects28 yo man whose skin looks like this. What ARV is he on?Atazanavircommonly causes an indirect hyperbilirubinemiararely causes jaundiceentirely harmless and goes away with discontinuationhttp://optimismandwhitepaint.blogspot.com/2009/08/house-beautiful-color-quiz.html

Side effects34 yo man started on ARVs 2 weeks ago who has been hanging out with this guy for the past 10 days.

Side effectshttp://horizoncomfortzone.blogspot.com/2011/01/amazing-toilet-facts.htmlWhat class of ARVs is he on?

Side effectsPIs (all cause nausea, vomiting and diarrhea and dyslipidemia) Atazanavir jaundice (elevated indirect bilirubinemia)excellent lipid profileDarunavircaution in sulfa allergic patientsexcellent lipid profileRitonavirreputation for bad nausea, vomiting, diarrhea

Side effects56 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

Efavirenzheadaches, 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)dyslipidemiahepatotoxicityteratogenic (neural tube disorders), dont use in the first trimester

Nevirapinehepatic necrosis (idiosyncratic, and increased risk at higher CD4 counts)

Side effects45 year old man recently started on ARVs and is experiencing no side effects, but is realizing that twice daily meds is harder than expectedRaltegravir very well tolerated occasional nausea, vomiting, headache, diarrhea, but usually no side effects. BID dosing

Drug-Drug Interactions1) Acid suppressants2) Anticonvulsants3) Statins4) TB medications5) Methadone6) Antidepressants7) Oral Contraceptives

Drug-Drug Interactions1) Acid suppressantsatazanavir 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 InteractionsAntidepressants 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 InteractionsAnticonvulsantsPhenytoin - 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 InteractionsStatinsNNRTIs (namely Efavirenz) will decrease the serum concentration of nearly all statins, adjust statin to meet LDL goalPIs Simvastatin CONTRAINDICATED with all PIs as it can increase serum concentrations up to 3000%Atorvastatin and Rosuvastatin, increased statin concentrations, but OK to usePravastatin - very little interaction with most PIs

Drug-Drug InteractionsTB medicationsRifampin is CONTRAINDICATED with all PIs as it will decrease PI serum concentrations. Efavirenz should be dose adjusted.

Drug-Drug InteractionsMethadonePIs and NNRTIs may decrease methadone serum concentrations

Drug-Drug Interactionshttp://reference.medscape.com/drug-interactioncheckerhttp://hivinsite.ucsf.edu/InSite

Case56 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 doesnt 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 DirectionsNew (possibly 1st line) ARVsDolutegravir (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 pillRilpivirene (new FDA approved once-a-day NNRTI without the bad CNS side effects) Also, rilpivirene coformulated with Truvada (B-tripla!)...its actually called CompleraRandomized trial of when to startStrategic Timing of Antiretroviral Treatment (START) trialhowever 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

Summary1) Why primary care doctors should care about HIV care2) The important societies making the rules for ARV management3) Historical context to when to start4) Reviewed the studies which are pushing the field towards earlier treatment5) Important drugs to know 6) Important concepts on what to start6) major ARV side effects7) major drug-drug interactions, and where to quickly trouble-shoot ARV interaction questions 8) Future directions

Thank you!