HIV infection and Primary Care. HIV Care in /30/2013. It s not the AIDS of 85. Stephen Raffanti MD MPH Vanderbilt University School of Medicine

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1 HIV infection and Primary Care Stephen Raffanti MD MPH Vanderbilt University School of Medicine HIV Care in 2013 Chronic lifelong treatment with all the associated issues: medication tolerability medication adverse events resistance drug-drug interactions polypharmacy adherence pharmacy costs and formularies General Medicine in the Fast Lane : Chronic inflammatory state Accelerated cardiovascular disease Metabolic disorders (obesity, DM. HTN. DL) Accelerated fragility Cognitive issues I aging patients Some Epidemiologic Considerations The changing role of the primary care provider It s not the AIDS of 85 1

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3 HIV Drug Approval Integrase Inh CCR5 Inh Fusion Inh PI NNRTI NRTI Relationship of Potent Therapy to Mortality Swiss Cohort Study Hasse B et al. Clin Infect Dis. 2011;53: Endpoint Total (%) Rate (95% CI)/1000PY Bacterial Pneumonia 201 (20) 9.03 ( ) Fracture 123 (12.4) 5.48 ( Non-AIDS malignancy 115 ( ( ) CDC Stage B event 100 (8) 4.52 ( CDC Stage C event 95 (8) 4.32 ( ) Coronary Angioplasty 76 (7) 3.38 ( ) Diabetes 70 (7) 3.12 ( ) Osteoporosis 61 (6) 2.71 ( ) Myocardial Infarction 55 (5.5) 2.44 ( ) Kidney events 31 (3) 1.37 ( ) 3

4 A, Numbers of different classes of non human immunodeficiency virus (HIV) medication, stratified by age. Hasse B et al. Clin Infect Dis. 2011;53: The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com. Co-receptor, CD4 binding inhibitors Maraviroc Vicriviroc TNX 355 Fusion Inhibitors Enfuvirtide Retrovirus Life Cycle Protease inhibitors SQV IDV RTV NFV FPV LPV ATV TPV DRV Reverse transcriptase inhibitors ZDV NVP ddi DLV ddc EFV d4t 3TC FTC ABC TDF Etravirine Rilpivirine Integrase inhibitors Raltegravir Elvitegravir (GSK364735) Current Guidelines Both the DHHS and the International AIDS Society- USA publish updated treatment guidelines for antiretroviral therapy on a regular basis; Recommendations are evidence based and identify preferred and non-preferred regimens and treatment thresholds. Criteria for treatment are clinical, immunological and virologic status. It is now recommended that all HIV infected patients be treated. 4

5 Issues related to treating HIV All antiretrovirals are experimental drugs: How can they be rated and compared? What about side effects? What about drug interactions? What about the aging population? How does the FDA rate the medications? Potency: Most drugs go through Phase I to Phase IV testing. Phase I tells about monotherapy, Phase II-III are clinical trials (RCT s) and Phase IV is post marketing. Comparions are made with other regimens, duration is usually weeks. Tolerability : Most RCT s screen for a healthier group of subjects; adherence is usually better than average. Adverse Events: Toxicities are screened in animal and cell culture trials. Toxicities are graded in clinical trials and reported. Most toxicities identified are short term. Resistance: Some in vitro and clinically related trial data is available before FDA approval. Clinical trials subjects are often different from clinic population Risks of Treatment Treatment with antiretrovirals carries with it the risk of short-term and long-term side effects. Some long term side effects may be irreversible. The longer a patient is treated, the greater the risk of side effects. Treatment promotes resistance. 5

6 Drug Toxicities/Tolerability Long-term toxicities: Now the major cause of treatment discontinuation and may have overlapping syndromes and pathways. Short-term toxicities are predictable, well known and relatively easy to manage. Physical Manifestations of HIV-Associated LD New England Journal of Medicine (1998:339;1296); International Journal of STD and AIDS (1198;9:596). Potential mechanisms of ART-associated metabolic complications Grinspoon and Carr. NEJM 2005; 352:

7 Metabolic Complications of Therapy In Addition to possibly irreversible Body Changes Hyperlipidemia: approximately 20% of patients on PI s will have elevated levels of TChol., LDL and triglycerides. Diabetes: Approximately 5% of patients receiving PI s will develop diabetes, more will develop insulin resistance. Hepatitis: Fulminant hepatitis can develop in patients started on HAART co-infected with HCV or HBV. Metabolic Syndrome: Associated with certain classes of antiretrovirals and co-morbidities Overall adjusted MI risk increased 16% per year ART exposure Increase in PI-exposed, not in NNRTI-exposed Risk with PIs increased ~10% per year after adjusting for lipids Resistance in HIV medicine Resistance: how we describe the changes the virus makes to replicate in the presence of external factors: Clinically significant mutations in appropriate genes; Clinically insignificant mutations in appropriate genes (polymorphs); Net phenotypic change from above mutations; Changes in receptor tropism; Immunologic al escape mechanisms;* Efflux mechanisms;*» *not extremely helpful for clinicians at this point 7

8 Resistance and second generation agents Resistance is measured by drug exposure, genotype and/or phenotype. Resistance is fairly well understood for older agents and some resistance crosses over to other agents. Second generation agents have been designed for people with HIV strains that have developed recognized resistance patterns. Resistance Tests Genotype: Reports multiple known mutations associated with resistance in vitro; may be more reliable with new drugs. Phenotype: Technically more complex, less available clinical data, may be helpful with highly resistant straintakes into account compensatory changes. Both tests reflect only the predominant strain at the time of specimen collection. 8

9 Resistance Tests Resistance testing should be utilized: In naive patients when significant (>4%) prevalence of resistance mutations occur; In treatment failures when medications are present or recently discontinued; Resistance data should be considered over time as if a super-mutant strain is being produced. What is a Drug-Drug Interaction? A drug interaction occurs when a drug interferes in a negative (or positive) way with another drug Can increase or lower drug levels Can occur between: Two drugs (prescription, over the counter, vitamins, supplements and illegal drugs) Drugs and foods/drinks 9

10 CYP450 and Drug Metabolism CYP1A2 CYP2C CYP2D6 CYP2E1 CYP3A4 Key points Majority of drugs metabolized by CYP3A4 and CYP2D6 CYP3A4 and CYP2D6 extensively involved with PI/NNRTI metabolism Enzymes can be induced or inhibited Drug Interactions All PI s and NNRTI s are metabolized by the P450 cytochrome system; each drug can be an inhibitor, inducer and a substrate. Ritonavir avidly binds the CYP34A enzyme causing extremely high levels of competing compounds. Important medications to remember include Versed, statin drugs, cafergot, Rhythmol, Viagra and rifampin. Drug-interactions are exploited to improve pk and dosing parameters of certain antiretrovirals. Adherence in HIV Non-adherence leads to resistance and treatment failure. Non-adherence is extremely common and minimal missed doses can have serious consequences. Adherence is difficult to predict and measure. Some regimens may offer a better chance of adherence than others. 10

11 Implication of Poor Adherence Adherence to ART Viral Load <400 >95% 78% 90-95% 45% 80-90% 33% 70-80% 29% <70% 18% Ann Intern Med 2000;133:21 Adherence Predictors Adherence is notoriously difficult for the provider to predict (CCC experience). Adherence is difficult to assess (surveys vs. pharmacy logs vs. MEMS). Adherence is less likely in the setting of active substance abuse, depression, frequent dosing, lack of rapport with provider and lack of belief in validity of treatment. Some barriers to adherence cannot be changed (CCC experience). Adherence: A Case Study 51 year old male on a 5 pill regimen for 8 months. Dispensing log reveals late pick-up equivalent to 85% adherence. He denies any perceived toxicities. What factors might be involved to explain his non-adherence? Educational level? Insurance status? Substance abuse? Mental Illness? Trust in provider? 11

12 Putting It All together How can all these factors be taken into account when designing a regimen? Patient factors: concurrent diagnoses, tolerances, adherence, insurance status; Viral factors: phenotype of current dominant strain, archived strains, viral fitness; Medication factors: dosing, drug interactions, short and long term toxicities. Comprehensive Care Center ART Conference All patients either starting, stopping or changing antiretroviral therapy; Presentation includes past regimens with labs, tolerances, genotypes, phenotypes; All co-morbidities included; Patient preferences included; Wide participation of clinical staff. Available at ART Conference Questions If the patient is naïve should HAART be initiated? If the patient is experienced is she failing therapy? Is the patient being presented to change a virologically successful regimen with toxicities? What are the goals of treatment? What other information is important before designing an effective regimen? What is the greatest obstacle to success? What should be done and in what order? 12

13 Naïve Patient 42 year old banker with CD4 count of 234 cells/mm 3 and HIV-1 RNA of 122,332 copies/ml: What is best regimen? Atripla (one pill a day); If he is a binge drinker? If he has already had cardiovascular event? If he has chronic dyspepsia? If he doesn t believe the medication will help him? Salvage Patient 32 year old retail clerk with 6 year history of HIV therapy. Currently failing his 4th regimen of Combivir and Kaletra. Genotype shows only two PI mutations both minor and the M184V in the RT gene. He has never had undetectable viremia. Current CD4 count is 134 cells/mm 3, HIV-1 RNA > 750,000 copies/ml. What medications are likely to be effective in treating his infection? What might we pursue to determine next best choice? What co-morbidities might be involved? 13

14 ART Recommendations Current virologically successful regimen: Lopinavir/Ritonavir 2 tabs BID; Efavirenz : 1 pill at night; Abacavir/lamivudine: 1 pill a day Total pill burden: 6 pills a day New recommendations: Darunavir : 2 tabs BID Ritonavir: 1 pill BID; Etravirine : 2 pills BID; Raltegravir: 1 pill BID; Total pill burden: 10 pills a day The Role of the Primary Care Provider External Factors: Improvement in treatment outcomes; Health Care Reform; Patient factors: Accelerated aging and associated morbidities; Polypharmacy; 14

15 Possible Care Models Generalist follows patient for all primary needs including HIV: Without input from HIV specialist; HIV primary care provider follows patient for all primary and HIV care needs. Generalist and HIV primary care providers collaborate in care. The Complexity of HIV care in 2013 It is a very different disease and requires coordination of internal medicine, pharmacology and HIV expertise. Aging, accelerated inflammatory phenomena, chronic medication toxicity and polypharmacy are the new challenges. The changing disease management model and healthcare reform will require new faces, new ideas. The rest of medicine has a lot to learn from the legacy of HIV care. 15

16 AIDS One Patient s Experience 322 IV insertions 14 hospital admissions 11 months of hospital stay 60 phlebotomies 32 chest x-rays 5 CT scans of head 3 abdominal ct scans 6 bronchoscopies 8 intubations 4 lumbar punctures 3 bone marrows 5 cycles of chemo 2 lymph node bx Resources Useful HIV Websites (DHHS, USPHS/IDSA Guidelines) (Resistance mutations)