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  1. 1. HIV Medications, Long Term Effects, Opportunistic Infections and Adherence Danielle Gill, PharmD, MPH
  2. 2. Objectives  Diagnosis of AIDS  Benefits of ART  HIV guidelines for treatment naïve  Mechanism of action of drug classes  Side effects and dosages of ART  Medication adherence  Opportunistic infections and prophylaxis  Long term effects of ART
  3. 3. Diagnosis of AIDS: CDC definition Less then 200 CD4 cells/mm3 of blood  One or more of following:  Candidiasis of bronchi, esophagus, trachea or lungs  Cervical cancer that is invasive  Coccidioidomycosis that has spread  Cryptococcosis that is affecting the body outside the lungs  Cryptosporidiosis affecting the intestines and lasting more than a month  Cytomegalovirus (CMV) disease outside of the liver, spleen or lymph nodes  Cytomegalovirus retinitis that occurs with vision loss  Encephalopathy that is HIV-related  Herpes simplex including ulcers lasting more than a month or bronchitis, pneumonitis or esophagitis  Histoplasmosis that has spread  Isosporiasis affecting the intestines and lasting more than a month
  4. 4. Diagnosis of AIDS: CDC  Kaposi's sarcoma  Lymphoma that is Burkitt type, immunoblastic or that is primary and affects the brain or central nervous system  Mycobacterium avium complex (MAC) or disease caused by M kansasii  Mycobacterium tuberculosis in or outside the lungs  Other species of mycobacterium that has spread  Pneumocystis jiroveci (PJP or PCP)  Pneumonia that is recurrent  Progressive multifocal leukoencephalopathy (PML)  Salmonella septicemia that is recurrent  Toxoplasmosis of the brain, also called encephalitis  Wasting syndrome caused by HIV infection
  5. 5. Clinical Question: � What is the thought to be the most important lab test to determine immune function and predict disease progression? A. Viral load (HIV RNA) B. CD4 C. CD8 D. transaminases
  6. 6. Lab tests in newly diagnosed  HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay’s limit of detection) (AI);  CD4 T-cell count (CD4 count) (AI);  Plasma HIV RNA (viral load) (AI);  Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses (AIII);  Fasting blood glucose and serum lipids (AIII)  Genotypic resistance testing at entry into care, regardless of whether ART will be initiated immediately (AII).  For patients who have HIV RNA levels <500 to 1,000 copies/mL, viral amplification for resistance testing may not always be successful (BII).
  7. 7. Why use ART (Antiretroviral Therapy)?  Effective ART with virologic suppression improves and preserves immune function (regardless of baseline CD4 count)  Earlier ART initiation may result in better responses and clinical outcomes  Reduction in AIDS- and non-AIDS-associated morbidity and mortality  Reduction in HIV-associated inflammation and associated complications  ART strongly indicated for all patients with low CD4 count or symptoms  ART can significantly reduce risk of HIV transmission  Recommended ARV combinations are effective and well tolerated
  8. 8. HIV ART in Treatment Naïve Patients Treatment naive patients 2 NRTIs (TDF/FTC)+ 1 NNRTI (EFV) 2 NRTIs (TDF/FTC) + 1 PI/r (ATV/r or DRV/r) 2 NRTIs (TDF/FTC) + 1 INSTI (DTG or RAL) Or 2 NRTIs (ABC/3TC)* + 1 INSTI (DTG) *patients must be HLA-B*5701 negative* NRTI: nucleoside/nucleotide reverse transcriptase inhibitors) NNRTI: non-nucleoside reverse transcriptase inhibitor PI: protease inhibitor INSTI: integrase strand transfer inhibitor Other classes not recommended for initial treatment CCR5 antagonist (Maraviroc) Fusion inhibitor (Enfuvirtide, Fuzeon)
  9. 9. Ritonavir
  10. 10. Clinical Question: �  What class or classes of ART work to prevent insertion of the virus into the host cell? A. NRTI B. Entry Inhibitor C. Fusion Inhibitor D. B and C
  11. 11. Mechanism of Action  CCR5 antagonist (Maraviroc)  Binds to CCR5 (a co-receptor for most HIV strains) and inhibits entry of the virus into the host cell  Fusion inhibitor (Enfuvirtide or Fuzeon)  Binding of the inhibitor to the HR1 region prevents the HR2 region from access to HR1 and inhibits the fusion process  NRTI: nucleoside/nucleotide reverse transcriptase inhibitors)  Block activity of reverse transcriptase (replicates HIV)  NNRTI: non-nucleoside reverse transcriptase inhibitor  Blocks activity of reverse transcriptase (replicates HIV)  INSTI: integrase strand transfer inhibitor  Prevent the binding of the pre-integration complex to host cell DNA, thus terminating the integration step of HIV replication  PI: protease inhibitor  block the protease enzyme and prevent the cell from producing new viruses
  12. 12. Antiretrovirals and Dosages Nucleoside/nucleotide Reverse Transcriptase Inhibitors
  13. 13. Antiretrovirals and Side Effects Nucleoside Reverse Transcriptase Inhibitors Emtricitabine lactic acidosis, hepatomegaly
  14. 14. Antiretrovirals and Dosage Non-nucleoside reverse transcriptase inhibitors
  15. 15. Antiretrovirals and Side Effects Non-nucleoside reverse transcriptase inhibitors Etravirine severe skin rash, nausea
  16. 16. Antiretrovirals and Dosage Protease Inhibitors
  17. 17. Clinical Question: � An HIV patient is noticing increased fat around their stomach region. Which class of drugs is likely the cause? A. NNRTI B. PI C. INSTI D. CCR5
  18. 18. Antiretrovirals and Side Effects Protease Inhibitors
  19. 19. Antiretrovirals, Dosage, and Side Effects Entry Inhibitor CCR5: Chemokine co-receptor antagonist Drug Maraviroc (MCV)
  20. 20. Antiretrovirals, Dosage, and Side Effects Fusion Inhibitors Drug Enfuvirtide (Fuzeon)
  21. 21. Anteretrovirals and Dosage Integrase Inhibitors
  22. 22. Antiretrovirals and Side Effects Integrase Inhibitors
  23. 23. Antiretrovirals, Dosage, and Side Effects PK Boosters
  24. 24. Question: � Which ART requires HLA-B*5701 testing before prescribing? A. Zidovudine B. Lamivudine C. Tenofovir D. Abacavir
  25. 25. Overlapping ART Toxicity • Peripheral neuropathy didanosine, isoniazid, ddc • Bone marrow suppression ZDV, dapson, hydroxyurea, ribavirin, TMP-SMZ • Hepatotoxicity Nevirapine, Efavirenz, maraviroc, NRTIs, Pis, macrolide, isoniazid • Pancreatitis didanosine, ritonavir, stavudine, TMP-SMZ, pentamidine
  26. 26. Renal and Hepatic Dosed ART  Zidovudine  CrCl <15 or HD: 100mg TID or 300mg daily  Truvada  CrCl 30-49: 1 tab Q48h  CrCl <30 or HD: Contraindicated  Stavudine CrCl 25-50: <60kg 20mgQ12h; >60kg 15mgQ12h CrCl <10-24 or HD: 20mgQ24h; 15mgQ24h  Abacavir Child/Pugh Score 5-6: 200mg BID >6 contraindicated  Didanosine EC CrCl 30-49: >60kg 200mg daily, >60kg125mg daily CrCl <10-29: 125mg daily 125mg daily  Zidovudine  CrCl <15 or HD: 100mg TID or 300mg daily  Truvada  CrCl 30-49: 1 tab Q48h  CrCl <30 or HD: Contraindicated  Stavudine CrCl 25-50: <60kg 20mgQ12h; >60kg 15mgQ12h CrCl <10-24 or HD: 20mgQ24h; 15mgQ24h  Abacavir Child/Pugh Score 5-6: 200mg BID >6 contraindicated  Didanosine EC CrCl 30-49: >60kg 200mg daily, >60kg125mg daily CrCl <10-29: 125mg daily 125mg daily
  27. 27. Renal and Hepatic Dosed ART
  28. 28. Renal and Hepatic Dosed ART
  29. 29. Combonation Product Names
  30. 30. Medication Adherence  Strict Adherence is important to lower viral load, reduce resistance, increase QOL, improve patient survival, and reducing risk of HIV transmission  Achieving >=90% to 95% adherence significantly reduces the likelihood of virologic failure and drug resistance*  ART regimens have improved but suboptimal adherence is common over time  It is important to assess patients readiness for ART therapy prior to initiating it and assess adherence at each appointment  Patient engagement and retention in care is important to increase and maintain medication adherence  Medication adherence is second only to CD4 count in accurately predicting progression to AIDS and death*
  31. 31. Measuring Adherence  No Gold Standard  HIV RNA suppression (most reliable)  Pharmacy records and pill counts  Patient Self-report may overestimate adherence  Suboptimal self-report indicates suboptimal therapeutic response
  32. 32. Factors Associated with Adherence Failure  Mental illness (depression)  Active drug use/alcoholism  Lack of patient education  Adverse effects of medications  Treatment fatigue  High cost medications/insurance  Nondisclosure of HIV status  Low literacy  Regimen complexity  Younger age  Stigma  Psycho-social stressors  Polypharmacy, cognitive impairment
  33. 33. Factors Associated with Adherence Success  Regimen simplicity  Low pill burden  Older Age  Good tolerability  Directly observed therapy  Trusting patient-provider relationship  Using motivational strategies  Multi-disciplinary care  Case managers, social workers, psychiatric care, pharmacists, nurses, etc.
  34. 34. Methods Improving Adherence  Establish readiness to start therapy  Strengthen early linkage to care and retention of care  Provide education on HIV disease, treatment, and prevention  Provide education on importance of adherence and consequences of poor adherence  Individualize treatment with patient involvement  Continuum of support services is needed  Team including providers from many disciplines
  35. 35. Specific Methods to Improve Adherence  Simplify regimen and food requirements  Review, anticipate and treat side effects  Identify all possible barriers to adherence before starting therapy  Use positive reinforcement  Systemically monitor treatment efficiency and retention in care  Use educational aids (pictures, pillboxes, and calendars)  Engage a support system  Utilize a team approach  Assess adherence at each visit  Identify type and reasons for nonadherence
  36. 36. Opportunistic Infections and Treatment
  37. 37. Oropharyngeal Candidiasis  Oropharyngeal candidiasis is characterized by painless, creamy white, plaque-like lesions that can occur on the buccal surface, hard or soft palate, oropharyngeal mucosa, or tongue surface.  Drug of Choice: Oral fluconazole is as effective as and, in certain studies, superior to topical therapy for oropharyngeal  Mild-to-moderate episodes of oropharyngeal candidiasis can be adequately treated with topical therapy, including once-daily miconazole in 50-mg mucoadhesive buccal tablets (BI)or clotrimazole troches 5 times daily
  38. 38. Disseminated Mycobacterium Avium complex (MAC) • Caused by bacteria commonly found in soil, food, and water • Symptoms: high fever, night sweats, abdominal pain, diarrhea, weight loss, fatigue, swollen glands, anemia • CD4 count <50 cells/µL • Prophylaxis • Azithromycin 1200 mg PO once weekly (AI), or • Clarithromycin 500 mg PO BID (AI), or • Azithromycin 600 mg PO twice weekly (BIII)
  39. 39. Cytomegalovirus Disease (CMV) Caused by common Herpes virus HHV-5 Symptoms: blind spots or moving black spots, blurred vision, blindness, diarrhea or abdominal pain, difficult swallowing, pain, weakness, or numbness at the base of your spine, causing trouble with walking Preferred Systemic Induction Therapy: Valganciclovir 900mg PO BID for 14-21 days Chronic Maintenance: Valganciclovir 900mg PO daily CMV Retinitis Induction Therapy: For Immediate Sight-Threatening Lesions (Adjacent to the Optic Nerve or Fovea):  Intravitreal injections of ganciclovir (2mg) or foscarnet (2.4mg) for 1-4 doses over a period of 7-10 days
  40. 40. Pneumocystis Pneumonia PCP or PJP  Caused by fungus called Pneumocystis jiroveci (PJP)  Still major cause of death in AIDS population  CD4<200  Symptoms: fever, dry cough, wheezing, SOB, rapid breathing, fatigue, major weight loss, chest pain when you breath  Prophylaxis  Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic agent (AI).39,41-43 One double-strength tablet daily is the preferred regimen (AI),  but one single-strength tablet daily43 also is effective and may be better tolerated than the double-strength tablet (AI).
  41. 41. Clinical Question: � An HIV patient comes to the pharmacy counter for treatment for skin lesions. What would you tell him? A. Use hydrocortisone cream B. Start an antibiotic C. Bathe in oatmeal soap D. Contact physician immediately
  42. 42. Kaposi Sarcoma HHV-8 Diseases (Kaposi Sarcoma [KS]) Initiate or optimize ART (AII) Symptoms: mucocutaneous lesions, lower extremities, face, trunk, orophyaryngeal mucosa, pulmonary involvement (males with HIV) Treatment: Chemotherapy (per oncology consult) + ART Primary , immunotherapy (interferon alpha, interlueki-12), and/or anti-HHV8 therapy
  43. 43. ART long term effects  Cardiovascular disease  Lipid abnormalities  Diabetes  MI  Malignancies  HCC  Cervical Cancer  Neurological complications  Insomnia  Depression  Peripheral neuropathy  Persistant Inflammation and immunodeficiency  HIV related nephropathy  Kidney damage
  44. 44. Facial Lipoatrophy
  45. 45. Key Points  Antiretroviral Therapy improves QOL, reduces HIV transmission, and reduces HIV related co-morbidities if taken consistently  The backbone of ART in treatment naïve patients is 2 NRTIs +1 PI or 1 INSTI or 1 NNRTI  There are currently 5 drug targets for HIV  Pis have the most drug interactions (CYP450)  Abacavir can cause hypersensitivity syndrome and requires patients get tested HLA B*5701  Efavirenz is teratogenic  Adherence rates 90-95% are needed to reduce virologic failure and drug resistance  Some long term ART side effects include increased cholesterol, increased cervical cancer, lipodystrophy, and diabetes  Some Opportunistic infections that may occur in patients with AIDS include Kaposi sarcoma, PJP, and CMV
  46. 46. References      adolescents-training-slide-sets   
  47. 47. AETC Contact Information  Pennsylvania/MidAtlantic AETC  Website:  Phone: 412-624-1895  Consultation: 888-664-AETC  National Clinician Consultation Service  800-933-3413  PEP Line  888-448-4911  Linda Frank, PhD, MSN, FAAN  412-624-9118 