HIVMedications, Long Term Effects, Opportunistic

Infections and Adherence

Danielle Gill, PharmD, MPH

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

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

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

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. CD4C. CD8D. transaminases

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).

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

HIV ART inTreatment Naïve Patients

Treatment naive patients2 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)

Or2 NRTIs (ABC/3TC)* + 1 INSTI (DTG)

*patients must be HLA-B*5701 negative*

NRTI: nucleoside/nucleotide reverse transcriptase inhibitors)NNRTI: non-nucleoside reverse transcriptase inhibitorPI: protease inhibitorINSTI: integrase strand transfer inhibitorOther classes not recommended for initial treatmentCCR5 antagonist (Maraviroc)Fusion inhibitor (Enfuvirtide, Fuzeon)

Ritonavir

Clinical Question: �

What class or classes of ART work to prevent insertion of the virus into the host cell?A. NRTIB. Entry InhibitorC. Fusion InhibitorD. B and C

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

Antiretrovirals and DosagesNucleoside/nucleotide Reverse Transcriptase Inhibitors

Micromedex.com

Antiretrovirals and Side EffectsNucleoside Reverse Transcriptase Inhibitors

Emtricitabine lactic acidosis, hepatomegaly

Antiretrovirals and Dosage

Non-nucleoside reverse transcriptase inhibitors

Antiretrovirals and Side EffectsNon-nucleoside reverse transcriptase

inhibitors

Etravirine severe skin rash, nausea

Antiretrovirals and DosageProtease Inhibitors

Clinical Question: �An HIV patient is noticing increased fat around their stomach region. Which class of drugs is likely the cause?A. NNRTIB. PIC. INSTID. CCR5

Antiretrovirals and Side EffectsProtease Inhibitors

Antiretrovirals, Dosage, and Side Effects

Entry InhibitorCCR5: Chemokine co-receptor antagonistDrugMaraviroc (MCV)

Antiretrovirals, Dosage, and Side Effects

Fusion Inhibitors

DrugEnfuvirtide (Fuzeon)

Anteretrovirals and DosageIntegrase Inhibitors

Antiretrovirals and Side EffectsIntegrase Inhibitors

Antiretrovirals, Dosage, and Side EffectsPK Boosters

Question: �

Which ART requires HLA-B*5701 testing before prescribing?

A. ZidovudineB. LamivudineC. TenofovirD. Abacavir

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

• Pancreatitisdidanosine, ritonavir, stavudine, TMP-SMZ, pentamidine

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

StavudineCrCl 25-50: <60kg 20mgQ12h; >60kg

15mgQ12hCrCl <10-24 or HD: 20mgQ24h; 15mgQ24h

AbacavirChild/Pugh Score 5-6: 200mg BID >6 contraindicated

Didanosine ECCrCl 30-49: >60kg 200mg daily, >60kg125mg

dailyCrCl <10-29: 125mg daily 125mg daily

Renal and Hepatic Dosed ART

Renal and Hepatic Dosed ART

Combonation Product Names

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*

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

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

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.

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

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

Opportunistic Infections and Treatment

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

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)

Cytomegalovirus Disease (CMV)Caused by common Herpes virus HHV-5Symptoms: 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 daysChronic Maintenance: Valganciclovir 900mg PO dailyCMV 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

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).

Clinical Question: �

An HIV patient comes to the pharmacy counter for treatment for skin lesions. What would you tell him?

A. Use hydrocortisone creamB. Start an antibioticC. Bathe in oatmeal soapD. Contact physician immediately

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

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

Facial Lipoatrophy

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

References

http://aidsinfo.nih.gov/contentfiles/perinatal_fs_en.pdf http://www.cdc.gov/hiv/risk/gender/pregnantwomen/emct.html http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-

guidelines/ http://hab.hrsa.gov/deliverhivaidscare/clinicalguidelines.html http://aidsetc.org/resource/guidelines-use-antiretroviral-agents-

adults-and-adolescents-training-slide-sets http://www.cdc.gov/hiv/prevention/research/tap/ www.Micromedex.com www.ucsfhealth.org

AETC Contact Information Pennsylvania/MidAtlantic AETC

Website: www.pamaaetc.org 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 frankie@pitt.edu