Pharmacology- HIV drugs

Currently Recommended HIV Therapy

2 NRTI+ NNRTI (or PI or integrase inhibitor)= initial HIV treatment regimen. multi-drug tx to prevent drug resistance.

Strategies to promote Medication Compliance with HIV Disease

Assess client's language needs, knowledge base, reading level, living situation & social support Help client develop strategies for establishing medication regimen & dealing with barriers—1 or 2x daily dosing; use of reminders/pill counters & alarms; pictures/med stickers Plan for side effects & management strategies to address; communication with prescriber Peer support groups can be helpful with medication adherence strategies; side effect management & addressing medication costs/ reimbursement strategies

Nucleoside Reverse Transcriptase Inhibitors ("Nukes")

Mechanism of action: false nucleotides that mess up the proper building of viral DNA, therefore stopping viral replication. Drug example: emtricitabine (FTC);tenofovir (TDF) Newer NRTIs emtricitabine (FTC), tenofovir (TDF), have longer half lives (daily dosing) & less toxicity; preferred drugs for HIV & Hepatitis B infection use: treat infection with HIV-1. Good at penetrating CNS, therefore most often used for cognition problems related to HIV. Drug of choice for mother/infant treatment as well. contraindications: hypersensitivity, hemophilia Adverse effects: anemia/neutropenia, potentially fatal lactic acidosis caused by mitochondrial toxicity-- nausea, vomiting, liver enlargement & abd. pain, lethargy & hyperventilation (inc. risk in pregnancy) administration considerations: may be given with or without food monitoring: (monitor CBC) drug interactions: do not use with other drugs that are severely nephrotoxic or that may affect the blood, as this can increase hematologic toxicity client teaching: instruct patient to take full dose and complete treatment regimen. report sx/sx severe rash, CNS issues, diabetes, pneumonia

Preventing Drug Resistance with HIV Infection Tx.

Multiple (3-4) drugs with at least 2 different mechanisms of action are required in HIV treatment to prevent drug resistance from emerging due to viral mutations

Acquired Immunodeficiency Syndrome (AIDS)

Occurs after prolonged HIV infection-> loss of CD4+ cells. Aids is defined by: <200 cell/ml of CD4+ + presence of opportunistic infection (loss of immune function can no longer protect against viral/fungal/bacterial infection to occur, as well as neoplasms)

HIV/AIDS Infection Prophylaxis

Persons with HIV infection & CD4+ counts <200cells/mm3 at risk for disseminated fungal, viral, bacterial infections & malignancies TMP/SMX (Bactrim/Septra): Pneumocystis pneumonia & Toxoplasmosis encephalitis Fluconazole ( Diflucan): Candidiasis & Cryptococcal encephalitis Isoniazid (INH): latent Tuberculosis

Challenges to Medication Compliance with HIV Drug Therapy

Psychosocial factors Language barriers Knowledge barriers Medication barriers

Human Immunodeficiency virus

RNA retrovirus which infects CD4+ helper lymphocytes and other immune macrophages (which have MHC molecules memory cells). viral RNA uses reverse transcription to integrate virus into cellular DNA and then replicates to make new HIV RNA viral particles CD4+ cell death leads to chronic immonosupression-> overwhelming infections and cancers->eventual host death Loss of immune function by T lymphocytes allows many normally non-pathogenic viral & fungal organisms to cause serious clinical illness; malignancies (e.g. Kaposi's sarcoma; non-Hodgkin's lymphoma) to emerge & latent bacterial infections (e.g. tuberculosis) to become activated

Treatment Goals in HIV Infection

Reduce HIV morbidity Prolong life Restore immunologic function Suppression viral load Prevent HIV transmission Prevent drug resistance

HIV Therapy in Pregnancy & Neonatal Period

Screen for HIV infection with initial prenatal visit. HIV therapy in pregnancy reduces perinatal transmission to infant 25-30% risk of transmission to newborn. If treatment starts, transmission is <2% zidovudine is NRTI drug that still is given perinatally. During labor the women is kept on a continuous infusion. The infant is then given a prophylactic treatment PO for 6 weeks after birth

Drugs for Treating HIV Infection

Work by: - disrupting viral processes of cell entry - block viral transcription - block viral replication - block viral release from the CD4+ cells 6 types that act along the viral pathway: 1) fusion inhibitors: work on preventing HIV entry into CD4 cell 2) nucleoside reverse transcriptase inhibitors ("nukes"): contain faulty versions of the building blocks (nucleotides) used by reverse transcriptase to convert RNA to DNA. When reverse transcriptase uses these faulty building blocks, the new DNA cannot be built correctly. In turn, HIV's genetic material cannot be incorporated into the healthy genetic material of the cell and prevents the cell from producing new virus. like: emtricitabine (FTC);tenofovir (TDF) 3) non-nucleoside reverse transcriptase inhibitors ("non-nukes"): attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA. In turn, HIV's genetic material cannot be incorporated into the healthy genetic material of the cell, and prevents the cell from producing new virus. like: efavirenz (Sustiva) 4) integrase inhibitors: work by blocking the integration of the viral DNA into the host DNA. like: ratelgravir (Isentress) 5) protease inhibitors: PIs block the protease enzyme from trimming HIV proteins- thus making functional HIV molecules. like: lopinavir/ritonavir (Kaletra); darunavir (Prezista); ritonavir 6) chemokine receptor antagonist: binds with the chemokine receptor 5 on the host cell membrane. by doing so it prevents HIV from binding to the receptor, thus preventing the HIV entry into the cell.

Highly active anti-retroviral therapy (HAART)

initiated with acute initial infection or when the pt. becomes symptomatic-- CD4 counts of 500-200 cells/mm3 Tx. efficacy: efficacy-undetectable viral RNA load w/i 3-6 months Long term compliance & ongoing follow -up is essential to prevent drug resistance from developing & to manage adverse effects of drug therapy-> patient usually builds strong relationship with care team Stopping drug therapy will result in return of viral replication & AIDS Drug resistance is best detected early by measuring serum viral RNA; levels > 50 copies/ml indicate drug resistance

Integrase Inhibitors (-gravirs)

mechanism of action: Enzyme prevents viral DNA from being integrated into host cell DNA Drug name: ratelgravir (Isentress) adverse effects: GI (nausea/diarrhea) & headache; elevated lipid levels & increased liver enzymes administration considerations: PO tablets daily without regard for food. Rapidly absorbed; highly protein bound; 10-12 hr ½ life; eliminated renally; no dose adjustment for liver/kidney disease monitoring: cholesterol & triglyceride levels & assess for signs of liver dysfunction/elevated liver function tests Monitoring of viral RNA for drug resistance every 3-6 months client teaching: should not be taken with antacids due to impaired absorption. report increasing muscle weakness since myopathy can develop with Integrase Inhibitors

Tenofovir Disoproxil Fumarate /TDF (Viread)

mechanism of action: Nucleotide reverse transcriptase inhibitor use: for HIV infection & Hepatitis B infection therapeutic effect: Intracellularly activated; interferes with viral DNA synthesis contraindications: shouldn't be used in renal failure adverse effects: effects—N/V, diarrhea, weakness & headache Osteoporosis with long term use Renal toxicity—elevated creatinine/proteinuria; administration considerations: Dosing -300mg PO daily, Taken without regard to food daily Long half-life; renally eliminated monitoring: monitor kidney function tests with tenofovir/TDF, Monitor for signs of renal dysfunction. Assess for compliance & enc. use of drug reminder strategies; labwork F/U for viral load Assess for adverse effects & provide sx. management strategies drug interactions: Eliminated through kidneys; few drug interactions client teaching: Encourage adequate intake of Vitamin D, calcium & weight bearing exercise to maintain bone density. Instruct client to report sx. lactic acidosis-vomiting; weakness; abd. pain & hyperventilation/ SOB

Protease Inhibitors (PIs) "-Navir Guys"

mechanism of action: Prevent new infectious viral particles from forming ; virus unable to be "cut" into functional units after replication Drug name: lopinavir/ritonavir (Kaletra); darunavir (Prezista) + ritonavir adverse effects: GI upset, diarrhea, fatigue, hyperlipidemia, hyperglycemia Rare serious—pancreatitis; prolonged PR interval Lipodystrophy—fat redistribution occurs with many Pis (40-50% clients) administration considerations: Ritonavir (Norvir)-PI that is used to increase effects of other PIs by inhibiting metabolism of the other drug >> higher PI blood levels & less risk of drug resistance ("ritonavir boosting"). Fixed 4:1 combination of 2 PIs combined to improve efficacy, prevent drug resistance & prolong drug activity Most PIs highly albumin bound; don't cross into CNS & have short half-lives but (taken with ritonavir "boosting" can be taken daily instead of 2x daily). Oral solution should be taken with food; tablets without regard to meals monitoring: Monitor for signs of dyslipidemia; ~70% of client will need lipid lower agents while taking PIs Body image changes due to lipodystrophy; may need to change therapy if too severe. Medication compliance & regular F/U labwork client teaching: sx. of hyperglycemia (thirst; frequent urination); abdominal pain & worsening rash to report to prescriber. Don't discontinue medication without contacting prescriber; drug resistance & rapid viral replication

Lopinavir/ritonavir (Kaletra)

mechanism of action: Prevent new infectious viral particles from forming ; virus unable to be "cut" into functional units after replication use: therapeutic effect: contraindications: adverse effects: GI upset, diarrhea, fatigue, hyperlipidemia, hyperglycemia Rare serious—pancreatitis; prolonged PR interval Lipodystrophy—fat redistribution occurs with many Pis (40-50% clients) adverse effects: GI upset, diarrhea, fatigue, hyperlipidemia, hyperglycemia Rare serious—pancreatitis; prolonged PR interval Lipodystrophy—fat redistribution occurs with many Pis (40-50% clients) administration considerations: Oral solution should be taken with food; tablets without regard to meals. Fixed 4:1 combination of 2 PIs combined to improve efficacy, prevent drug resistance & prolong drug activity monitoring: Monitor for signs of dyslipidemia; ~70% of client will need lipid lower agents while taking PIs Body image changes due to lipodystrophy; may need to change therapy if too severe. Medication compliance & regular F/U labwork client teaching: sx. of hyperglycemia (thirst; frequent urination); abdominal pain & worsening rash to report to prescriber. Don't discontinue medication without contacting prescriber; drug resistance & rapid viral replication

Darunavir /DRV (Prezista)

mechanism of action: Prevent new infectious viral particles from forming ; virus unable to be "cut" into functional units after replication use: therapeutic effect: contraindications: adverse effects: GI upset, diarrhea, fatigue, hyperlipidemia, hyperglycemia Rare serious—pancreatitis; prolonged PR interval Lipodystrophy—fat redistribution occurs with many Pis (40-50% clients) adverse effects: GI upset; rash; headache common Lipodystophy & dyslipidemia can occur; hyperglycemia less common with darunavir than with other Pis Rare, serious- Stevens-Johnson syndrome; hepatotoxicity administration considerations: PI "boosted" with ritonavir for daily dosing Oral dosing taking with food improves bioavailability monitoring: Monitor for signs of dyslipidemia; ~70% of client will need lipid lower agents while taking PIs Body image changes due to lipodystrophy; may need to change therapy if too severe. Medication compliance & regular F/U labwork client teaching: sx. of hyperglycemia (thirst; frequent urination); abdominal pain & worsening rash to report to prescriber. Don't discontinue medication without contacting prescriber; drug resistance & rapid viral replication

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) "Non-nukes"

mechanism of action: bind to reverse transcriptase enzyme & inhibit viral DNA synthesis by acting as "block" in viral DNA transcription Drug name: efavirenz (Sustiva) use: have synergistic effect with the NRTIs & often given together with 2 NRTIs as HIV therapy Potent effects against HIV 1 virus; but some drug resistance has occurred contraindications: liver failure, pregnant (Cat D) adverse effects: Liver toxicity can occur with all NNRTIs, Rash, teratogenic effects administration considerations: Metabolized via P450 liver enzyme system; Liver toxicity can occur with all NNRTIs monitoring: Liver toxicity—signs of jaundice, abd. pain, elevated liver function tests (LFTs), CNS effects-sleepiness, confusion, vivid dreams/hallucinations usually decrease with continued therapy w/i several weeks; titration schedule over 2 weeks may used to decrease effects drug interactions: anything that is metabolized on P450 liver enzyme client teaching: Take medication on empty stomach @ bedtime to minimize CNS effects, Contraception teaching due to teratogenic effects

Efavirenz (Sustiva)

mechanism of action: bind to reverse transcriptase enzyme & inhibit viral DNA synthesis by acting as "block" in viral DNA transcription use: have synergistic effect with the NRTIs & often given together with 2 NRTIs as HIV therapy Potent effects against HIV 1 virus; but some drug resistance has occurred contraindications: liver failure, early pregnancy; Category D; risk for fetal neural tube defects; not for children < 3yrs. adverse effects:CNS symptoms-dizziness, drowsiness; nightmares; rash; liver damage administration considerations: PO absorption increased by high fat meal; crosses into CNS; long half-life-40-55 hr.; liver metabolism by P450 enzymes; renal + GI excretion; can inhibit P450 enyzmes monitoring: effects-sleepiness, confusion, vivid dreams/hallucinations usually decrease with continued therapy w/i several weeks; titration schedule over 2 weeks may used to decrease effects drug interactions: anything metabolized on P450 client teaching: Take medication on empty stomach @ bedtime to minimize CNS effects. Contraception teaching due to teratogenic effects; Rash-skin protection; usually resolves w/i a few weeks. Liver toxicity—signs of jaundice, abd. pain, elevated liver function tests (LFTs)

Emtricitabine (FTC/Emtriva)

mechanism of action: prodrug which is activated intracellularly to inhibit viral DNA synthesis use: Used for HIV disease & Hepatitis B infection contraindications: severe kidney dysfunction adverse effects: usually mild-headache, nausea, diarrhea, rash; hyperpigmentation Rarely-lactic acidosis administration considerations: Available PO-- as capsules & oral solution. Well absorbed; taken w/o regard to meals. dose adjustment renal failure monitoring: Monitor for signs of renal dysfunction. Assess for compliance & enc. use of drug reminder strategies; labwork F/U for viral load Assess for adverse effects & provide sx. management strategies drug interactions: Eliminated through kidneys; few drug interactions client teaching: Encourage adequate intake of Vitamin D, calcium & weight bearing exercise to maintain bone density. Instruct client to report sx. lactic acidosis-vomiting; weakness; abd. pain & hyperventilation/ SOB

Post-exposure Prophylaxis (PEP) for HIV Risk Exposure

recommended for healthcare workers who are potentially exposed to HIV virus through body fluid contact based on risk assessment; risk of blood transmission of HIV <1% Needs to be started in <72 hr. ideally w/i 24 hr. of potential exposure to prevent HIV virus from getting established in lymph nodes; reduces risk of transmission by `90% Baseline labwork drawn then 2-3 different drugs given orally for a month Emtricitabine/tenofovir -(Truvada) often used for post-exposure prophylaxis Follow-up blood testing recommended- 6 weeks,3 months, 6 months post-exposure