Antiretroviral Drugs

Nonnucleoside Reverse Transcriptase Inhibitors: Efavirenz Drug interactions

*NOT* recommended for concurrent use: - Rifapentine - Midazolam, triazolam - Voriconazole Monitor when used with: - Atorvastatin - warfarin - rifampin, rifabutin, clarithromycin - Ethinyl estradial

Antiretroviral Agents Combination Therapy

*ONLY* approved mode of therapy - increases long-term viral suppression - decreases rate of resistance development - Nucleoside analogs (Nukes) a. mainstay in therapy b. in combination w/: NNRTI, PI, Integrase inhibitors

Fusion Inhibitors: Enfuvirtide

- Blocks entry of HIV-1 into CD4+ cells. Binds gp41 subunit HIV envelope glycoprotein. - Prevent conformational change required for fusion of viral and cellular membranes

Entry Inhibitors: Maraviroc characteristics; CCR5 antagonist

- For use in treatment-experienced patients - Entry inhibitor - Binds to CCR5 and blocks the HIV gp120 from associated with the receptor. HIV is then unable to bind and enter cells - Does not prevent HIV-1 entry into CXCR4 tropic or dual tropic cells - requires co-receptor tropism assays before use.

Other pharmacokinetic Enhancers: Cobicistat

- used in combination with elvitegravir - Potent P450 inhibitor (CYP3A4) - inhibits the tubular secretion of creatinine clearance of > 70 mL/min

Goals for treatment for HIV

1. Maximally and durably suppress HIV viral load 2. Restore and/or preserve immunologic function 3. Reduce HIV-related morbidity and mortality/improve quality of life 4. Prevent HIV transmission

Antiretroviral drug classes

1. Nucleoside analogs (NRTIs or nukes) 2. Nonnucleoside reverse transcriptase inhibitors (NNRTI) 3. Protease Inhibitors 4. Integrase Inhibitors 5. Fusion Inhibitors 6. Entry inhibitors - CCR5 antagonists

Nonnucleoside Reverse Transcriptase Inhibitors: Efavirenz

Advantages: *potent* antiviral activity Low pill burden and frequency (1 tablet/day) Disadvantages - *Neuropsychiatric side effects* - Rash - *teratogenic*: reported cases of neural tube defects - *Metabolized by P450* (mixed inducer/inhibitor)

Nonnucleoside Reverse Transcriptase Inhibitors: Nevirapine

Advantages: Virologic activity is similar to efavirenz No food effect *Safe* to fetus in all stages of *pregnancy* Disadvantages - *Rash* including rare, but serious *hypersensitivity* reactions (Steven-Johnson Syndrome or toxic epidermal necrolysis) - symptomatic *hepatitis*, including fatal hepatic necrosis, but OK if CD4 < 250cells/ml -Metabolized by P450 (3A Inducer)

Drug Resistance Testing

Before initiation of ART: - Transmitted HIV resistance in 6-16% of pts - Drug-resistance testing recommended for all pts at entry of care and all pregnant women Patients with virologic failure: - perform while patient is taking ART or <4 weeks after discontinuing therapy - Interpret in combination with ART history and adherence Genotypic testing - preferred to than phenotypic testing Phenotypic testing - for known or suspected complex drug resistance pattern

Entry Inhibitor: Drug Names

CCR5 Antagonist - Maraviroc

What proteins are involved in the HIV entry process?

CD4 - protein receptor on surface of Helper T cells GP120 - protein on HIV surface that binds to CD4 receptor CCR5 - 2nd receptor found on CD4 receptors; chemokine CXCR4 - chemokine co-receptor on CD4+ cells GP41 - HIV protein, assoc. w/gp120, penetrates the cell membrane

Monitoring Virologic and Immunologic efficacy of ART

CD4 Count - Major indicator of immune function - Most recent CD4 count best predictor of disease progression - key factor in decision to start ART - Important in determining response to ART - Adequate response: CD4 increase 50-150 cells/mm3 per year HIV RNA - *best primary assay to see if ART is working* - Viral load is surrogate marker for treatment response: - Goal: HIV RNA below limit of detection (<20-75 copies/mL, depending on assay. Suppression generally achieved in 12-24 weeks. Virologic failure considered w/viral load >200 copies

Protease Inhibitors: MOA

Competitive *inhibition* of viral *protease* irreversible bind to the protease active site = no maturation of virions

What are potential limitations of Early Therapy?

Drug-related toxicities non-adherence to ART Drug Resistance Cost

Nonnucleoside RT Inhibitors: Drug Names

Efavirenz Nevirapine

Nonnucleoside Reverse Transcriptase Inhibitors: characteristics

Efavirenz, Nevirapine, Delavirdine, Etravirine, Rilpivirine Direct acting drugs that are not prodrugs that need to activated like Nuceloside analogs Disadvantages: Low genetic barrier to resistance - 1 mutation to do it Prevalence of resistance in treatment-naive pts Toxicity and drug-drug interactions

Nonnucleoside Reverse Transcriptase Inhibitors: Class Drug Interactions

Eliminated by Hepatic Metabolism (CYP3A4) Efavirenz and Nevirapine are CYP3A4 inducers -Plasma levels of concomitant drugs can increase/decrease Potential for *MAJOR* interactions with numerous HIV (PIs) and non-HIV drugs - do not prescribe without first checking interactions - may be *contraindicated* or need for dose adjustments

Protease Inhibitors: Drug drug Interactions

Eliminated via *hepatic metabolism* - Use caution when co-administering drugs that are substrates, inducers, or inhibitors of CYP3A4 Acid reducers (H2 antagonists, PPIs) Anticoagulants Anticonvulsants Antidepressants Antifungals Anti-mycobacterials Benzodiazepines Cardiac medications Corticosteroids Hormonal contraceptives HMG-CoA Reductase Inhibitors

Fusion Inhibitors: Drug Names

Enfuvirtide

Drug Class Disadvantages: PIs

GI intolerance Hepatotoxicity Metabolic Complications - Lipodystrophy - Dyslipidemia - Insulin Resistance CYP3A4 inhibitors and substrates - potential drug drug interactions

Nonnucleoside Reverse Transcriptase inhibitors: MOA

Inhibit HIV-RT - different modality than nucleoside analogs - bind directly to HIV-RT; site other than Nukes do - Drugs inhibit the HIV-RT polymerase activity

When to Start ART?

Initiation of therapy strongly recommended - Hx of AIDS-defining symptoms/illnesses - Pregnancy - Coinfection with HBV If CD4 counts <350 cells/mm - Initiate Treatment If CD4 counts < 500 cells/mm - Treatment Recommended If CD4 counts > 500 cells/mm - Experts suggest starting treatment *ART is now recommended for all HIV-infected pts regardless of viral load or CD4 count. *

Drug Class Disadvantages: NRTI

Lactic Acidosis Hepatic Steatosis (least drug drug interaction problems)

Nucleoside Analogs: Drug Names

Lamivudine Zidovudine Stavudine Didanosine

Nucleoside Analogs: Characteristics

Lamivudine, Zidovudine, Stavudin, Didanosine, Emtricitabine, Tenovir, Abacavir Analogs of Thymidine, Deoxycytidine, Deoxyadenosine, or deoxyguanosine - same mechanism of action, but different activation pathways, and different toxicities/side effect profiles Drugs converted to active triphosphate form inside lymphocytes - incorporated into viral DNA by HIV-reverse transcriptase (HIV-RT) *Established back bone of ART* *Class has minimal drug-drug interactions* with most other medications *ENTIRE CLASS IS BLACK BOXED FOR LACTIC ACIDOSIS WITH HEPATIC STEATOSIS*

FDA Approved Anti HIV Drugs: Entry Inhibitors

MEMORIZE THESE *Currently recommended 1st line agents* CCR5 antagonist - Maraviroc

FDA Approved Anti-HIV drugs: Fusion Inhibitors

MEMORIZE THESE *Currently recommended 1st line agents* Enfuvirtide en*fu*virtide *fu* for Fusion

FDA Approved Anti-HIV drugs: Nucleoside analogs

MEMORIZE THESE *Currently recommended 1st line agents* Lamivudine Zidovudine Stavudine Didanosine Emtricitabine Tenovir Abacavir "LaZiStDiEm" end in -ine "TeAb" end in -vir

FDA approved Anti HIV drugs: Integrase Inhibitors

MEMORIZE THESE *Currently recommended 1st line agents* Raltegravir Dolutegravir Elvitegravir "RED" end in -gravir

FDA Approved Anti-HIV drugs: Nonnucleoside RT Inhibitors (NNRTIs)

MEMORIZE THESE *currently recommended 1st line agents* Efavirenz Nevirapine Delavirdine Etravirine Rilpivirine "ENDER" that most end with -ine and the middle has -vir NOTE: Efavirenz is the exception

FDA Approved Anti-HIV drugs: Protease Inhibitors (PIs)

MEMORIZE THESE *currently recommended 1st line agents* Ritonavir Indinavir Fosamprenavir Nelfinavir Saquinavir Darunavir Atazanavir Lopinavir/RTV "RIFNSDAL" all end in -navir

Initial treatment for HIV: *recommended regiments*

NNRTI - Efavirenz + (Tenofovir + Emtricitabine) Boosted Protease Inhibitor Options - Atazanavir +Ritonavir + (Tenofovir + Emtricitabine) - Darunavir + Ritonavir + (Tenofovir + Emtricitabine) Integrase Inhibitor Option - Raltegravir + (Tenofovir + Emtricitabine) - Dolutegravir + (Tenofovir + Emtricitabine) NOTE: Tenofovir and Emtricitabine are nucleoside analogs - VERY EXPENSIVE

What are the favorable triple combination (standards of ART) therapy?

NNRTI-based regiment - 1 NNRTI +2 nukes PI-based regimen - 1 PI +2 nukes Integrase inhibitors-based regimen - 1 Integrase Inhibitor + 2 nukes

Drug Class Disadvantages: NNRTI

Neuropsychiatric effects w efavirenz Skin Rash Potential for CYP450

Nucleoside Analogs: Phamacokinetics

Notable mentions: Zidovidine: 1 hour half life (but trapped in cell)dose 1/day. - Eliminated *Metabolically* Lamivudine: Eliminated Renally Abacavir: Eliminated *Metabolically* Emtricitabine: Eliminated Renally Tenofovir: 15 hour half life - eliminated Renally CLASS has - good bioavailability - renally cleared (note the exceptions above) - Minimal DDI issues *ENTIRE CLASS IS BLACK BOXED FOR LACTIC ACIDOSIS WITH HEPATIC STEATOSIS*

Fusion Inhibitor: Enfuvirtide characteristics

Primary used in highly drug experienced patients Required subcutaneous injection 2x/day Adverse effects: injection site reactions Most expensive HIV Meds

What is the biggest problem(s) with triple combination therapy?

RESISTANCE (primary) and COMPLIANCE - compliance because side effects and pill burden

Integrase inhibitor: Drug Names

Raltegravir

Integrase Inhibitors

Raltegravir Dolutegravir Elvitegravir *Raltegravir* Fewer drug-drug interactions than with PIs or NNRTIs - eliminated by Phase II Metabolism MOA: Blocks HIV integrase from inserting viral genome into host cell DNA

Protease Inhibitors: Drug Names

Ritonavir Indinavir Fosamprenavir Nelfinavir Saquinavir

Protein Inhibitors: Advantages of boosted PIs

Ritonavir boosting - Significantly improves bioavailability - More predictable efficacy - better compliance; less complex regimens and low pill burden - NOTE: while on ritonavir (HIV PI), it is primarily used in clinical practice as a *clinical enhancer* for other PIs. Frequently in combination with: Atazanavir, Fosamprenavir, Lopinavir, Darunavir

Protease Inhibitors: Class characteristics

Ritonavir, Indinavir, Fosamprenavir, Nelfinavir, Saquinavir, Darunavir, Atazanavir, Lopinavir/RTV *Prevent* Immature virions from becoming *mature*, infectious viruses

Protease Inhibitors: Tolerability and Toxicity of PIs

Tolerability: - *Gastrointestinal* (diarrhea, nausea, vomiting) Toxicity: *Hepatotoxicity* complications - *Lipodystrophy* (body fat redistribution): Fat accumulation in waist, between shoulders, and around neck, and in some cases Lipoatrophy (fat loss). - *Hyperlipidemia*: elevated cholesterol, low-density lipoprotein, and triglycerides - *Insulin Resistance*

Protein Inhibitors: PK enhancement (boosting) of protease Inhibitors

Trying to alter metabolism in order for other drug to work. Example: Using Ritonavir to "destroy" the GI tract and inhibit P450 so that Lopinavir (PI) can be much more effective. *plasma trough concentration is the critical PK parameter for PIs and NNRTIs

Nucleoside Analogs: Adverse Effects

Zidovudine: BMD(Bone marrow density?) & Lipoatrophy Lamivudine: *minimal toxicity* Abacavir: rash, hypersensitive and HLAB57A screening! Emtricitabine: *minimal toxicity* Tenofovir: Renal toxicity and osteoporosis *ENTIRE CLASS IS BLACK BOXED FOR LACTIC ACIDOSIS WITH HEPATIC STEATOSIS*