HIV Infection Staging

G: HIV Wednesday, October 16, 2024 11:27 PM Abbreviations: • 3TC – lamivudine • ABC – abacavir • ATV – atazanavir • DRV – darunavir • DTG – dolutegravir • EFV – efavirenz • EVG – elvitegravir • FTC – emtricitabine • RAL – raltegravir • RPV – rilpivirine • LPV – lopinavir • CAB – cabotegravir • RTV – ritonavir • TAF – tenofovir alafenamide • TDF – tenofovir disoproxil • TFV – tenofovir • OCT – organic cation transporter HIV Infection Staging • Defined by CD4+ T-lymphocyte count or CD4+ T-lymphocyte percentage of total lymphocytes ○ If no CD4+ count, can also be defined by AIDS-defining conditions • INSTI – integrase strand transfer inhibitor (mainstay therapy) ○ MOA: bind to viral integrase + DNA complex inhibiting viral DNA integration into host chromosomal DNA (prevents HIV DNA from incorporating into host genome) ▪ Pathophysiology Step 4 (integration) ○ Side effects ▪ Mild-moderate rash ▪ Dizziness, nausea ▪ HA Adult Dosing for HIV Side Effects Isentress Brand Raltegravir Generic RAL Abbreviation 400 mg PO BID **double dose if coadministered w/ rifampin • • • • • GI HA/fatigue Sweating Rash ↑ CK (risk myositis, rhabdomyolysis) Viteka Elvitegravir + cobicistat EVG/COBI 150/150 mg PO QD WITH FOOD • • • • • Nausea Diarrhea Depression + suicidal ideation (rare) Requires boosting with COBI Many DDIs Stribild * Elvitegravir + cobicistat + TDF + emtricitabine EVG/COBI/TDF/FTC Tivicay Dolutegravir • HIGH BARRIER TO RESISTANCE DTG • 50 mg PO QD • W/ rifampin, EFV, CYP3A4 inducer • 50 mg PO BID • • • • • • Insomnia HA Hyperglycemia HSR SCr elevations May be teratogenic • But per updates: ○ "Preferred drug for pregnant women, irrespective of trimester and alternative drug for women who are trying to conceive" Triumeq * Dolutegravir + abacavir + lamivudine DTG/ABC/3TC Genvoya * Elvitegravir + cobicistat + TAF + emtricitabine EVG/COBI/TAF/FTC Juluca * Dolutegravir + rilpivirine DTG/RPV Biktarvy * Bictegravir + TAF + emtricitabine • HIGH BARRIER TO RESISTANCE BIC/TAF/FTC 50/25/200 mg PO QD • N/D • HA • DDI: • Rifampin • Dofetilide Dovato * Dolutegravir + lamivudine DTG/3TC Cabenuva (LAinjectable) Cabotegravir + rilpivirine CAB-LA/RPV Administered ONLY by health care provider • 30 mg PO QD with meal x 4 weeks ○ Given with RPV (rilpivirine) 25 mg PO QD ○ May also be for PPX • • • • • • • ○ Nausea HA Abnormal dreams Anxiety Depressive disorders Hepatotoxicity Injection site reactions w/ IM formulations ○ * = single tablet regimens • PI – protease inhibitor ○ MOA: competitive inhibitors that directly bind to HIV protease preventing cleavage of polypeptides by Gag-pol (inhibits maturation of virions) ▪ Pathophysiology Step 6 (budding) ○ ○ Side effects ▪ DDIs (inhibitors of CYP3A4) ▪ ↑ lipids ▪ ↓ insulin sensitivity → ↑ glucose ▪ Lipodystrophy ▪ Hypertriglyceridemia Often CO-ADMNISTERED w/ CYP3A4 inhibitor or boosting agent to ↑ exposure of 3A4 substrates Brand Norvir Generic Ritonavir Abbreviation Adult Dosing for HIV Side Effects RTV • • • • • • RTV NOT USED for ARV activity • If co-administered w/ rifampin – double dose • COBI (Tybost) – analog w/ no ARV activity ○ Take with food GI HA/fatigue Sweating Rash ↑ CK DDI • AVOID pregnancy (2nd + 3rd trimester) • AVOID statins ○ Kaletra Ritonavir + lopinavir RTV/LPV Reyataz Atazanavir ATV Prezista Darunavir DRV Evotaz Atazanavir + cobicistat ATV/COBI Prezcobix Darunavir + cobicistat • ↑ tbili/jaundice - "banana-vir" • Hepatotoxicity • PR prolongation • Cholethiasis/nephrolithiasis Given w/ RTV (ATV/RTV) Hepatically dosed Dose adjust w/ EFV • N/V/D • Rash, SJS/TEN • Hepatotoxicity • ↑ LFTs • HA • Hyperglycemia DRV/COBI ↑ SCr 800/150 mg PO QD 600/100 mg PO BID • NNRTI – non-nucleoside reverse transcriptase inhibitor ○ MOA: non-competitively binds to HIV-1 RT in hydrophobic binding pocket inhibiting reverse transcription of viral DNA ○ Side effects ▪ Hepatotoxicity = ↑ LFTs ▪ Rash SJS/TEN ○ Low genetic barrier to resistance – single point mutation can cause high-level cross-resistance Brand ○ Abbreviation Adult Dosing for HIV Side Effects Sustiva Efavirenz Generic EFV QHS on EMPTY STOMACH • Psychosis (associated w/ vivid dreams & nightmares initially or if taken w/ high fat meal) • Can worsen psychiatric conditions • False + for THC • Preg Cat D – neural tube defects • Teratogenic Atripla * EFV + emtricitabine + TDF EFV/FTC/TDF Edurant Rilpivirine RPV FULL MEAL > 500 kcal • Depressive disorders • Mood changes • Insomnia • ↑risk of virologic failure if initial CD4+ < 200 or VL > 100K Complera Rilpivirine + emtricitabine + TDF * RPV/FTC/TDF Odefsey * Rilpivirine + emtricitabine + TAF RPV/FTC/TAF Pilfetro Doravirine DOR Delstrigo * Doravirine + lamivudine + TDF DOR/3TC/TDF ○ * = single tablet regimens "ACOD" • NRTI – nucleoside reverse transcriptase inhibitor ○ MOA: Premature termination of DNA elongation during reverse transcription inhibiting transcription of viral DNA ▪ Pathophysiology Step 3 (reverse transcription) Brand ○ Generic Abbreviation Adult Dosing for HIV Side Effects ↑ peripheral neuropathy Epivir Lamivudine 3TC Renally dosed Ziagen Abacavir ABC Hepatically dosed Hypersensitivity reaction (HSR): • Fever, SOB, rash, fatigue, GI upset, CVD Risks HLA-B*5701 genetic testing required • Need to negative to use drug Epzicom Abacavir/Lamivudine ABC/3TC Viread Tenofovir disoproxil fumarate TDF Renally dosed • Renal toxicity • Renal tubulopathy (Fanconi Syndrome) • Osteomalacia (↓ bone mineral density) Emtriva Emtricitabine FTC 200 mg PO QD DO NOT combine w/ lamivudine Truvada TDF/Emtricitabine TDF/FTC Vemlidy Tenofovir alafenamide TAF • Prodrug w/ 91% less circulating plasma TFV 25 mg PO QD • Similar to TDF w/ significant reduced risk • Mild-moderate ↑ lipid levels Descovy TAF/Emtricitabine TAF/FTC • Fusion/Entry Inhibitors Brand Generic Abbreviation Adult Dosing for HIV Side Effects Selzentry Maraviroc MVC CCR5/CXCR4 tropism testing REQUIRED • • • • • Fuzeon Enfuviritide T20 SQ • Local injection site rxns Rukobia Fostemsavir FTR PO • QTc prolongation • DDR • Strong CYP450, 3A4 inducers Trogarzo Ibalizumab-uiyk IBA IV • IRIS • Infusion related rxns ○ URTIs Hepatotoxicity Eosinophilia, fever/fatigue/HA Cough, vertigo Abdominal pain Guidelines: • US Department of Health and Human Services (DHHS) ○ Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (September 2024) • World Health Organization (WHO) ○ Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring (July 2021) Pathophysiology: Steps 1. Adsorption = attachment of HIV particles in bloodstream to immune cell a. NO drugs are available to inhibit this step 2. Penetration across cell membrane + uncoating a. CD4, macrophages, dendritic cells infected b. Drugs that inhibit this step i. Entry inhibitors/fusion inhibitor • Enfuvirtide • Fostemsavir ii. CCR5 (chemokine) antagonist • Maraviroc 3. Reverse transcription of RNA → DNA by viral reverse transcriptase enzyme a. Poor fidelity contributes to mutation b. Drugs that inhibit this step i. NRTIs ii. NNRTIs ["nucs" and "non-nucs"] 4. Integration of retroviral DNA into host chromosome by viral integrase enzyme a. Viral DNA may then remain dormant (latent infection) b. Drugs that inhibit this step i. Integrase inhibitors (INSTIs) 5. Transcription and translation by host enzymes in activated cells a. No drugs available to prevent 6. Assembly of immature virions + budding + maturation by viral protease enzyme a. Drugs that inhibit this step i. Protease inhibitors (PIs) HIV Diagnosis • 4th Generation HIV Test – HIV Antigen/Antibody Combination Immunoassay ○ HIV-1 (more common than HIV-2) ○ Patient must be informed before testing and can opt out Treatment • Goals of therapy ○ Viral load < 50 copies/mL (undetectable levels) ○ Target CD4+ count > 500 cells/µL (↑ 50 every 3 months) ○ ↓ morbidity + mortality ○ Improve QOL ○ Prevent further transmission • Overview ○ Initiate early tx appropriate ART ASAP regardless of CD4+ count ▪ 4 weeks after initiation of ART • Expect ↓ viral load by 10-fold • Goal: "undetectable" viral load (< 50) ▪ 3 months after initiation of ART • Expect ↑ CD4+ count by 50 cells/µL • Goal: CD4+ count range 500-1000 cells/µL • Constructing ART Regimen ○ NRTI + NRTI + Active ARV non-NRTI agent ± "booster" • What ART to start ○ • Switching Regimens (not recommended if patient is stable) ○ Confirmation ○ PMH ○ Analysis ○ Evaluate ○ Consultation ○ Initiate • ARV Drugs that: Must be given w/ Have sulfa-Moiety Prolong PR interval boosting agent ○ • PIs • ATV • DRV • LPV • TPV • SQV • INSTIs • EVG • PIs • DRV • TPV • FPV • PIs • ATV • SQV • Monitoring ○ Timely labs to assess efficacy and safety (baseline VL and CD4+) ○ AEs from therapy ○ DDIs ○ Adherence ○ Mental health Presence of Co-Infection(s) Co-Infection Considerations Rationale/Comments • HBV • Biktarvy • Use TDF or TAF w/ FTC or 3TC • TDF + FTC (Truvada) • TDF + 3TC • TAF + FTC (Descovy) • TAF + 3TC • If TDF and TAF contraindicated: • FTC or 3TC w/ entecavir and a suppressive ART regimen • TDF, TAF, FTC, and 3TC = active against BOTH HIV and HBV • D/cing can cause serious HBV reactivation sx HCV • ART may slow progression of liver dx by preserving or restoring immune fxn • For most patients with HCV/HIV coinfection, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. • Therefore, ART should be initiated in all patients with HCV/HIV coinfection, regardless of CD4 T lymphocyte cell count • Selected with special consideration for potential DDIs and overlapping toxicities • Monitor for DDIs/AEs/SEs TB • Recommended regimens may require dose adjustment when treating TB disease with rifamycin antibiotics (rifabutin, rifampin, and rifapentine). • Any ART regimen can be used when isoniazid alone is used for LTBI treatment • Rifamycin abx are inducers of CYP3A4 and UGT1A1 enzymes • significant ↓ concentrations of PIs, INSTIs, and RPV Prophylaxis for Opportunistic Infections ART Resistance • • Genetic Barrier by Class ▪ INSTIs High (DTG, BIC highest) PIs High NRTIs Moderate/variable NNRTIs Low Entry/Attachment Inhibitors T20 = Low MVC & IBA = uncertain/assays under development DDIs • Absorption Medication DDI Management ATV (atazanavir) + acid-reducing agents (PPIs, antacids, H2RAs) • ATV AUC ↓ • ATV requires acidic pH for absorption ▪ • Separate doses • Limit dose • Do not co-administer unboosted ATV w/ PPI RPV (rilpivirine) + acid-reducing agents • RPV AUC ↓ + Cmin ↓ • Separate doses • RPV requires acidic pH for absorption • C/I with RPV INSTIs + polyvalent cations (Al2+, Ca2+, Mg2+, Fe3+) • Chelation • Separate doses (time depends on INSTI) • Do not co-administer use alternative acid-reducing agents • Elimination Medication ▪ DDI Management COBI + statins Inhibits active tubular secretion of creatinine Initiation: SCR increases by 10-20% within 1-2 weeks and plateau (may stay elevated) Monitor SCr DTG + BCT Metformin is eliminated through OCT2 and MATE-1. Initiation: SCR increases by 10-20% within 1-2 weeks and plateau (may stay elevated) Monitor SCr Start metformin at lowest dose titrate based on glycemic control Dofetilide is eliminated through OCT2 and MATE-1 Dofetilide C/I with dolutegravir and bictegravir Inhibit OCT2 and MATE-1 and inhibit active tubular secretion of creatinine. • Always monitor for DDIs in HIV patients • MTM opportunity • Avoid changes to suppressive ART regimen whenever possible Vaccination Schedule for Adult Patients with HIV Pre-Exposure Prophylaxis (PrEP)P • Daily Oral PrEP Use ▪ Truvada ≤ 90 day supply or ▪ Men + transgender women = Descovy ≤ 90 day supply ▪ Clinically eligible if: ▪ Documented HIV Ag/Ab negative within 1 week before initially prescribing PrEP ▪ No s/sx of acute HIV infection ▪ Estimated CrCl ≥ 30 mL/min ▪ No contraindicated medications • Cabotegravir Injection PrEP Use ▪ 600 mg cabotegravir as 3 mL IM in gluteal muscle Post-Exposure Prophylaxis (PEP) • Health-care personnel (HCP) who have occupational exposure to blood and/or other body fluids that might contain HIV (e.g., needlesticks) • Possibly recommended only if ≤ 72 hours since exposure • If appropriate, tx should be started ASAP (b/w 1- 72 hours) ▪ Truvada + RAL PO QD x 28 days (alternative available) ▪ HIV testing immediately, and at 4-6 weeks, and 3 months post-exposure California Rules • CA SB-159 ▪ Allows California Pharmacists to: ▪ Furnish PrEP and PEP without a physician’s prescription ▪ Furnish at least a 30-day supply, and up to a 60-day supply, of pre-exposure prophylaxis ▪ Furnish a complete course of post-exposure prophylaxis, 28-day supply • Requires referral for ongoing care for pre-exposure prophylaxis and follow up care for post-exposure prophylaxis. • CA SB-339 ▪ Authorize a California Pharmacists to ▪ Furnish up to a 90-day course of preexposure prophylaxis, or preexposure prophylaxis beyond a 90-day course, if specified conditions are met.