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  1. Anti Retroviral Therapy Presenter : Dr.LakshmiPrasad L, PG-Y1 Moderator : Dr.Brinda G David, Prof. DVL
  2. Classification
  3. NRTI
  4. Name Composi tion Dose Elimination Adverse effects Zidovudine (AZT) azidothy midine 300 mg BD Glucuronidation and Renal elimination(Tubula r secretion) Anemia, neutropenia, bone marrow suppression, GI intolerance, headache, insomnia, myopathy, lactic acidosis, skin and nail hyperpigmentation Lamivudin e (3TC) synthetic cytidine analog 150 mg BD, or 300 mg OD predominantly (70%) cleared unchanged in the urine Headache, fatigue, rashes nausea, anorexia, abdominal pain Tenofovir Disoproxil Fumarate (TDF) Nucleoti de 300 mg OD Renal (renal failure with a Fanconi’s- type proximal tubulopathy) Bone demineralization, nausea, flatulence, abdominal discomfort, loose motions and headache
  5. Emtricitabine (ETC) Fluorinated analog of lamivudine Capsule (200 mg) predominantly (70%) cleared unchanged in the urine Diarrhea, rash, insomnia, Neuritis, paresthesia, myalgia and rarely LA Abacavir (ABC) Carbocyclic nucleoside 300 mg BD or 600 mg OD hepatic glucuronidation and carboxylation Hypersensitivity reaction (HSR), predominantly in patients carrying the HLAB*5701 allele. Lipodystrophy is least likely
  6. Mitochondrial toxicity • All NRTIs inhibit cellular DNA polymerases including DNA polymerase- beta and mitochondrial DNA polymerase- gamma. • Accumulation of ROS, decreased tissue oxidative respiration, and increase in anaerobic respiration, resulting in increased production of lactic acid as a byproduct • C/F :Hepatic steatosis, lactic acidosis, myopathy, peripheral neuropathy, pancreatitis and loss of peripheral adipose tissue (lipoatrophy) • Discontinuation with supportive management of acidosis and end- organ dysfunction
  7. Lipoatrophy • Progressive loss of subcutaneous adipose tissue, approximately 6 months after initiation • maintenance of muscle mass and stable or increasing visceral adiposity • associated with dyslipidemia, T2DM • thymidine analog NRTI zidovudine and stavudine • Discontinuation or substitution
  8. NNRTI
  9. Name Compositi on Dose Elimination Adverse effects Efavirenz (EFV) Benzoxazin e derivative 600 mg OD on empty stomach Hepatic elimination (CYP2B6 > CYP3A4) metabolism rash – common, often mild CNS (insomnia, dizziness and vivid dreams to frank psychosis and depression), first 2 weeks after initiation. Teratogenic Nevirapin e (NVP) Dipyridodi azepinone initially 200 mg daily, raising to 400 mg daily after 2 weeks of therapy Hepatic elimination (CYP3A4 >CYP2B6) metabolism Rash is common, rarely SJS Hypersensitivity reaction and hepatotoxicity(higher CD4+ T- cell counts)
  10. Etravirine (ETV) Di aryl pyrimidine 200 mg twice daily CYP450 metabolism, >80% eliminated unchanged in the feces Rash, Nausea, GI disorders, Peripheral neuropathy, rarely – SJS & EM
  11. DRUG–DRUG INTERACTIONS WITH NNRTIS • Methadone replacement therapy - opiate addiction • Methadone metabolism is increased when co administered with efavirenz or nevirapine • methadone withdrawal, methadone toxicity. • buprenorphine, an alternative opiate substitute, are also reduced • Rifampicin, a potent inducer of the CYP450 enzyme system • Decrease the conc. of efavirenz • Recommending an increase in the does of efavirenz from 600 mg daily to 800 mg daily in patients weighing over 60 kg when co administered with rifampicin • nevirapine with rifampicin- increased rates of virological failures
  12. Protease Inhibitors
  13. Name Composition Dose Elimination Adverse effects Ritonavir (RTV) Powerful inhibitor of the CYP3A4 isozyme L-Valinamide derivative 100 mg once or twice daily according to the PI to be boosted Primarily by Cytochrome P450 3A isozymes & to a lesser extent by CYP2D6 Common: GI (diarrhea, nausea, vomiting, abdominal pain; Rarely, neurological disturbances (including paresthesia), dyslipdemia Darunavir (DRV) Darunavir ethanolate 600 mg twice a day (when used with Ritonavir 100 mg twice daily) Hepatic metabolism through CYP3A4 with approx. 7% of the drug eliminated through the kidney Hepatotoxicity, skin rash (10%)( sulfonamide moiety), diarrhea, nausea, headache, hyperlipidemia, serum transaminase elevation, hyperglycemia
  14. Lopinavir/ ritonavir (LPV/r) Heat- stable tablets Dicarboxylic acid diamide 200 mg Lopinavir/ 50 mg Ritonavir Fixed dose tablet 2 tablets twice daily Hepatic metabolism via CYP3A4 with renal elimination Diarrhea, nausea, vomiting, abnormal lipid profiles, glucose intolerance Atazanavir (ATV) / ritonavir (ATV/R) Atazanavir sulfate (dipeptide analogue) 300 mg daily with 100 mg ritonavir / 400 mg without ritonavir via CYP3A4 and is also a potent inducer of P-gp in the enteric lumen Unconjugated hyperbilirubinemia, lipid abnormality, hyperglycemia, fat maldistribution, nephrolithiasis, cholelithiasis, PR prolongation
  15. Other • Indinavir -tolerability issues and heavy pill burden CYP3A4 system and is dosed at 800 mg twice daily with ritonavir boosting. Principal toxicities - renal dysfunction secondary to crystalopathy, (crystalluria, nephrolithiasis, and renal angle pain) Hydration of 150 ml/ hr • Nelfinavir is another PI that is no longer recommended- lack of potency and intolerance (diarrhea)
  16. Dyslipidemia • high total, LDL, TGL and decreased HDL cholesterol. • More with LPV/r • Associated with increased insulin resistance and diabetes. • partially reversible upon switching away from PIs • Use of lipid lowering agents has limited benefit.
  17. Cardiovascular disease and Myocardial infarction • Indinavir and LPV/r • risk persisted after correction for dyslipidemia • dyslipidemia induced by antiretroviral exposure is thought to play a role • Also seen in Abacavir (inflammation and platelet dysfunction giving rise to prothrombotic states)
  18. Entry inhibitors
  19. Maraviroc (MVC) • Allosteric reversible inhibitor of the CCR5 co-receptor. • 150 mg and 300 mg tablet with variable dosing • Metabolized by CYP3A4 with P-gp transportation in addition to significant renal elimination(25%) • No cross resistance with other classes • Virologic failure may be related to emergence of CXCR4 tropic virus or resistant mutations within CCR5-tropic virus(V3 loop)
  20. Enfuvirtide (T-20) • Large peptide comprised of 36 amino acids, • Inhibits fusion by binding to gp41 • subcutaneous injection dosed at 90 mg twice daily • Poor CNS penetration • Resistance can rapidly develop, No cross resistance with other classes • The major treatment limiting side effect is injection site reactions
  21. Ibalizumab (IBA) • IgG4 humanized Mab, Under phase 3 study • Binds epitope in domain 2 of CD4 • IV infusion (150mg/ml) or SC inj • single-loading dose infusion of IBA 2,000 mg over 30 min followed by a maintenance dose of IBA 800 mg IV over 15 min every 2 weeks. • AE : More common: Rash, diarrhoea, headache, nausea, dizziness, depression ; Less common (more severe): Immune reconstitution inflammatory syndrome (IRIS), hypersensitivity reaction
  22. Integrase inhibitors
  23. Raltegravir (RAL) persistent intracellular inhibition of HIV integrase - “post-antibiotic” effect” 400 mg twice daily Metabolized via UGT1A1-mediated glucuronidation myopathy is a potential toxicity, Stevens-Johnson’s syndrome, Toxic Epidermal Necrolysis Dolutegravir (DTG) currently the preferred drug in the first-line and also in second-line treatment regimens 50 mg once daily primarily by UDP- glucuronosyltransferas e (UGT) 1A1 and cytochrome P450 (CYP) 3A4 Insomnia, Headache, Dizziness, Tiredness, Allergic reactions, Weight gain Elvitegravir (EVG) (modified quinolone antibiotic structure) Selectively inhibits strand transfer reaction by binding to Magnesium cations 80mg OD or 150mg OD metabolized via CYP3A4 Combined with cobicistat, tenofovir, and emtricitabine to produce a four-drug FDC—the “Quad” pill
  24. Newer drugs
  25. Cobicistat • Selective inhibitor of CYP3A4 • pharmacological enhancer of PI and Elvitegravir • Help replace ritonavir especially in HAART • Adv : Lack of antiviral activity and decreased dyslipidemia • Highly water soluble • Mild increase in serum creatinine with unchanged creatinine clearance
  26. Rilpivirine (RPV) • second-line NNRTI (Phase III trials) • Strong binding properties and conformational flexibility • Metabolism : CYP3A4 enzyme activity and is slowly metabolized in human hepatocytes through glutathione-dependent conjugative metabolism • oral bioavailability is significantly increased with food • The two phase III clinical trials, ECHO and THRIVE, compared rilpivirine with efavirenz when used with a NRTI backbone = non- inferior virological efficacy with rilpivirine
  27. Goals of ART
  28. Indications for ART Clinical Category CD4+ cell count Plasma HIV RNA Recommendations AIDS defining illness or severe symptoms Any value Any value Start HAART Asymptomatic CD4+ <200 cells/mm3 Any value Start HAART Asymptomatic CD4+ 200-350 cells/mm3 Any value Offer HAART Asymptomatic CD4+ >350 cells/mm3 >100,000 Some experts recommend starting HAART Asymptomatic CD4+ >350 cells/mm3 <100,000 Defer HAART
  29. Evaluation before initiating • Complete history and physical examination • Ophthalmological examination • CBC, blood glucose and lipid profile • CD4+ cell count • Plasma HIV RNA measurement • Other : VDRL, Mantoux test, Toxoplasma IgG serology, CXR
  30. 1st line (NACO) • Triple drug combination from two different classes of ARVs. • NRTI backbone, preferably Non-Thymidine (Tenofovir plus Lamivudine) and one INSTI, preferably DTG. • The preferred first-line ART regimen for all PLHIV with age >10 years and weight >30kg is as follows: • Tenofovir (TDF 300 mg) + Lamivudine (3TC 300 mg) + DOLUTEGRAVIR (DTG 50 mg) regimen (TLD) as FDC in a single pill once a day (at a fixed time every day as per patient’s convenience)
  31. Monitoring of therapy
  32. Antiretroviral drug combinations to be avoided 1.Zidovudine + stavudine: Pharmacodynamic antagonism 2.Stavudine + didanosine: Increased toxicity (neuropathy, lactic acidosis) 3. Lamivudine + didanosine: Clinically not additive
  33. Changing a failing regimen • An ART regimen is considered to have failed when: oPlasma HIV-RNA count is not rendered undetectable (<50 copies/μl) within 6 months therapy. oRepeated detection of virus in plasma after initial suppression to undetectable levels despite continuation of the drug regimen. oClinical deterioration, fall in CD4 cell count, serious opportunistic infection while continuing drug therapy. • Failed regimen should be changed entirely
  34. Some antiretroviral combinations 1. Lamivudine 150 mg + Zidovudine 300 mg tab (1 tab BD); COMBIVIR, CYTOCOM, DUOVIR, LAMUZID tab. 2. Lamivudine 150 mg + Stavudine 30 mg or 40 mg tab (1 tab BD); LAMIVIR-S, LAMOSTAD, VIROLIS tab. 3. Lamivudine 150 mg + Zidovudine 300 mg + Nevirapine 200 mg tab (1 tab BD); DUOVIR-N, CYTOCOM-N,NEXIVIR-Z. 4. Lamivudine 150 mg + Stavudine 30 mg or 40 mg + Nevirapine 200 mg tab (1 tab BD); LAMOSTAD-N, TROMUNE, VIROLANS. 5. Lamivudine 150 mg + Zidovudine 300 mg 2 tab and Efavirenz 600 mg 1 tab kit; CYTOCOM-E kit.
  35. Post-exposure prophylaxis of HIV
  36. • Basic (2 drug) regimen (for low risk) Zidovudine 300 mg + Lamivudine 150 mg = Twice daily for 4 weeks • Expanded (3 drug) regimen (for high risk) Zidovudine 300 mg + Lamivudine 150 mg + (Twice daily) Indinavir 800 mg(or another PI) (Thrice daily) = all for 4 weeks
  37. Perinatal HIV prophylaxis • Highest risk (>2/3rd) of transmission is during the birth process • Current recommendation : all HIV positive women, not on ART, should be put on the standard 3 drug ART, continued through delivery and into the postnatal period. • Zidovudine + Lamivudine + Nevirapine • If not on ART, Zidovudine (300 mg BD) started during 2nd trimester and continued through delivery to postnatal period, with treatment of the neonate for 6 weeks, reduce mother-to-child transmission by 2/3rd. • Breastfeeding is contraindicated
  38. Pre exposure prophylaxis As of January 2019, FDA has approved three medications as PrEP for HIV: 1.Truvada (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg) 1. preferred oral regimen for daily or on-demand dosing. 2.Descovy (tenofovir alafenamide 25 mg/emtricitabine 200 mg) 1. alternative oral regimen used only in daily dosing for cisgender MSM and transgender women. 2. Descovy is not approved for use by cis-gender women and is not for use during pregnancy. 3.Apretude (Long-acting injectable cabotegravir 600 mg) 1. preferred regimen. 2. Apretude is generally not an option during pregnancy. 3. Not all clinical settings are prepared to administer long-acting injectable PrEP.
  39. Thank you

Editor's Notes

  1. Zidovudine Effective in decreasing MTCT of HIV DI : Ganciclovir, Paracetamol, Azoles. Lamivudine (3TC) Anti - HIV 1 & 2, Hep B For chronic hepatitis B—100 mg OD Concentrations are increased in patients with moderate to severe renal impairment. Tenofovir Disoproxil Fumarate Bypasses rate-limiting phosphorylation, hydrolyzed by plasma esterases and metabolized intracellularly to the active triphosphate form. Poor CSF penetration
  2. Emtricitabine (ETC) Longer half-life, once-daily dosing, resulted in its use in fixed-dose combination (FDC) form with TDF (Truvada®) and with TDF and efavirenz (Atripla®). Ineffective in viruses harboring a resistance mutation in the reverse transcriptase gene. Abacavir Increased risk of myocardial infarction in some studies Good CSF penetration
  3. Efavirenz First-line HAART regimes for ARV-naive patients Highly protein bound (approx 99%), the free fraction penetrates the CSF and may resolve without discontinuing. Nevirapine Most commonly used NNRTI in India Induces its own metabolism within the first 2 weeks of therapy and is. DI : Antihistamines, antifungals.
  4. Etravirine FDA approved in January 2008 for treatment-experienced HIV-infected patients. Decreases the Cmin of the protease inhibitor atazanavir, Increases concentrations of the protease inhibitor fosamprenavir.
  5. Ritonavir Require refrigeration Bioavailability - 60–80% and is almost entirely protein bound at 99%. DI : HMG-Co A reductase inhibitors, Fluticasone and PDE inhibitors. Darunavir Approved for use in both antiretroviral naive and treatment-experienced patients Absorption is dependent on P-gp protein transportation across the intestinal lumen and it is highly protein bound (approx 95%).
  6. Atazanavir metabolized inhibits UDP-glucuronyl transferase - ↑ unconjugated bilirubin combination with the NNRTI etravirine is not recommended as atazanavir exposure is signiicantly reduced & vice versa with Nevirapine Poor CSF penetration
  7. Elvitegravir Susceptible to boosting with both ritonavir and cobicistat Dolutegravir Both HIV type 1 & 2 DI : Amodiaquine, Carbamazepine, Phenytoin and phenobarbital, Metformin, Rifampcin