Antiretroviral drugs
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Antiretroviral drugs are used to manage HIV infection. There are several classes of antiretroviral drugs that work by inhibiting different stages of the HIV lifecycle, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry inhibitors. The goals of antiretroviral therapy are to suppress viral replication, restore and preserve immune function, prolong the lifespan of the patient, and improve their quality of life. National and international guidelines recommend combinations of at least three antiretroviral drugs from different classes for long-term HIV treatment.
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Antiretroviral drugs
- 2. Learning objectives • Enumerate the drugs used in management of HIV infection & their MOA • Describe the drug interactions and adverse effects related to antiretroviral drug • Enumerate the drug regimen used in HIV infection & HIV in pregnancy • Describe the drugs used for post exposur prophylaxis
- 3. What is retrovirus • RNA virus • Have enzyme RT • Inserts copy of its genome -host cell • Changing the genome of that cell • HIV virus, HTLV-1& 2
- 4. Structure of HIVvirus • Icosahedral enveloped • Family – Retrovirus • Subfamily – Lentivirus • Two single stranded RNA • RT - Transcribe RNA to DNA
- 6. • Outer envelope – lipid matrix – gp • gp -120 recognition of target cell –CD4 cells • Gp 41 – fusion to host cell memb • Confirmational changes – CCR4, CXCR4 • Bind to chemokine R– macr& Th lympho • Core capsid – P24 &P7
- 7. • HIV RNA 3 structural genes • Gag gene – group specific ag – p24, 7, 17 • Env gene – envelope – gp 120, 41 • Pol gene- polymerase – p66, 51 –RT, P31-EN
- 9. Drug used in ART
- 10. Classification Nucleoside Reverse Transcriptase Inhibitors( NRTIs)- Zidovudine, Stavudine, Lamivudine, Abacavir, Zalcitabine, Emtricitabine, Didanosine, Tenofovir Non-nucleoside Reverse Transcriptase Inhibitors( NNRTIs)- Efavirenz, Nevirapine, Delavirdine, Etravirine, Rilpivirine
- 11. Protease inhibitors(PI)- Saquinavir, Indinavir, Nelfinavir, Amprenavir, Fosamprenavir, Ritonavir, Lopinavir, Atazanavir, Tipranavir, Darunavir Entry/ fusion inhibitors- Enfuvirtide CCR5 inhibitors- Maraviroc Integrase inhibitors- Raltegravir, Elvitegravir
- 13. NRTI • MOA: • Activated by triple phosphorylation in cytoplasm except tenofovir • Inhibits HIV RT enzyme • Incorporated to growing viral DNA – premature termination of chain
- 15. • USES: as part of multidrug therapy in HAART • ADR- fatal lactic acidosis - severe hepatomegaly & steatosis BM toxicity Lipodystrophy Perp neuritis -
- 16. Drug PK ADR USES DOSAGE Zidovudine First drug OB-60-65% T1/2 -1-3hrs Met liver – CYP450 Exc – kidney CNS-more pen Cross placental Barrier Myelosuppresion Myopathy, CMP Fattyliver, LA, Tremor, anxiety HIV 1&2, HTLV1&2 PEP in HCW Neotatal inf Prevent perinatal transmission 200mg tds 300mgBD Didanosine Second drug Empty stomach –best absorbed Met liver – CYP450 Exc - kidney painful sensory peripheral neuropathy-30% High doses – pancreatitis-10% hypertriglyceridem ia, asymmetric hyperuricemia, retinal changes and optic neuritis in high doses Resistant to zdv >60 200mg BD <60 kg 125mg BD
- 17. DRUG PK ADR USES/DI DOSE zalcitabine Rarely used OB- 80% Met liver – CYP450 Exc - kidney peripheral neuropathy, pancreatitis, oral & oesophageal ulcerations, headache , rash & arthralgia Avoide in pts with neuropathy or pancreatitis 0.75 mg tds Stavudine Fourth drug Met liver – CYP450 Exc -kid peripheral neuropathy, LA, hepatic steatosis ZDV +STAV not to be used together lipodystrophy synd wt>60kg 40mg bd: wt<60kg 30mg bd Lamivudine Least toxic Low toxicity - low affinity to human DNA polymerase Cross placenta headache,dizzi ness, insomnia, fatigue & GI discomfort Excellent synergy with other drugs HBV 150mg BD or 300mg OD
- 18. DRUG PK ADR USES/ CI DOSAGE Emtricitabine Flourinated analog of lamivudine Longer t1/2 Met liver – CYP450 High BA headache, N,D, hyperpigmenta tion of palms and soles hepatotoxicity & pancreatitis CI in young children, pregnancy, renal and hepatic failure 200mg OD Abacavir Resistance develops slowly Met by alcohol dehydrgenase HST reactions N, V,D- 300mg bd Tenofovir Met liver – CYP450 Enzyme inducer N,V,D, ARF and Fanconi syndrome C.I. Renal failure 300mg od ,taken with food
- 19. NNRTI No phosphorylation required Inhibit RT directly No activity against HIV 2 Cross resistance - other NNRTI not-NRTI,PI Skin rash, GI intolerance Drug interactions- inducers & inhibitors
- 21. DRUG PK ADR USES/DI DOSE Nevirapine Resistance develop rapidly Well abs orally Cross placenta Sec in br milk mp rash, rarely SJS and TEN hepatitis Enzyme inducer- OCPs, PIs, antifungals RFM – reduces conc of NVP Perinatal transmission prevention 200mg bd Efavirenz Long t1/2 Empty stomach Highly protei bound N,V,D, skin rash Dizziness, insomnia, headcahe, confusion, inc liver enzymes, crystalluria Teratogenic – NT defect Enzyme inducer- OCPs, PIs, antifungals 600mg od
- 22. Ertavirine • Dosage 200mg bd taken after meal • S/e – rash, nausea, diarrhoea, increased cholesterol, glucose and TGL, abn LFTs • No cross resistance • Active against NNRTI resistance strains
- 23. Rilpivirine • Dosage-25mg od • S/e- similar to EFV but very milder • No cross resistance with NNRTI • But shares cross resistance with Etravirine • Active against NNRTI resistance strains and better tolerated than Etravirine
- 24. Protease inhibitor protease enz - conversion of immature PP proteins - mature proteins of virion core active against both HIV 1&2 Well abs –orally, met liv, renal exc ADR -GI symptoms Metabolic disturbances- hyperglycemia, hypercholestrelemis, Buffalo hump, fat in abdomen, insulin resistance
- 25. DI • Enzyme inhibitor – increase toxicity of warfarin, atorvastatin, antiepileptics • RFM – inducer - reduces level of PI • Ritonavir, Amprenavir & Tipranavir both inducer & inhibitor
- 26. DRUG PK, USES/DI ADR Saquinavir Enzyme inhibition least Git , lipodystrophy Ritonavir 100mg BD Potent enzyme inhibitor Pk enhancer Boosted therapy RFM Circumoral parasthesia lipodystrophy Indinavir Rapid oral absorption –on empty stomach 2l/day H2O reduces crystalluria Atazanavir Excellent penetration in seminal fluid Metabolic syndrome least likely Lopinavir Fatty meal inc oral absorption Extensive first pass metabolism – subtherapeutic conc RTV blocks 1st pass met N,v,d Inc Cho, Nelfinavir Not given with RTV – both enz inducer Teratogenic Inc cho, TGL Glu intolerance
- 27. Entry /fusion inhibitors • Enfuvirtide –gp41 blocker • Active HIV-1only • Used parentrally 90mgsc bd • T1/2 -4hrs • Used in failure of therapy • S/E- injection site reactions lymphadenopathy, pneumonia
- 28. CCR5 receptor inhibitor • Maraviroc • Entry inhibitor • High conc in cervicovaginal secretions • Resistance do not occur readily • Uses – failure to other anti-HIV drugs • Vicriviroc
- 29. Integrase ihibitor • Raltegravir -Active against HIV 1&2 • Inhibits integrase – no replication • Rifampicin not to be used • Resitance not yet reported • Myopathy & rhabdomyolysis • Elvitegravir
- 30. Drug treatment of AIDS
- 31. General principles • To prevent viral replication – prevent CD4 depletion – maintain immunity • Multiple drugs • Treat AIDS associted opportunistic infection – MAC, CMV retinitis ,fungal • NACO guidelines / Low cost generic drugs • FDC easy to use • Drugs prescribed –associated disease Hep B, TB
- 32. Goal of therapy • To decrease virus replication • To restore, preserve immunological function • To prolong life span of patient • To improve quality of life of patient
- 33. NACO & WHO guidelines Decision to start therapy – individualised depending on CD4 count plasma HIV -1 RNA >1,00,000 start therapy Selection of drugs – HAART – 3-4 drugs used Careful selection of drug combination Response is optimum – HIVRNA <50 copies -6m Lifelong treatment
- 35. HAART • Firstline ART – 2NRTI+1NNRTI LAM +ZDV/TDF+NVP/EFZ • Second line drug- bPI + 2NRTI ATZ or SAQ or LOP/r + ten + aba
- 36. Failure of therapy • No satisfactory response or improvement – CD4 / HIV RNA assay • Clinical, immunological, virological • Resistance/ ADR/poor compliance • Pts condition deteriorates • Severe opportunistic infection • Change drug or regimen
- 37. AIDS in Pregnancy • Guidelines are similar / Avoid efavirenz • Mother to child transmission prevention: Start ZDV – 2nd trimester till labour - Neonate 6 weeks prophylaxis Single dose 200mg NVP to mother at the onset of labour -single dose2mg/kg to neonate within 72 hrs of delivery
- 39. Summary
- 40. Thank you….
- 41. Questions • Drug causing BM suppression • Resistance to zido • Integrase inhibitors • HIV/HBV – Dual activity • Inhibit post translational modification • Metabolic synd not produced by PI • Fusion inh acts at what site • Boosting effect
Editor's Notes
- Cd4 –macrophages,monocytes, thelper, microglial,dendritic, langerhan cwklk
- women, obese persons & alcoholics are more prone - drug should be withdrawn if toxicity occurs