Pharmacotherapy and Drugs used in HIV.pptx

Pharmacotherapy of HIV (2024)

1. DRUGS USED IN HIV INFECTION by DR VISHAL BONDE (JR2)

2. CONTENT Introduction History Microbiology Pathogenesis Diagnosis Classification of drugs & MOA NRTIs NNRTIs Protease Inhibitors Integrase Inhibitors Entry Inhibitors NACO - India ART Summary 2

3. INTRODUCTION HIV is a virus → attacks and weakens immune system (CD4 T cells). No true latency period. Human & non-human primates are only natural hosts. Estimated 39 million PLHIV* globally, in which 1.5 million are children (0-14 yrs ). 630,000 people died from HIV related causes globally. In India, 2.5 million PLHIV, 68000 are children & 40000 deaths. *PLHIV – people Living with HIV 3

4. State Wise Adult Prevalence (%)* 4

5. STATE WISE PLHIV* 5 in lakhs

6. STATE/UT – WISE NO. OF NEW ANNUAL INFECTION* 6 (In thousand) *INDIA ESTIMATES 2022 NATIONAL AIDS CONTROL ORGANISATION | ICMR -NATIONAL INSTITUTE OF MEDICAL STATISTICS HIV [Internet].

7. 1 DECEMBER 7

8. HISTORY 8

9. HISTORY 9 Dr. Françoise Barré- Sinoussi won Nobel prize for discovery of HIV. (2008)

10. HISTORY 10 Dr. Françoise Barré- Sinoussi won Nobel prize for discovery of HIV. (2008)

11. MICROBIOLOGY HIV II – Intrinsic resistance to NNRTIs N, O, P – animal Subtype C – mc India Subtype B – mc US 11

12. MICROBIOLOGY HIV II – Intrinsic resistance to NNRTIs N, O, P – animal Subtype C – mc India Subtype B – mc US 12

13. MICROBIOLOGY 13

14. PATHOGENESIS 14

15. 15

16. 16

17. PATHOGENESIS 17

18. Immune Response P24 ag is most abundant HIV protein. Essential for assembly of HIV capsid. Use to clinical diagnosis early HIV infection. 18

19. Diagnosis Strategy 1 – one test (highly sensitive) – Blood screening Strategy 2 – Dx of symptomatic (2 test) 19

20. Diagnosis (Strategies of testing) Strategy 3 – Dx in asymptomatic patients (3 tests) Results 1 st test 2 nd test 3 rd test Positive + + + Negative + - - Intermediate + + - + - + Confirmed by western blot 20

21. Diagnosis (Monitoring) Viral Load (rate of progression of disease) CD4+ (immune status of patient) CD4 count Repeat at <350 & not on ART 3 months >350 & not on ART 6 months Any value (on ART) 6 months >500 Annual Severity of immunosuppression CD4 count (cells/mm 3 ) Not significant >500 Mild 350-499 Advanced 200-349 Severe <200 21

22. Classification of Drugs 22

23. MOA of drugs 23

24. Entry Inhibitors Reverse Transcriptase Inhibitors 24

25. Integrates Inhibitors Protease Inhibitors 25

26. NRTIs – Nucleoside RT Inhibitors Competitive inhibitors of HIV – I. All are prodrug; get phosphorylated. Common toxicity includes – anemia, granulocytosis , myopathies, peripheral neuropathy, pancreatitis, lactic acidosis, hepatic stenosis. Additional anti – HBV are Emtricitabine, Lamivudine, Tenofovir. Additional anti – herpes are Tenofovir Zidovudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine, Stavudine, Didanosine. 26 No effect on proviral DNA that has already integrated into host chromosome.

27. NRTIs – Zidovudine (AZT) 1 st approved anti – retroviral (1985) – Prototype NRTI. Synthetic thymine analogue. More active in activated cells (S phase) than resting cells. Zidovudine Zidovudine – 5 – triphosphate Phosphorylation prevent elongation of proviral DNA prevent mitochondrial polymerase 𝛾 FDA approved for HIV in adults & children. 300mg BD, 180mg/m 3 27

28. NRTIs – Zidovudine (AZT) High fat meals decrease bioavailability. Metabolism by glucuronidation. ✔️ BBB & Placenta, breast milk, semen. 28

29. NRTIs – Zidovudine (AZT) S/E – Macrocytic anemia & neutropenia fatigue, malaise, myalgia, headache & insomnia. Nail hyperpigmentation (with chronic therapy) Skeletal myopathies Hepatic stenosis & lactic acidosis Resistance to AZT d/t mutations at RT codons such as 41, 44, 67, 70 k/a Thymidine Analogue Mutations (TAMs) 29

30. NRTIs – Zidovudine (AZT) Drug Drug Interactions Probenecid, fluconazole, PCM – may increase AZT concentration (inhibition of glucuronosyl transferase). Stavudine & Zidovudine compete for intracellular phosphorylation – avoid using simultaneously. 30

31. NRTIs – Lamivudine (3TC) Cytidine analogue, active against HIV I, HIV II & chronic HBV . Approved for adult & children >3 months old. (150 mg BD / 300mg OD). Lamivudine Lamivudine – 5 – triphosphate. Low affinity to human DNA polymerase. Excreted in urine. Phosphorylation 31

32. NRTIs – Lamivudine (3TC) S/E – one of the least toxic Neutropenia, headache, nausea pancreatitis Rebound HBV Resistance d/t single amino acid substitution : M184V. 32

33. NRTIs – Abacavir (ABC) Synthetic purine analogue, for HIV I. Approved for adults & children >3 months. Abacavir Carbovir – 5 – triphosphate. Phosphorylation 33

34. NRTIs – Abacavir (ABC) Presence of food doesn't affect oral bioavailability. Neither a substrate nor an inhibitor of CYPs. Use in patients with renal insufficiency. Metabolism by dehydrogenation, glucuronidation. 34

35. NRTIs – Abacavir (ABC) S/E – HSN Reaction with maculopapular rash ( linked to HLA B*5701 & M493T). Respiratory complaints (cough, pharyngitis, dyspnea). Increase aminotransferase & Sr creatinine. Screening before starting Presence of concurrent headache, abdominal pain & rash within 6 weeks – STOP ABC 35

36. NRTIs – Abacavir (ABC) Resistance d/t substitutions of K65R, L74V, Y115F, M184V. K65R – cross resistance to all NRTIs except AZT . 36

37. NRTIs – Tenofovir (TDF) Only nucleotide analogue for HIV infection. Approved for HIV, HBV & preexposure prophylaxis of HIV. TDF approved for adults and children >2 years. 70-80% excreted unchanged in urine. 37

38. NRTIs – Tenofovir (TDF) S/E - Acute renal failure & Fanconi syndrome. Rebound HBV replication. Resistance d/t K65R substitution in RT. Discontinue if new onset proteinuria, GFE <30 mL/min, glycosuria. 38

39. NRTIs – Emtricitabine (FTC) Cytidine analogue, active against HIV I, HIV II, HBV. Approved for PrEP (with tenofovir). Emtricitabine Emtricitabine – 5’ – triphosphate. Excreted primarily unchanged in urine. phosphorylated 39

40. NRTIs – Emtricitabine (FTC) S/E – One of the least toxic drug . Hyperpigmentation of skin of palms & soles. Rebound HBV replication. Resistance d/t – M184I/V. K65R 40

41. NRTIs – Others Stavudine (d4T) & Didanosine ( ddI ) – no longer widely used. 41

42. NNRTIs – NonNucleoside RT Inhibitors Drugs are – N -Nevirapine E - Efavirenz E - Etravirine D - Delavirdine Doravirine R ti - Rilpivirine Non – competitive inhibitor Active drug, Hepatic metabolism Efavirenz, etravirine, nevirapine – inducers Delavirdine – CYP3A4 inhibitor All except etravirine, rilpivirine – high drug resistance Nevirapine, efavirenz, rilpivirine , etravirine – SJS, DRESS. Nevirapine – fatal Hepatitis. Never be used as monotherapy 42

43. NNRTIs – Nevirapine (NVP) Approved for HIV I in adult & children, infant >15 days. Earlier, Single dose 200mg – in pregnant ♀ f/b 2mg/kg to newborn. Meta by CYP 3A4 > CYP 2B6. CYP inducers → own metabolism ∴ initial dose 200mg OD x 14 days f/b 200mg BD 43

44. NNRTIs – Nevirapine (NVP) S/E – Rash (gradually increase dose). SJS & TEN (discontinue if present). Hepatitis. Fever, fatigue, headache. Moderate inducer of CYP3A4 – avoid use with atazanavir, dolutegravir, ketoconazole & rifampin. Alterative birth control methods. 44

45. NNRTIs – Efavirenz (EFV) Approved for adults & children >3 months & wt > 3.5kgs. OD combination with tenofovir / emtricitabine & lamivudine. Safely combined with rifampin Bioavailability increase with fatty meals Meta by CYP 3A4 < CYP 2B6. 45

46. NNRTIs – Efavirenz (EFV) S/E – CNS & psychiatric s/e, congenital abnormalities. Dizziness, impaired concentration, dysphoria, insomnia Rashes, SJS Increase hepatic transaminase, sr. cholesterol Prescribed in >8 weeks of pregnancy. 46

47. NNRTIs – Rilpivirine (RPV) Potent against HIV I, that are resistant to NPV & other NNRTIs. Dose is 25mg/day Approved for adults and children >12 years with wt >35 kgs. Nanocrystalline long-acting inj. approved in 2021. Metabolized by 3A4, 3A5. pH dependent absorption. 12 hr before / 4 hr after antacids 47

48. NNRTIs – Rilpivirine (RPV) S/E – Best S/E profile among NNRTIs. Rashes ↑ QT ↑ hepatic transaminase ↑ sr creatinine. 48

49. NNRTIs – Etravirine (ETR) Potent even in NNRTIs resistance mutations (K103N & Y181C). Approved for adult & children > 2 years with wt ≥ 10 kgs. Dose 200mg Metabolized by 3A4, 2C9, UGT. combined with ritonavir 49

50. NNRTIs – Etravirine (ETR) S/E – Rash, SJS & TEN ↑ hepatic aminotransferase, TAG, sr. cholesterol. 50

51. NNRTIs – others Doravirine (DOR) Useful in EFV resistant cases. Rx failure d/t mutations V106I, F227C. Delavirdine (DLV) Rarely used d/t TDS dosing. 51

52. PIs – HIV Protease Inhibitors Prevent processing of viral proteins into functional conformations → production of immature & non – infective viral particles. All except Nelfinavir metabolized by CYP3A4. (Nelfinavir 2C19 > 3A4) Combined with ritonavir / cobicistat. ✔️ cross resistance 2 nd line ARTs. Cobicistat – (150mg / day) Ritonavir analogue without anti retroviral activity. PK enhancer. Reversible increase of sr creatinine. 52

53. PIs – Ritonavir (RTV/r) Effective against HIV I & II. Mainly use as PK enhancer (100/200 mg). 53

54. PIs – Ritonavir (RTV/r) S/E – GI toxicity – nausea & vomiting, diarrhea, anorexia Peripheral & perioral paresthesia. ↑ sr cholesterol & TAG. 54

55. PIs – Ritonavir (RTV/r) Drug – Drug interactions – One of the most potent CYP 3A4 inhibitor. Should not combined with drugs which is substrate for 3A4 & narrow therapeutic index. Avoid with rifampin. Capsule & solution formulation contains alcohol. Alternative contraceptive methods should be used. 55

56. PIs – Lopinavir (LPV/r) Against HIV I & II. Only in Coformulation with ritonavir. LPV/r – 400mg/100mg BD or 800mg/200mg OD. Approved in neonates > 14 days 56

57. PIs – Lopinavir (LPV/r) S/E – GI toxicity ↑ TAG, sr cholesterol, aminotransferase. liquid formulation contains 42% alcohol ↑ QT 57

58. PIs – Atazanavir (ATV) Approved for adults & children >3 months with wt ≥ 5 kgs. With ritonavir (300mg/100mg) or without ritonavir (400mg). Elimination through biliary. pH dependent absorption. 58

59. PIs – Atazanavir (ATV) S/E – Inhibition of UGT1A1 – unconjugated hyperbilirubinemia. Peripheral neuropathies, SJS Cholecystitis, cholelithiasis, nephrolithiasis Oral powder contains phenylalanine. 59 C/I in Hepatic Insufficiency. C/I Phenylketonuria.

60. PIs – Darunavir (DRV) With combination for adults & children >3 years. DRV/r – 800mg/100mg OD or 600mg/100mg BD. S/E – Contains sulfa moiety hepatotoxic 60

61. PIs – Others Fos amprenavir (FPV) Co administration with r. Contains sulfa moiety. Oral solution contains propylene glycol C/I pregnant, young, renal / hepatic impairment, oral solution of ritonavir. Indinavir (IDV) s/e includes unconj . Hyper bilirubinemia, nephrolithiasis, Acute renal failure & interstitial fibrosis, MI, acute hemolytic anemia. 61

62. PIs – Others Nelfinavir (NFV) Oral powder contains phenylalanine. C/I phenylketonuria. s/e includes insulin resistance, hyperglycemia & lipodystrophy. Tipranavir (TPV) Indicated in other PI resistant cases. C/I in Hepatic Impairment. Contains sulfa moiety. S/e – intracranial hemorrhage C/I Head Trauma & Bleeding Disorder 62

63. Integrase Inhibitors Prevent formation of covalent bond between host & viral DNA. Rapidly ↓ viral RNA than any other ARTs. Drugs are Raltegravir , Elvitegravir, Dolutegravir, Bictegravir Use of antacids / sucralfate – before 6 hours / after 2 hours. 63

64. Integrase Inhibitor - Raltegravir Against HIV I & II. Approved for adult & children >2 kgs. Fatty meal ↑ plasma concentration. Eliminated mainly via glucuronidation by UGT1A1. dose ↑ with CYP inducers. Dose – 400mg BD / 1200mg OD oral 64

65. Integrase Inhibitor - Raltegravir S/E – Headache, nausea, fatigue ↑ creatine kinase, myopathies, rhabdomyolysis DRESS 65

66. Integrase Inhibitor - Elvitegravir Against HIV I & II. Approved for adults and children > 12 years. Fatty meal ↑ plasma concentration. Mainly eliminated by CYP3A4. Require boosting with PK enhancers. 66

67. Integrase Inhibitor - Dolutegravir Against HIV I & II. Approved for adults & children > 4weeks with weight >3kgs. Metabolized by CYP3A4 & UGT1A1. Single tablet OR coformulation with TDF + 3TC. Dose → 50mg/OD. 67

68. Integrase Inhibitor - Dolutegravir S/E— Weight gain, insomnia, headache. Neural tube defects. HSN reaction – rashes, organ dysfunction ↑Se. creatinine (reversible) & ↑ metformin plasma concentration. 68

69. Integrase Inhibitor - Dolutegravir 69

70. Integrase Inhibitor - Bictegravir Against HIV I & II. Si ngle tablet OR coformulation with TDF & FTC. Metabolized by CYP3A4 & UGT1A1. S/ E are similar to dolutegravir. 70

71. Entry Inhibitors - Fostemsavir Approved by US FDA in 07/2021. MOA – Binds to gp120 → prevent binding to CD4. Prodrug of temsavir . Use in Rx experienced adults with multidrug resistant HIV I. Metabolized by esterase & CYP3A4. Resistance d/t amino acid substitutions – S375H/M, L116P. 71

72. Entry Inhibitors - Fostemsavir S/E includes ↑ hepatic transaminase, ↑QT. Inhibits OATP1B1 & OATP1B3 → should not combined with statins. 72

73. Entry Inhibitors - Ibalizumab MOA – binds to CD4 → hinderance of confirmation changes in gp120-CD4 complex. Use in Rx experienced adult with multidrug resistant HIV I. IV infusion / 2 weeks Well tolerated with few s/e (diarrhea, dizziness, rash). Rapidly develops resistance if not combined with other ART. Resistance d/t ↓ expression of N linked glycosylation site of gp120. 73

74. Entry Inhibitors - Maraviroc MOA – blocks the binding site of gp120 to CCR5. Use in adults who has infected with CCR5 tropic HIV. Dose is dep on LFT & concomitant use of CYP +/-. Dose With CYP3A4 - → 150mg BD With CYP3A4 + → 600mg BD With others → 300mg BD 74

75. Entry Inhibitors - Maraviroc S/E – Orthostatic hypotension Hepatotoxic URTIs, pyrexia, muscle & joint pain MI 75

76. Entry Inhibitors - Enfuvirtide MOA – binds to gp41 → inhibits fusion of gp41 & CD4 interaction. Use in adults & children >11kgs with HIV I. Resistance d/t mutation in gp41. S/E – injection site reaction, lymphadenopathy, pneumonia. 76

77. ARV Drugs in National Program Generic Name Dose NRTIs TDF 300mg OD AZT 300mg OD 3TC 150mg BD / 300mg OD ABC 300mg BD / 600mg OD NNRTIs EFV 600mg HS NVP 200mg OD x 14 days f/b 200mg BD Integrase Inhibitors DTG 50mg OD RAL 400mg BD Protease Inhibitors ATV/r 300mg + 100mg OD LPV/r 200mg + 50mg BD DRV 600mg BD RTV 100mg OD / BD 77

78. ARV Drugs in National Programe Generic Name Dose NRTIs TDF 300mg OD AZT 300mg OD 3TC 150mg BD / 300mg OD ABC 300mg BD / 600mg OD NNRTIs EFV 600mg HS NVP 200mg OD x 14 days f/b 200mg BD Integrase Inhibitors DTG 50mg OD RAL 400mg BD Protease Inhibitors ATV/r 300mg + 100mg OD LPV/r 200mg + 50mg BD DRV 600mg BD RTV 100mg OD / BD 78

79. NACO 79

80. NACP: Evolution & Progress 80

81. NACP V 81

82. NACP V 82

83. 83

84. ART 84

85. General Principles Treat all approach. OIs should be treated first before starting ART. At least one NRTI should be in regimen. FDC are preferred. DTG based regimen are preferred. Rapid ART initiation. 85 NO PERMENANT CURE FOR HIV AIM – DECREASE THE VIRAL LOAD AS SOON AS AND AS LONG AS POSSIBLE.

86. First-Line ART * TDF 300mg + 3TC 300mg + DTG 50mg *age >10 years and weight >30kgs. 86

87. ALTERBATIVE FIRST-LINE ART Condition Alternative first-line ART Weight <30 kgs ABC 600mg + 3TC 300mg + DTG 50 mg High creatinine ABC 600mg + 3TC 300mg + DTG 50 mg PLHIV on rifampicin-based ATT TDF + 3TC + DTG + DTG 50mg (12 hrs after FDC) ♀reproductive age TDF + 3TC + EFV 600mg OR TDF + 3TC + LPV/r (200/50mg) 87

88. ART IN PREGNANCY EMTCT – Elimination of Mother To Child Transmission 88

89. ART IN PREGNANCY* TDF + 3TC + DTG for pregnant / breastfeeding ♀. 89 *Currently 1 st line ART

90. INFANT ARV PROPHYLAXIS Low risk infants (mothers with <1000copies/ml) – syp NVP or syp AZT till 6 weeks High risk infants* – syp NVP + syp AZT till 6 weeks / 12 weeks * High risk infants – Mother not on ART. Viral load not done after 32 weeks of pregnancy. Viral load not suppressed after 32 weeks. Newly dx mother within 6 weeks If AZT not available replace with syp LPV/r All HIV-exposed infant should receive CPT at 6 weeks of age. 90

91. FIRST-LINE ART in children < 6 years & < 20kgs ABC + 3TC + LPV/r 6-10 years & 20-30 kgs ABC + 3TC + DTG >10 years & >30 kgs TDF + 3TC + DTG 91

92. PREVENTION OF OPPORTUNISTIC INFECTION MOST COMMON CAUSE OF DEATH IN HIV – OIs. MOST COMMON OPPORTUNISTIC INFECTION – TB. 92

93. PREVENTION OF OPPORTUNISTIC INFECTION Prevention of OIs under NACP – Prophylaxis for PCP. Prophylaxis for tuberculosis. Prophylaxis for Cryptococcal meningitis. 93 *Causative agent of Pneumocystis Pneumonia (PCP) – Pneumocystis Jirovecii .

94. PREVENTION OF OPPORTUNISTIC INFECTION Against PCP, toxoplasmosis, Nocardiosis, bacterial pneumonias etc For pts with CD4 <350 cells / mm 3 or WHO 3 & 4 stage. Cotrimoxazole (SMX 800mg + TMP 160mg) infant >6 weeks – 25mg + 5mg/kg/day. ✔️ in pregnancy and breastfeeding. If allergic – Dapsone 100mg OD. Discontinue - CD4 >350 cells / mm 3 . CPT – Cotrimoxazole Prophylaxis Therapy 94

95. PREVENTION OF OPPORTUNISTIC INFECTION Primary prophylaxis not recommended. CrAg not available & CD4 <100 cells / mm 3 – Fluconazole 100mg OD at least 1 year. Cryptococcal disease 95

96. PREVENTION OF OPPORTUNISTIC INFECTION INZ 100mg + pyridoxine 50mg OD x 6 months. ✔️ pregnancy & breastfeeding. IPT – Isoniazid Prophylaxis Therapy 96

97. HIV-TB COINFECTION Scenario Treatment TB & HIV diagnosed simultaneously ATT f/b ART (within 2 weeks) Pt > 30kgs - TDF + 3TC + DTG + DTG Pt < 30kgs / ↑ creatinine – ABC + 3TC + DTG + DTG ♀ in reproductive age – TDF + 3TC + EFV / DTG + DTG or TDF + 3TC + LPV/r (Rifampicin ⇋ Rifabutin) If Pt is already on ART Continue ART / appropriate modification ART/ATT 97

98. TB ASSOCIATED IRIS* *IRIS – Immune Reconstitution Inflammatory Syndrome Within 2 weeks – 2 year. Improvement after ↓ HIV RNA. Mild – No Rx req. Severe – Steroids. 98

99. PRE-EXPOSURE PROPHYLAXIS (PrPE) 99

100. POST EXPOSURE PROPHYLAXIS (PEP) 100

101. RECENT ADVANCES 101

102. LA Cabotegravir Integrase Inhibitor. IM LD 600mg f/b MD 400mg monthly. Approved for adults with chronically suppressed plasma HIV RNA (<50 copies / mL). Metabolized by UGT1A1. If expect to miss scheduled injection by > 7 days – continue oral therapy till next schedule injection 102

103. LA Rilpivirine NNRTI Approved for adults with chronically suppressed plasma HIV RNA (<50 copies / mL). IM – LD 900mg, MD 600mg / monthly. S/E – DRESS (in minutes), ↑QT (dose dependent), hepatotoxic, depressive symptoms. If expect to miss scheduled injection by > 7 days – continue oral therapy till next schedule injection 103

104. Islatravir NRTI Inhibition of R T/RNA complex → blocks HIV replication. t 1/2 – 78-129 hrs. Once OD/SC implant.

105. Lenacapavir Inhibits HIV capsid protein Ap proved by US FDA in 12/2022. HIV prophylasix & treatment S/C 900mg t 1/2 – 38 days.

106. Summary HIV is major global public health issue with increasing trends in new infection. There is NO PERMENANT CURE for HIV , however with access to effective HIV prevention, diagnosis, treatment and care, HIV infection has become a manageable chronic health condition . The most common cause of mortality ISN’T HIV, BUT OIs ∴ OIs should be treated first. According to latest NACP guidelines – 1 st Line ART are TDF + 3TC + DTG. 106