AIDS

Management of AIDS

1. Management of AIDS Dr. Irfan Ahmad Khan Dept. Of Pharmacology,JNMC,AMU .

2. Outline Epidemiology HIV life cycle Clinical staging Antiretroviral drugs Guidelines for ART Post exposure prophylaxis Conclusion

3. Epidemiology There were 2.39 million people living with HIV/AIDS at the end of 2010(NACO annual report 2010-2011).(34 million in world) The estimated adult prevalence in the country is 0.31%. High prevalence in high risk groups Injectable drug users- 7.2% Homosexual men – 7.4 % Female sex workers- 5.1 % STD clinic attendees – 3.6 % “Concentrated epidemic” The prevalence rate of HIV infection in the country has stabilized over the last few years

4. Etiological agent Human immunodeficiency virus HIV-1  most epidemic,worldwide HIV-2 western Africa,SIV Family retroviridae , subfamily lentiviruses . Adapted for chronic persistent infection with gradual onset of clinical symptons . Reverse Transcriptase(RT) RNADNA RT is very error prone & lacks proof reading function, so resistance develops rapidly. Transmission routes– hetero/homo-sexual, blood /blood products, transplacental , Injecting drug use. Central core contains  RNA & 3 genes gag, pol , env gag  polyproteinstructural protein gag & pol  RT,Protease,Integrase Env  envelope protein

5. The replication cycle of HIV gp 120 + gp41 CCR5/ CXCR5 Nucleocapsid Cholesterol-rich lipid rafts

6. Natural history of HIV infection

7. WHO clinical staging of HIV/AIDS for adults and adolescents Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy

8. Clinical stage 2 Unexplained moderate weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis ) Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections

9. Clinical stage 3 Unexplained severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (above 37.5 °C intermittent or constant for longer than one month) Persistent oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis Severe bacterial infections (e.g. pneumonia, empyema , pyomyositis , bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis , gingivitis or periodontitis Unexplained anaemia (<8 g/dl), neutropenia (<0.5 X 10 9 /litre) and or chronic thrombocytopenia (<50 X 10 9 /litre)

10. Clinical stage 4 HIV wasting syndrome  Involuntary wt. loss >10% of baseline body weight associated either with Chronic diarrhoea for more than one month OR Chronic weakness & documentad fever for more than one month Pneumocystis pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection ( orolabial , genital or anorectal of more than one month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis HIV encephalopathy

11. Clinical stage 4 (Cont.) Extrapulmonary cryptococcosis including meningitis Disseminated non- tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis Chronic isosporiasis Disseminated mycosis ( extrapulmonary histoplasmosis , coccidiomycosis ) Recurrent septicaemia (including non- typhoidal salmonella) Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy

12. ANTIRETROVIRAL DRUGS 1.NRTIs  Zidovudine(AZT), Lamivudine (3TC), Stavudine (D4T), Zalcitabine ( ddC )*, Didanosine ( ddI ), Abacavir (ABC), Emtricitabine (FTC)* 2.NtRTIs  Tenofovir 3.NNRTIs  Nevirapine (NVP), Efavirenz (EFV), Delavirdine *, Etravirine * Indinavir,Saquinavir,Nelfinavir,Ritonavir,Fosamprenavir *, Lopinavir,Atazanavir,Tipranavir *, Darunavir * Enfuvirtide Maraviroc Raltegravir

13. gp 120 + gp41 CCR5/ CXCR5

14. Reverse Transcriptase Inhibitors

15. Nucleoside analogs (NRTI's) Prevent infection of susceptible cells but do not eradicate the virus from the cell that already harbor integrated proviral DNA All require intracytoplasmic activation to triphosphate form  substrate for reverse transcriptase Mechanism of action – Competitively inhibiting incorporation of native nucleotides Can also get incorporated into nascent proviral DNA and cause chain termination.

16. NRTIs- mechanism of action

17. NRTIs Active for both HIV1 and HIV2. Some have affinity for the mitochondrial DNA polymerase γ and can cause lactic acidosis, fatty liver, anemia,granulocytopenia,myopathy , peripheral neuropathy and pancreatitis. Incidence of mitochondrial toxicity: Stavudine > Didanosine , Zalcitabine > Zidovudine > Lamivudine , Emtricitabine , Tenofovir

18. Pk of NRTIs Most NRTIs are eliminated from the body primarily by renal excretion( Zidovudine & abacavir hepatic glucuronidation ) Plasma t1/2 of parent compound – 1-10 hours T1/2 of Intracytoplasmic nucleoside triphosphate – 2-50 hours. Given once/ twice daily No significant PK drug interaction as not major substrate for hepatic CYPs. Drug resistance slower compared to NNRTIs & PI

19. NRTIs- key points Drug Relevant toxicity Remarks Zidovudine Bone marrow suppresion  Anaemia , neutropenia Nail hyperpigmentation (chronic) Also active against HTLV 1&2 Generally well tolerated. Probenecid,fluconazole , valproic acid ↑ AZT↓ Glucuronosyl transferase Hb monitoring recommended Stavudine Peripheral neuropathy(mc) Pancreatitis Mitochondrial toxicity+++ Fat wasting Good efficacy, cheap. Used in place of AZT if Hb <8. Dose ↓ in pt. with low body wt. Didanosine Peripheral neuropathy Pancreatitis Retinal changes & optic neuritis Diarrhea(antacid) Hyperuricemia HTLV-1 Acid labile Food ↓ bioavailability(30 min before/2 hr after meal) Tab. contains phenylalanine. Powder contains sodium.

20. NRTIs- key points (Contd.) Zalcitabine Peripheral neuropathy Pancreatitis Oral ulcers Rarely used due to inferior antiviral activity,toxicity & thrice daily use. Not available in India Lamivudine Neutropenia , headache,nausea Hepatotoxicity Best tolerated, least toxic Used in all first line regimes, once daily dosing. Effective against HBV. Abacavir Hypersensitivity reaction (HLA-B57) cant be restarted once stopped Good efficacy Once daily No mitochondrial toxicity Emtricitabine Hepatotoxicity Hyperpigmentation HBV Similar efficacy and safety as Lamivudine Once daily dosing Not available in India

21. Nucleotide analogue Tenofovir disoproxil fumarate (TDF)- analogue of AMP lacking a complete ribose ring. Active against HIV1, HIV2, HBV, Herpes virus Tenofovir diphosphate is active metabolite Low affinity to DNA polymerase - α ,- β and - γ Poor oral bioavailability(25%) High fat meal ↑ bioavailability(40%) Once daily dosing Renal excretion It ↑ conc. of didanosine by inhibiting purine nucleoside phosphorylase (PNP  didanosine hypoxanthineuric acid) ADR: Flatulence Acute renal failure & Fanconi syndrome

22. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's) Non- competitive inhibitors of reverse transcriptase. NO action against HIV-2.(strain specific) Do not require triple phosphorylation No mitochondrial toxicity Very susceptible to high level viral resistance, even after a single dose. Resistance extends to whole class.

23. NNRTIs- Mechanism of action Hydrophobic pocket in p66 subunit

24. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's)-ADRs Maculopapular rash- first few weeks of therapy, sometimes severe (Stevens –Johnson syndrome) Fat accumulation(chronic) Drug interactions- NNRTIs are substrates of CYP3A4. can act as inducers( Nevirapine ), inhibitors ( Delavirdine ), or mixed inducer and inhibitor ( Efavirenz ).

25. NNRTIs – Key points Drug Toxicity Remarks Nevirapine Skin r ash Fatal hepatitis (women with CD4>250, pregnancy) Prevention of mother to child transmission Can’t be used with rifampin containing ATT. ↓plasma ethinyl estradiol Once daily dosing Efavirenz Neuropsychiatric symptoms. Skin rash Teratogenecity Negative pregnancy test required. Woman should use 2 methods of contraception. Convenient, effective & long term tolerability Once daily dosing Etravirine Rash, nausea, headache Inhibits RT resistant to other NNRTIs (positional flexibility) Once daily dosing Should not be combined with other NNRTIs Delavirdine Skin rash Elevated liver enzymes Inhibitor of CYP3A4 Well absorbed at pH<2 t1/2-5.8 hr & Thrice daily dosing

26. Protease inhibitors (PI) Competitive inhibition of virus aspartyl protease responsible for cleavage of Gag- Pol polyproteins . Immature, non-infectious virus particles are formed. All are inhibitors of CYP3A4, ritonavir being most potent. Clinically significant pharmacokinetic interactions Boosted regimes- combination of PIs with low dose ritonavir . (except nelfinavir CYP2C19) Active against HIV1, HIV2 Once/twice daily

27. Homodimer of two 99 AA monomers Structural protein & enzymes Mature virus Human Proteases 1 polypeptide chain

28. Protease inhibitors (PI) GI side effects  nausea,vomiting , diarrhea Metabolic complications (hyperglycemia, hyperlipidemia , fat redistribution), least with atazanavir Indinavir – crystalluria & Nephrolithiasis (poor solubility) Excess water Avoid antacid Tipranavir - intracranial hemorrhage,rash (sulfa moiety) Pill burden Not used as first line drugs

29. Fusion inhibitors / entry inhibitors Enfuvirtide * Maraviroc * Binds to gp41 of HIV envelope Not active against HIV-2 Twice daily s.c . inj. ADRs Inj. Site reactions Increase in bacterial pneumonia & LAP CCR5 antagonist Licensed in 2007 Food ↓bioavailability Eliminated via CYP3A4 Twice daily ADRs - fever, rash, myalgia , postural hypotension, hepatotoxicity Reserved for treatment of HIV resistant to multiple antiretroviral drugs

30. Enfuvirtide

31. Integrase inhibitors- Raltegravir * Approved in 2007 Only for HIV resistant to multiple classes of drugs Very well tolerated, minimal side effects. Active for both HIV-1 and HIV-2. High fat meal ↑ ses bioavailibility Eliminated via glucuronidation by UGT1A1 ADRs  headache,nausea,fatigue,myopathy,creatine kinase elevation .

32. MOA Formation of covalent bond b/w host & viral DNA

33. Drugs under development Vicriviroc - fusion inhibitor, blocks CCR5 receptor. Under Phase III trial. Pro 140- CCR5 antagonist, s.c . inj. every 2 weeks. Under Phase II trial. Elvitegravir – integrase inhibitor in phase III trial. Maturation inhibitors- interfere with the budding process of HIV . Bevirimat , Vivecon under phase II trial. Rilpivirine - NNRTI in phase III trial. Once daily dosing. Ibalizumab – monoclonal antibody against CD4. I.V. infusion every 2-4 weeks. New NRTIs – Apricitabine , Elvucitabine , Racivir .

34. Guidelines for ART

35. Initiation of ART based on CD4 count and WHO clinical staging Classification of HIV-associated clinical disease WHO clinical stage CD4 test not available (or result pending) CD4 test available Asymptomatic 1 Do not treat Treat if CD4 <200 Mild symptoms 2 Do not treat Treat if CD4 <200 Advanced symptoms 3 Treat Consider treatment if CD4 <350 and initiate ART before CD4 drops below 200 Severe/advanced symptoms 4 Treat Treat irrespective of CD4 count

36. Principals of ART Minimum three drugs simultaneously for entire duration of Tt NOT RECOMMENDED Monotherapy / dual therapy Induction- maintenance Structured treatment interruptions Sequential adding of drugs

37. Recommended first-line antiretroviral regimens Preferred first-line regimen Zidovudine + Lamivudine + Nevirapine Alternative first -line regimens Zidovudine + Lamivudine + Efavirenz Stavudine + Lamivudine + (NVP or EFV) Other options Tenofovir + Lamivudine + (NVP or EFV) or Zidovudine + Lamivudine + Tenofovir

38. Drug combinations- Not Recommended Antagonism Added toxicity Stavudine + Zidovudine Zalcitabine + Lamivudine Zalcitabine + Stavudine Zalcitabine + Didanosine Stavudine + Didanosine

39. Laboratory Monitoring for Toxicity and Effectiveness of ART Minimum Tests Basic Tests Desirable Tests Optional Tests Hemoglobin White blood cell count/ differential Liver enzymes Serum creatinine and/ or blood urea nitrogen Serum glucose Pregnancy test CD4 cell count Bilirubin Amylase Serum lipids HIV-1 RNA Serum lactate

40. ART: Problems Cost Pill burden Complex dosing schedules Drug interactions Cure not possible Drug toxicity Need for strict adherence Viral resistance

41. Post-exposure prophylaxis (PEP) of HIV

42. HIV transmission risk of different routes Exposure route Risk Blood transfusion 90-95% Perinatal 20-40% Sexual intercourse 0.1-10% Injecting drugs use 0.7% Needle stick exposure 0.3% Mucous membrane splash to eye, oro -nasal 0.09%

43. Potentially infectious body fluids Exposure to body fluids considered ‘ at risk’ Exposure to body fluids considered ‘ not at risk’ Blood Semen Vaginal secretions Cerebrospinal fluid Synovial, pleural, peritoneal, pericardial fluid Amniotic fluid Other body fluids contaminated with visible blood Tears sweat Urine and faeces Saliva unless these secretions contain visible blood

44. HIV Post-exposure Prophylaxis evaluation Exposure Status of source HIV+ and asymptomatic HIV+ and Clinically symptomatic HIV status unknown Mild Consider 2-drug PEP Start 2-drug PEP Usually no PEP or consider 2-drug PEP Moderate Start 2-drug PEP Start 3-drug PEP Usually no PEP or consider 2-drug PEP Severe Start 3-drug PEP Start 3-drug PEP Usually no PEP or consider 2-drug PEP

45. Post-exposure prophylaxis of HIV 2-drug PEP 3-drug PEP Zidovudine 300 mg BD+ Lamivudine 150 mg BD Zidovudine 300mg BD+ Lamivudine 150mg BD+ Lopinavir / ritonavir 400/100mg BD All for 4 weeks PEP must be initiated as soon as possible, preferably within 2 hours

46. CONCLUSIONS Benefits of ART continue to strongly outweigh the disadvantages Challenges remain Eradication of latent reservoirs Managing drug toxicities & resistance Improving adherence Improving access to ART

47. Thank you

48. Pk of Protease inhibitors

49. Definitions of treatment failure for first-line regimen Clinical failure New or recurrent WHO stage 4 condition, after at least 6 months of ART Immunological failure Fall of CD4 count to pre-therapy baseline (or below) 50% fall from the on-treatment peak value (if known) Persistent CD4 levels below 100 cells/mm Virological failure Plasma viral load > 10,000 copies/ mL

50. Pk of NNRTIs Hepatic metabolism