Drug Treatment of HIV/AIDS

1. Drug Treatment of HIV/AIDS Dr F. A. Fehintola FMCP

2. Introduction • HIV/AIDS • Aetiology is retroviruses HIV-1 & -2 • First described in 1980s • Over 30m deaths attributable to the dx • Over 14m orphaned • Still no cure yet • Estimated 13,000 new cases each day

3. Introduction • 95% of new cases occur in developing countries • Poverty • poor health system • Limited resources for prevention • In 2004, • 4.8m new cases were recorded • 2.9m deaths recorded • ~50% of new cases occur in 15-24 year olds

4. Introduction • Rate of mother-child transmission • 25-45% in Africa (50% due to breastfeeding) • ~3% in the U.S. • ~7% in Europe • Life expectancy has dropped by ~ 15 years as result of HIV/AIDS (yet still dropping!) • TB aids HIV/AIDS and vice versa • 30-40% HIV related deaths results from TB

5. Introduction • Associated problems • Stigmatization • Discrimination • Rejection • Major disease burden worldwide • Impacts negatively on economic development • 4th greatest cause of death worldwide

6. Pathogenesis • Transmission • Blood & blood products transfusion • Sexual intercourse • mucosa lining of genitals, rarely mouth • Damage to lining ↑the risk • Use of un-sterilized instruments • Exchange of needles by drug addicts • The target are the CD4+ cells, mostly helper T cells (800-1200/mm3 = Ñ) • Eventual immune paralysis • Opportunistic infections, malignancy

7. Pathogenesis

8. Pathogenesis • Genes involved in structural proteins • Gag • Pol • env • Other genes – for regulatory proteins • Nef, vpu, tat, rev, vpr and nif

9. Pathogenesis • HIV binds CD4 molecules on the target cells using its gp120 • Usually requires co-receptors • CCR5 • CXCR4 • Access probably involves ‘lipid rafts’ • RT converts RNA to DNA strand • Integrase ensures incorporation into host DNA

10. Pathogenesis • Transcription • Aided by cytokines e.g. TNF-α • Myco. tuberculosis • mRNA • Translation • Regulated by rev gene • Protein synthesis apparatus taken over • Production of structural proteins

11. Pathogenesis • Budding follows • Assembly of Immature proteins • Acquisition of viral envelope • But the virus is not infectious • Maturation involves • Cleavage by Protease

12. Pathogenesis • Cell deaths: • Directly • Overwhelming by the viral particles • Distortion of cell function • Apoptosis • Programmed death • Innocent Bystander • Attacked by Killer cells

13. Pathogenesis • Infection usually manifest as flu-like(3/52 after) • Activity of the virus initially abates only to resume years later (lentivirus) • Activity may take 12 years or more to resume • But may be as short as 2 years in few cases • Factors in progression & severity • Virulence of the strain • Age • Genetic differences e.g. mutant gene of co-receptor • Other microbes

14. HIV/AIDS stages Four stages described • Stage 1: primary infection • Lasts few weeks • Flu-like illness usually occur • diagnosis may be missed unless sero-converted

15. HIV-AIDS stages • Stage 2: Clinically Asymptomatic Stage • Lasts average of 10 years • No symptoms • Glandular enlargement • Virus may be low • Antibody test is positive

16. HIV-AIDS stages • Stage 3: symptomatic HIV infection • Marked damage to the immune system • Recurrent bacterial infections • Persistent weight loss • PTB • Persistent oral candidiasis • Unexplained chronic diarrhoea • Unexplained persistent fever • Unexplained anaemia

17. HIV-AIDS stages • Stage 4: AIDS • AIDS - defining diseases • Opportunistic infections & cancers • Extra-pulm. TB • PCP • Chronic herpes infection > 1 month • CMV retinitis • Oesophageal candidiasis • CNS toxoplasmosis • Kaposi sarcoma • Very low T-helper cells (when possible)

18. Targets for Drugs • Virus receptor and entry • Reverse transcriptase • RNAase • Integration • Viral gene expression • Viral protein synthesis • Viral budding

19. Classes of Antiretroviral drugs • Nucleoside Reverse Transcriptase Inhibitors NRTI • Non-Nucleoside inhibitors Reverse Transcriptors Inhibitors (nNRTI) • Protease Inhibitors(PIs) target viral assembly by inhibiting the activity of protease • Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. Raltegravir the first to receive FDA approval in October 2007.

20. Classes of Antiretroviral drugs • Entry inhibitors interfere with • binding, • fusion and • entry of HIV-1 to the host cell by blocking one of several targets. • Maraviroc and • Enfuvirtide the two currently available agents in this class. • Maturation inhibitors prevents cleavage of viral capsid polyprotein • Bevirimat and Vivecon are examples

21. Drug Combination • Serves to create multiple obstacles • Reduce replication • Prevents emergence resistant strains • Usually three in number: triple cocktail • 2 NRTIs + 1 nNRTI (or 1 PI)

22. Anti HIV drugs • HAART is: Highly Active Anti Retroviral Therapy

23. Issues with Drug Combinations • Fixed Dose Formulations • Ease of administration • Compliance → • Effectiveness • ADRs • Interactions e.g. ddI and AZT inhibit each other

24. Regimens • 2 nucleoside RTI: Zidovudine or Stavudine + Lamivudine or Didanosine • Plus either 1 non-nucleoside RTI: Nevirapine, Efavirenz • OR 1 protease inhibitor: Indinavir, Nelvinafir, Saquinavir • OR 2 protease inhibitors: Ritonavir + Saquinavir • 3 NRTI: Zidovudine + lamivudine + Abacavir

25. Current guidelines for Tx HIV-infection confirmed plus one of the following conditions: • Clinically advanced HIV disease; • WHO Stage IV HIV disease, irrespective of the CD4 cell count; • WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making; • WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.

26. NRTIs • Examples include: • Abacavir • Didanosine • Lamivudine • Stavudine • Tenofovir* • Zalcitabine • Zidovudine * A nucleotide inhibitor

27. NRTIs • Zidovudine • Formerly called Azidothymidine [thus AZT] • A de-oxythymidine analogue • First licensed anti-retroviral drug • Inhibits RNA dependent DNA polymerase • Initial phosphorylation by thymidine kinase • Eventual triphosphate gets incorporated into DNA resulting in chain termination

28. NRTIs • Zidovudine • Rapidly absorbed orally with >60% bioavailability • Food retards absorption (cf: tenofovir) • CSF conc: 24-53% of plasma • T1/2 (plasma) ~ 1.5 hours • Plasma protein binding ~ 20-38% • Excretion as glucuronide conjugates • Clearance impaired in renal insufficiency • Probenecid inhibits both renal and hepatic clearance

29. NRTIs • Zidovudine • Decreases rate of progression of clinical dx and prolongs survival • Reduces chance of vertical transmission if used in pregnancy and in the first 6/52 of life • Resistance: • Any 3 of: M41L, D67N, K70R, T215F, K219Q

30. NRTIs • Zidovudine ADRs: • Myelosuppression (most common) • Anaemia • neutropenia • GI upset • Headaches, Insomnia • Myalgia, fever, confusion

31. NRTIs Zidovudine interactions • Drugs that increase plasma conc: • Valproic acid • Methadone • Fluconazole • atovaquone • Reduce plasma conc of AZT • Clarithromycin • Reduces absorption of AZT

32. NNRTIs Examples: • Nevirapine • Delavirdine • Efavirenz • Lovirdine • Etravirine • Rilprivirine

33. NNRTIs • Structurally diverse group of drugs • Mainly active against HIV-1 • Usually given in combination • Resistance develops very easily • But does not share cross resistance with NRTIs or PIs • Unlike NRTIs they do not require phosphorylation to become active

34. NNRTIs Nevirapine • Excellent oral bioavailability (90%) • Absorption not altered by food • Highly lipophylic • CSF ~ 45% of plasma conc • protein binding ~ 60% • Hydroxylation by CYP3A

35. NNRTIs Nevirapine • Proven efficacy in prevention of mother-child if given at • onset of labour (single dose) and • Neonate (2mg/kg X 3 days) • Administered as a component of HAART

36. NNRTIs • Nevirapine ADRs • Severe and life-threatening skin rash • Rash occurs in 17% of cases • Typically 4-8 weeks of therapy • May be dose dependent • Dose escalation is recommended for prevention • Fulminant hepatitis (4-6 weeks of therapy) • Monitor LFT • Others: fever, nausea, somnolence

37. NNRTIs Nevirapine interactions • Nevirapine is a substrate of CYP3A • Potent inducer of CYP3A ~ auto-inducer • Reduces conc of • Saquinavir • Indinavir • Nevirapine conc is increased by: • Cimedine, erythomycin

38. NNRTIs Nevirapine interactions • Inducers of CYP3A will reduce concentration of Nevirapine • Rifamicin • Rifabutin • Barbiturates • Carbamazepine

39. Protease Inhibitors • Examples • Amprenavir • Indinavir • Lopinavir • Neltinavir • Ritonavir • Saquinvir

40. Protease Inhibitors • Activity against the protease enzymes • Thus inhibition of maturation • Resistance is common and • Cross resistance is common • Cushingoid syndrome is associated • Glucose intolerance and Insulin resistance • Bleeding diathesis in Haemophiliacs • Generally inhibit CYP3A isozymes

41. Protease Inhibitors Saquinavir • Poor oral bioavailability • High 1st pass effect (CPY3A4) • Enhanced absorption when taken with meals • Large volume of Distribution • But poorly penetrates the CSF • Elimination half-life ~ 12 hours • Excretion usually in feces

42. Protease Inhibitors Saquinavir • Both a substrate and inhibitor of CYP3A4 • With Ritonavir (inhibitor) efficacy improves ADRs • Nausea, Vomiting, diarrhoea • Dry mouth, taste disturbance • Myalgia, pruritus, alopecia • Hepatitis, haemolytic anaemia, erythema multiforme, leukopenia, hyperpigmentation

43. Entry/Fusion inhibitors • Enfuvirtide • Maraviroc • Blocks HIV-1 access to CCR5 • No evidence in case of HIV-2 or CXCR4-tropic viruses • Oral bioavailability is good • Only slight, non-clinical reduction with meals • Plasma protein binding ~ 76% • Metabolism by CYP3A mainly • Biliary>> and urinary excretion occur

44. Entry/Fusion inhibitors • Maraviroc • Adverse events recorded • Cough • Dizziness • Abdominal pain • Skin rash • Inducers of CYP3A reduce conc • Rifampicin, efavirenz • Inhibitors increase conc • delavirdine, saquinavir, ketoconazole

45. Drug resistance in HIV • In chronic HIV infection • 10Bilion new viral particles may be generated per day • All potential mutations can occur • Resistance to lamivudine requires single codon mutation • Whereas AZT, PIs require multiple mutations • This occurs under selective pressure • Mutants, not suppressed, thus replicate

46. Drug resistance in HIV • Spontaneous mutations occur during replication • Mutants are identified • D30N for Nelfinavir • D [aspartic acid – replaced amino acid] • 30 [codon number] • N [asparagine – substitute amino acid] • Exposure to sub-therapeutic concentration promotes mutants

47. Testing for resistant strains • Genotypic testing • Looks for specific genetic materials • Requires ~ 1000 mutants/ml • May involve use of molecular probe • Phenotypic testing • Also requires viral load of ~ 1000 mutants/ml • Akin to culture and sensitivity testing • IC50 & IC90 compared with sensitive

48. When HAART fails • Mega-HAART is used • Induction of mutation to less virulent strains with lamivudine • Drug holidays ADDM

49. Letters representing amino acid • A - Alanine • C – Cytosine • D- Aspartic acid • E – Glutamic acid • F – Phenyalanine • G- Glycine • H – Histidine • I – Isoleucine • K – lysine

50. Letters representing amino acid • L – Leucine • M – Methionine • N – Asparagine • P – Proline • Q – Glutamine • R – Arginine • S – Serine • T – Threonine • V – Valine • W - Trytophan • Y - Tyrosine