Drug Treatment of HIV/AIDS

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Drug Treatment of HIV/AIDS

• Dr F. A. Fehintola FMCP

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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

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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

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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

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Introduction

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

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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

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Pathogenesis
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Pathogenesis

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

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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

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Pathogenesis

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

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Pathogenesis

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

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Pathogenesis

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

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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

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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

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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

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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

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HIV-AIDS stages

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

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Targets for Drugs

• Virus receptor and entry
• Reverse transcriptase
• RNAase
• Integration
• Viral gene expression
• Viral protein synthesis
• Viral budding

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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.

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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

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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)

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Anti HIV drugs

• HAART is
• Highly
• Active
• Anti
• Retroviral
• Therapy

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Issues with Drug Combinations

• Fixed Dose Formulations
• Ease of administration
• Compliance ?
• Effectiveness
• ADRs
• Interactions e.g. ddI and AZT inhibit each other

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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

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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.

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NRTIs

• Examples include
• Abacavir
• Didanosine
• Lamivudine
• Stavudine
• Tenofovir
• Zalcitabine
• Zidovudine
• A nucleotide inhibitor

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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

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NRTIs

• Zidovudine
• Rapidly absorbed orally with gt60 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

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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

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NRTIs

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

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NRTIs

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

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NNRTIs

• Examples
• Nevirapine
• Delavirdine
• Efavirenz
• Lovirdine
• Etravirine
• Rilprivirine

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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

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NNRTIs

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

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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

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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

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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

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NNRTIs

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

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Protease Inhibitors

• Examples
• Amprenavir
• Indinavir
• Lopinavir
• Neltinavir
• Ritonavir
• Saquinvir

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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

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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

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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

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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
• Biliarygtgt and urinary excretion occur

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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

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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

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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

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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

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When HAART fails

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

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Letters representing amino acid

• A - Alanine
• C Cytosine
• D- Aspartic acid
• E Glutamic acid
• F Phenyalanine
• G- Glycine
• H Histidine
• I Isoleucine
• K lysine

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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