Antiretroviral by mikeholy

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									Treatment of HIV

   DR Sara Woods
   GUIDE Registrar
  St James’s Hospital
Number of people living with
       HIV/AIDS
Total                 33.6 Million

Adults                32.4 Million

Women                 14.8 Million

Children < 15 years   1.2 Million
    AIDS Deaths in 1999
Total                 2.6 Million

Adults                2.1 Million

Women                 1.1 Million

Children < 15 years   470,000
                  HIV Infection in Ireland
                                     AIDS cases   HIV cases
Number of Cases


                  400
                  300
                  200
                  100
                   0
                     90

                     91

                     92

                     93

                     94

                     95

                     96

                     97

                     98

                     99

                     00
                   19

                   19

                   19

                   19

                   19

                   19

                   19

                   19

                   19

                   19

                   20
                            Year of Diagnosis
 Goal of Antiretroviral Therapy

To  the length/quality of life by
• Reducing the Viral Load (VL)
• Preventing infection of new cells
• Preventing further damage to the immune
  system ( CD4)

  AIM:VL<50 copies/ml and CD4>>200
          BHIVA Guidelines
When to start therapy?
• VL >30,000 & CD4 350-500
• CD4 <350
• Symptomatic
Starting Tx early
• Drug toxicities
• Drug resistance/limit future drug options
Delayed Treatment
• Limit capacity for immune restoration
 Antiretroviral Agents (HAART)
Divided into 4 groups
• Nucleoside reverse transcriptase
  inhibitors (NRTIs)
• Protease Inhibitors (PIs)
• Non- nucleoside reverse transcriptase
  inhibitors (NNRTIs)
• Fusion Inhibitors
                            Life Cycle of HIV
                                                                                        Inhibited by:
                                                                                   Saquinavir, Ritonavir,
                                                                                    Indinavir, Nelfinavir,
                          BINDING                                                  Amprenavir,Lopinavir,


                                                                               PROTEASE




                                                              viral proteins
                                                                                          cell
                                                      TRANSLATION                         membrane
                                                                                  ASSEMBLY
     UNCOATING
                                    double stranded   viral
                      genomic       DNA                                             genomic
                      RNA                             mRNA
                                                                                    RNA
                                    INTEGRATION
            REVERSE
            TRANSCRIPTION

                                                                    proviral
     Inhibited by:                                                  RNA
                                           TRANSCRIPTION
ZDV, ddI, ddC, 3TC, d4T
 Abacavir, Nevirapine ,                    cell nucleus
 Delavirdine, Efavirenz
         Antiretroviral Therapy
Nucleoside          Non Nucleoside    Protease Inhibitors
Analogue            (NNRTI)           (PI)
(NRTI)
Zidovudine(AZT)     Nevirapine (NVP) Rtonavir (RTV)
Stavudine (d4T)     Efavirenz (EFV)   Indinavir (IND)
Didanosine (ddI)    Delaviridine      Nelfinavir (NFV)
Lamivudine (3TC)                      Amprenavir (AMP)
Zalcitabine (ddC)                     Saquinavir (SQV)
Abacavir (ABC)                        Lopinavir/Rtn (Kal)
Tenofovir (NtRTI)                     Tipranavir (Tip)

                                      Atazanavir (Ataz)
                  NRTIs
• 1st drugs licensed
• Backbone of HAART
• Similar in structure to nuclesides present in
  HIV RNA
• During viral replication – become
  incorporated into the genome, competing
  with cellular nucleosides
• Bring about chain termination & incomplete
  replication
Zidovudine (AZT)             Lamivudine (3TC)
• Dose: 300mg -1000mg        • Dose 150mg BD
  daily
                             • 90% renal excretion
• Metabolism – hepatic
  and renal                  • Hepatitis B
• Reduces risk of vertical
  transmission of HIV
• Good CNS penetration       Side Effects
                             • Pancreatitis
Side Effects
                             • Abnormal LFTs
• Bone Marrow
   Suppression               • Peripheral neuropathy
• Nausea                     • Headache
• Headache
• Insomnia
• Myalgia
Emtricitabine (FTC) Tenofovir (TEN)
• Dose 200mg OD             • Dose 245mg OD
• Take with/without food.   • Take with food
• CrCl <50ml/min – dose
                            • Hepatitis B
   adjustment
• Hepatitis B               Side Effects
Side Effects                • Hypophosphatemia
• Headaches, diarrhoea,     • Diarrhoea, nausea,
   nausea                      vomiting
•  CK – muscle pain &      • Pancreatitis
   weakness                 • Renal failure, acute
•  Tg,  blood sugar,        renal failure, proximal
   WCC & RBC                   tubulopathy
• Disturbance of liver,
   kidney & pancreas
           Protease Inhibitors
Act on the HIV Protease Enzyme – prevent
  production of essential proteins.
Benefits:
• Dramatic decline in clinical progression of HIV
  disease/related deaths followed PI introduction in
  1996
Drawback:
• Pill Burden
• Long term metabolic complications
   Cholesterol/Lipodystrophy Syndrome/Diabetes
• Food/fluid restrictions
• DRUG INTERACTIONS
Ritonavir (RTN)         Atazanavir
                        Azapeptide PI
• Dose Escalation
  600mg bd              Superior lipid profile to other
                        PIs
• 50% discontinuation
  rate                  Dose: 400mg OD
                        Or 300mg OD Ataz/100mg
                        OD Ritonavir
Side Effects            Boosted if coprescribed with
• N/V/D                 Ten or EFV or previous PI
• Perioral/Peripheral   exposure
   Neuropathy           With food
• Malaise
• Fever                 Side effects
                        Diarrhoea, nausea, vomiting
                        (taken with RTN)
Tipranavir                 Atazanavir
                           • Azapeptide PI
• Novel nonpeptidic PI
                           • Superior lipid profile to
• Active against HIV 1       other PIs
  strains which            • Dose: 400mg OD
  demonstrate resistance   Or 300mg OD Ataz/100mg
  to other PIs               OD Ritonavir
• Dose: 500mg Bd           • Boosted if coprescribed
  Tip/200mg Bd Ritonavir     with Ten or EFV or
                             previous PI exposure
Side Effects               • With food
• Diarrhoea, nausea,
   vomiting (taken with    Side effects
   RTN)                    • Diarrhoea, nausea,
                              vomiting (taken with
                              RTN)
        Drug Interactions - PIs
• PIs metabolised by CYP 450 isoenzyme system
• Coadministration of enzyme inducers may 
  levels of PIs – risk of resistance (eg Rifampicin)
• Coadministration of enzyme inhibitors may 
  levels of Pis – risk of toxicity
• PIs inhibit CYP3A4 –  levels of other drugs
          RTN>>IND=NFV=AMP>>SQV
            (eg/Pethidine/Antiepileptics)
• Some PIs induce isoenzymes  levels of other
  drugs (eg Methadone/O.C.)
               NNRTIs
• Act on reverse transcriptase enzyme –
  preventing HIV RNA from being processed
• Simplier to take than PIs/no food
  restrictions
• Resistance develops quickly – interclass
  resistance
• ?delayed toxicities
Nevirapine (NVP)           Efavirenz (EFV)
• Dose: 200mg OD x 14/7,   • Dose 600mg OD
  then 200mg BD            • Induces and inhibits
                             CYP 450
• Metabolised by and
  inducer of CYP 450       • Teratogen

                           Side Effects
Side Effects
                           • Dizziness/Headache
• Rash
                           • Insomnia
• Fever                    • Increased Dreaming
• Nausea                   • Irritability
• Hepatotoxicity           • Decreased
                              Concentration
    Drug Interactions NNRTIs
• NNRTIs metabolised by CYP 450
  isoenzyme system
• Coadministration of enzyme inducers may
   levels of NNRTIs -  risk of resistance
• Coadministration of enzyme inhibitors may
   levels of NNRTIs – risk of toxicity
• NNRTIs induce isoenzymes  levels of
  other drugs
        Patient Monitoring
• Baseline – VL/CD4/FBC/LFTs
• 1 Month – VL/CD4/FBC/LFTs
• Then every 3 Months – VL/CD4/FBC/LFTs
          Virologic Failure
• VL > 50copies/ml on 2 occasions more than
  one month apart
Reasons
• ? Patient Adherence(<95%)/Intolerance
• ? Pharmacological Issues
• ? Poor Pharmacokinetics

Perform Resistance Test and change therapy
  accordingly
            HIV Resistance
   Reduced Susceptibility of Virus to ART
• Virus replicates in the presence of drugs –
  can result in development of mutations
• Results in changes in structure/function of
  protease & RT enzymes –less susceptible to
  drugs
       HIV Resistance Testing
• Two types -both require VL > 1000copies/ml
Phenotypic Assay:
• Measures ability of a HIV isolate from patient to
  grow in presence of specific drugs
• Time consuming & expensive
Genotypic Assay:
• RT/Protease genes from patients virus sequenced
  to determine mutations within these genes
• Insensitive to presence of minor variants
   Genital Wart Therapies
                     Clearance     Recurrence
                        Rate          Rate
Podophyllin           38-79%         21-65%
Surgical Excision     89-93%         19-22%
Electrodesiccation     94%              25%
CO2 Laser             72-97%          6-49%
Cryotherapy           70-96%         25-39%
Interferons           36-53%         21-25%

                          Beutner K, Am J Med, 1997.
Patient Applied Therapies

                    Clearance Recurrence
                       rate      rate

Imiquimod             40-77%      13%

Podophyllotoxin 68-88%           16-34%

5-FU*                 68-97%      0-8%

* No longer recommended

                               Beutner K, Am J Med, 1997.
      Trichomonas vaginalis
• Treatment –
• Rx; Metronidazole 2g
  stat dose
• Rx; Metronidazole
  400mg bd x 5/7
• Contraindicated in
  first trimester
• Treat Partner
            Bacterial Vaginosis
• Treatment –                   120
                                                    BV     lactobacilli
                                      normal
                                100
                                                           Gardnerella
  Metronidazole 400mg            80                        anaerobes
  BD x 5d                        60

                                 40            increasing pH

                                 20              increasing symptoms

• Avoid alcohol as                0
  possibilty of a disulfiram-
  like reaction
        Treatment of chlamydia
• Azithromycin 1g po stat.
• Doxycycline 100mg bd x 7/7

• In pregnancy / breastfeeding:             Erythromycin
  500mg bd x 14/7


• Contact tracing
  concordance rate 65% of F contacts [80% if epididymitis],
  53% M contacts
• Test of cure
                       NSU
• Treatment –
Azithromycin 1g stat dose
or
Doxycycline 100mgs BD x 7d

Alternative regimens

Erythromycin 500mgs QDS x 7 days or 250mgs QDS x 14d
or
Olfloxacin 300mgs BD x 7d
                      Gonorrhoea
• IM Ceftriaxone 250mg stat
• Screening for other STD
• Contact tracing

• Pregnancy / Breastfeeding - Ceftriaxone
  250mg im stat.
• Contact tracing
  concordance rates: 78% F contacts, 86%
  M
• Test of cure
       Herpes simplex genitalis
• HSV-1 and 2
• Symptomatic primary infection in adult life, as likely to be
  HSV-1 as HSV-2

• Antivirals
  Valcyclovir 500mg bd x 5/7- acute attack
  Valcyclovir 500mg od x 1 year –suppression
  Acyclovir 200mg five times day - pregnancy

• Saline baths/Analgesia/Local anaesthetic/Counselling

• May require admission and suprapubic catheterisation
• Treatment of syphillis
 Benzathine penicillin 2.4MU once/week
 x 3 weeks

 If allergic - doxycycline 200mg od x 14d
           or erythromycin 500mg QDS x 14d

								
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