Dr' Thomas Mathew

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Highly Active Antiretroviral Therapy (HAART)

• Dr. Thomas Mathew
• Prof Head, Community Medicine
• TDMC, Alappuzha

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CD4 Cell Counts and Opportunistic Infections
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Relating Disease Progression to Plasma HIV-1 RNA
Level and CD4 Cell Count
Viral Load
1,000
100
10,000
200
100,000
300
400
1000
900
800
700
600
500
CD4 COUNT

Adapted with permission from Coffin. AIDS.
199610(suppl 3)S75-S84.
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Goals of Antiretroviral Therapy

• Maximal durable suppression of viral
  replication
• Preservation and/or restoration of immunologic
  functions
• Improvement of QOL
• Reduction of HIV-related morbidity mortality

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Goals of Therapy

• Eradication of HIV? Not yet
• in spite of plasma RNA below detection there is
  evidence of genetic evolution in reservoirs.

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Current Ultimate Goal of HAART
CD4 T-cells
Relative Levels
Plasma HIV Viremia
Limit of detection
Months
Years After HIV Infection
Acute HIV infection Symptom
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Highly Active Antiretroviral Therapy (HAART)

• Combination of different classes of
  antiretrovirals
• to achieve maximal (below level of detection) and
  most durable suppression of viral replication
• prevent emergence of drug resistant mutants
• to improve survival quality of life

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HAART Problems

• Cost
• Pill burden
• Complex dosing schedules
• Drug interactions
• Cure not possible
• Drug toxicity
• Need for strict adherence
• Viral resistance

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Currently Available Antiretroviral Drugs
Fusion Inhibitor Enfuvirtide (T-20)
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Viral zinc-finger nucleocapsid proteins
Fusion inhibition
Viral protease
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
DNA
DNA
RT
Viral regulatory proteins
DNA
DNA
DNA
DNA
Provirus
Viral integrase
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Highly Active Antiretroviral Therapy (HAART)

• COLUMN A
• AZT 3TC
• AZT ddI
• d4T 3TC
• d4T ddI

• COLUMN B
• NVP
• EFV
• IDV
• NFV
• SQV-SGC
• RTV SQV
• RTV IDV
• RTV LPV

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Initial Treatment Regimens for Previously-Untreate
d Patients

• Three categories
• One NNRTI two NRTIs
• One PI/boosted-PI two NRTIs
• Three NRTIs
• Few clinical endpoints to guide choices
• Advantages and disadvantages to each type of
  regimen
• Individualize regimen choice
• Regimen should be potent, tolerable, preserve
  future options

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Not Recommended

• Stavudine Zidovudine
• Zalcitabine Lamivudine
• Zalcitabine Stavudine
• Zalcitabine Didanosine

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Hit HIV-1 Hard, but only when necessary

• Harrington M, Carpenter CJ
• Lancet 2000355(7)2147-52

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Recommendations for Initiating ART in Adults with
HIV Infection (WHO)

• If CD4 testing available
• WHO Clinical Stage IV disease
• WHO Clinical Stage I , II and III disease with
  CD4 lt200 cells/mm3
• If CD4 testing NOT available
• WHO Clinical Stage III and IV disease
• WHO Clinical Stage II disease with ALC lt1200/mm3

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Considerations Before Initiating HAART

• Patient readiness
• Medical eligibility
• OI treated/stabilized
• Concomitant medical conditions medications
• Sustainable drug supply

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Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)

• NRTI's or "nukes" block reverse transcriptase,
  preventing the transformation from RNA to DNA.
• Without the DNA, HIV is unable to make functional
  copies of itself and its proliferation in the
  body is halted

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Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)

• AZT
• Lamivudine (3TC)
• Stavudine (D4T)
• ddC (Zalcitabane)
• ddI (Didanosine)
• Abacavir

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AZT (Zidovudine)

• Form 100mg capsule and 300mg tablet
• Usual Dosage 300mg twice per day
• Instructions taking with food may help reduce
  nausea

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AZT (Zidovudine)

• ADR
• Anemia, neutropenia
• Nausea / vomiting
• Drug interactions or incompatibility
• D4T will decrease the effectiveness of AZT
• Concomitant use with nephrotoxic /
  myelosupressive / cytotoxic drugs eg. Flucytosine
  may increase toxicity risk
• Phenytoin altered levels.Phenytoin also
  decreases AZT clearance

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Lamivudine (3TC)

• Form 150mg tablets
• Usual Dosage 150mg twice per day
• ADR Well tolerated Nausea /
  vomiting
• DI Nil

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Stavudine (D4T)

• Form 30mg and 40mg capsules
• Usual Dosage 40mg twice per day for gt 60 Kg. And
  30 mg BD for lt60 Kg.
• ADRPerepheral neuropathy
• Abdominal pain, Nausea / vomiting
• Drug interactions or incompatibility
• Should not be co administered with AZT
• Use with caution in combination with other
  drugs that cause peripheral neuropathy

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DdI/Didanosine

• Form 100 mg tablet
• Usual Dosage 200 mg two times per day for gt60 Kg
  and 125mg for lt60 Kg.
• Instructions take 30min before or 2 hours after
  food,

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DdI/Didanosine

• ADR
• Peripheral neuropathy
• Pancreatitis
• Lactic Acidosis
• Drug Interactions
• Possible interactions with ketoconazole and
  quinolones

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ddC/Zalcitabane

• Form 0.75mg tablet
• Usual Dosage 0.75mg three times per day
• ADR
• Peripheral neuropathy
• Nausea / vomiting
• Ulcers in mouth
• Drug interactions or incompatibility
• Don't use with ddI
• Don't take with magnesium or aluminum containing
  antacids

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTI's)

• Nevirapine
• Efavirenz
• Delavirdine

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Nevirapine

• Form 200mg tablet
• Usual Dosage Lead-in dosing helps decrease the
  incidence of side effects. 200mg once per day for
  the first 14 days then 200mg twice per day.
• ADR Rash, hepatitis in 6 wks, liver enzyme
  elevation
• DI may decrease the effectiveness of oral
  contraceptives

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Efavirenz

• Form 200mg capsule and 600mg tablet
• Usual Dosage 600mg once a day
• Instructions Take on empty stomach or with a
  light snack. Recommended to be taken at bedtime..
• ADR Dizziness, insomnia, Vivid dreams, Mood
  changes CNS side effects.Transient rash, liver
  enzyme inducer

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Protease Inhibitors

• block the functioning of the enzyme protease
• without functioning protease, HIV is unable to
  mature and therefore can not make more copies of
  itself.

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Protease Inhibitors

• Indinavir
• Saquinavir
• Nelfinavir
• Ritonavir
• Amprenavir

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Indinavir

• Form 400mg capsule
• Usual Dosage 800mg three times per day
• Instructions Take on empty stomach 1 hour before
  or 2 hours after eating (may be taken with a
  light, low fat snack). Must drink at least 1 1/2
  liters of water per day.
• ADR Nausea / vomiting
• Diarrhea, Abdominal pain
• Kidney stones
• indinavir is sensitive to moisture. It should be
  stored in its original bottle which contains a
  desiccant (a material that keeps the drug dry).
• Rifampicin decreases the levels

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Saquinavir

• Form 200mg soft gel capsule / 200mg capsule
• Usual Dosage 1200mg three times per day
• Instructions Must be taken on full stomach for
  proper absorption. Keep at room temperature. In
  hot climates should be refrigerated.

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Saquinavir

• ADR
• Nausea / vomiting
• Diarrhea
• Numbness, tingling, or burning in feet or hands
• Drug interactions or incompatibility
• Rifampin and Rifabutin should not be used with
  saquinavir because it decreases blood levels. 

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Nelfinavir

• Form 250mg tablet
• Usual Dosage 750mg three times per day or 1250mg
  twice per day
• Instructions Take with a meal or a light snack.
• ADR Diarrhoea, nausea, rash

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Ritonavir

• Form 100mg capsule or 400mg
• Usual Dosage 600mg twice per day. Escalate dose
  over 14 days from 300 BD
• Instructions Preferably a high fat meal.
  Capsules need to be refrigerated.
• ADR Nausea / vomiting,.Abdominal pain
• Numbness, tingling,burning in feet or hands

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Drug Toxicity

• Hypersensitivity (ABC)
• Drug rash (NNRTI)
• Mitochondrial dysfunction (NRTI)
• Lipodystrophy (PI)
• Hyperglycemia (PI)
• Hyperlipidemia (PI)
• Osteonecrosis, osteoporosis

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Laboratory Monitoring for Toxicity and
Effectiveness of ARV Therapy
Adapted from WHO 2002.
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Criteria for Changing Therapy

• Less than a 0.5-0.75 log reduction in plasma HIV
  RNA by 4 weeks following initiation of therapy,
  or less than a 1 log reduction by 8 weeks
• Failure of a 1st or 2nd line regimen to suppress
  plasma HIV RNA to undetectable levels within 4-6
  months of initiating therapy
• Repeated detection of virus in plasma after
  initial suppression to undetectable levels,
  suggesting the development of resistance

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Long-term Efficacy of HAART No Magic Bullet, No
miracle
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence
Adherence Adherence Adherence

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Adherence

• 95 doses to be taken for complete viral
  suppression
• No evidence that degree of adherence required
  varies with different classes/drugs
• Poor adherence ? resistance ? virologic failure

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Predictors of Poor Adherence

• Poor patient-doctor relationship
• Active alcohol/drug use
• Active mental illness
• Lack of patient education
• Adverse drug reactions

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Causes of Treatment Failure

• Sequential monotherapy
• Sub-therapeutic plasma drug levels
• Nonadherence
• Inter-patient variability (pharmacokinetics)
• Bioavailability
• Drug-drug interactions
• Resistance/cross-resistance
• Advanced HIV disease (low CD4, high VL)

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Impact of Various ART Strategies in South Africa
Based on Wood E et al. Lancet 20003552095-2100
25 Antiretroviral Therapy Use
Life Expectancy at Birth
No Therapy
Year
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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

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