Dr' Tokugha Yepthomi

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Update on Highly Active Antiretroviral Therapy
(HAART) in HIV Management

• Dr. Tokugha Yepthomi
• Clinician Researcher
• YRG Centre for AIDS Research and
  EducationVoluntary Health Services
• Chennai, INDIA

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Adults and children estimated to be living with
HIV as of end 2005
Eastern Europe Central Asia 1.6 million 990
000 2.3 million
Western Central Europe 720 000 570 000 890
000
North America 1.2 million 650 000 1.8 million
East Asia 870 000 440 000 1.4 million
North Africa Middle East 510 000 230 000 1.4
million
Caribbean 300 000 200 000 510 000
South South-East Asia 7.4 million 4.5 11.0
million
Sub-Saharan Africa 25.8 million 23.8 28.9
million
Latin America 1.8 million 1.4 2.4 million
Oceania 74 000 45 000 120 000
Total 40.3 (36.7 45.3) million
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Estimated number of adults and childrennewly
infected with HIV during 2005
Eastern Europe Central Asia 270 000 140 000
610 000
Western Central Europe 22 000 15 000 39 000
North America 43 000 15 000 120 000
East Asia 140 000 42 000 390 000
North Africa Middle East 67 000 35 000 200
000
Caribbean 30 000 17 000 71 000
South South-East Asia 990 000 480 000 2.4
million
Sub-Saharan Africa 3.2 million 2.8 3.9 million
Latin America 200 000 130 000 360 000
Oceania 8200 2400 25 000
Total 4.9 (4.3 6.6) million
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Estimated adult and child deaths from AIDS
during 2005
Western Central Europe 12 000 lt15 000
Eastern Europe Central Asia 62 000 39 000
91 000
North America 18 000 9000 30 000
East Asia 41 000 20 000 68 000
North Africa Middle East 58 000 25 000 145
000
Caribbean 24 000 16 000 40 000
South South-East Asia 480 000 290 000 740
000
Sub-Saharan Africa 2.4 million 2.1 2.7 million
Latin America 66 000 52 000 86 000
Oceania 3600 1700 8200
Total 3.1 (2.8 3.6) million
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About 14,000 new HIV infections a day in 2005

• More than 95 are in low and middle income
  countries
• Almost 2000 are in children under 15 years of age
• About 12 000 are in persons aged 15 to 49 years,
  of whom
• almost 50 are women
• about 50 are 1524 year olds

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HIV Scenario in India

• 5.137 million infections
• Growing number of AIDS cases
• gt 85 infections in the age group of 15-49 years
• 75 are men

Chennai
Source NACO
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Leading causes of disease burden India, 2002
Rank of total
1 HIV/AIDS 2 Acute lower respiratory
infections 3 Diarrhoeal diseases 4 Childhood
cluster diseases 5 Low birth weight 6 Malaria 7
Unipolar depressive disorders 8 Ischaemic heart
diseases 9 Tuberculosis
9.0 8.2 6.3 5.5 5.0 4.9 3.1 3.0 2.9
Source The World Health Report 2002, WHO
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HIV disease

• Effective chemoprophylaxis for Opportunistic
  infections and use of antiretroviral therapy-
• delay in the onset of AIDS, a longer survival
  and a change in the pattern of opportunistic
  infections in the developed World ( Porter K, et
  al 1996 Brodt HR, et al 1997)

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Management of HIV Disease

• Management of Opportunistic Infections
• Prevention of Opportunistic Infections
• Psychosocial support
• Antiretroviral therapy

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Virion interaction with CD4 receptor and CXCR4
co-receptor
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Life cycle of the human immunodeficiency virus
New HIV Particle
HIV virion
Host chromosome
Genomic RNA
c DNA
Capsid protein
Proviral DNA
Viral
CD4 receptor
mRNA
Unintegrated ds DNA
RER
Nucleus
Reverse Transcription
Transcription
Attachment
Assembly release
Translation
Uncoating
Integration
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Current antiretroviral targets
Fusion
Viral protease
T20
Entry CCR5 antag.
SQV RTV IDV NFV APV LPV FOS ATZ
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
ZDV, ddI, ddC, d4T, 3TC, ABC, TDF, FTC DLV,
NVP, EFV
DNA
RT
DNA
DNA
Provirus
Integrase
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Currently available drugs
NRTIs Zidovudine (ZDV) Dideoxyionisine
(ddI) Dideoxycytidine (ddC) Stavudine
(d4T) Lamivudine (3TC) Abacavir
(ABC) Emtricitabine (FTC)
PIs Saquinavir (SQV) Ritonavir (RTV) Indinavir
(IDV) Nelfinavir (NFV) Amprenavir
(APV) Lopinavir/Ritonavir (LPV/r) Atazanavir
(ATV) Fos-amprenavir (f-APV) Tipranavir
NtRTIs Tenofovir (TDF)
NNRTIs Delaverdine (DLV) Nevirapine
(NVP) Efavirenz (EFV)
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Currently available drugs
NRTIs Zidovudine (ZDV) Dideoxyionisine
(ddI) Stavudine (d4T) Lamivudine (3TC) Abacavir
(ABC)
PIs Saquinavir (SQV/r) Indinavir
(IDV/r) Nelfinavir (NFV) Lopinavir/Ritonavir
(LPV/r)
NtRTIs Tenofovir (TDF)
NNRTIs Nevirapine (NVP) Efavirenz (EFV)
ENTRY-INHIB Enfuvirtide (T20)
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Generic Antiretroviral Drugs in India
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Reduction in death rate following
HAARTKumarasamy, et al. Clin Infect Dis 2005
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Natural history of HIV disease in South India
(Kumarasamy et al.CID Jan 2003)
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Indications for Antiretroviral Therapy

• 1) Acute Infection
• 2) Symptomatic
• 3) Asymptomatic CD4lt350-200 cells -Observe
• 4) Asymptomatic CD4 lt200 cells
• 5) If affordable /available

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HIV infected patient
API ASI-ART Guidelines 2005-2006
History and Physical examination
No symptoms
AIDS defining Illness/some Non-AIDS defining
illness
CD4 counts
CD4gt350
CD4 200-350
CD4 lt200
Stabilize OIs CD4 counts
Defer
CD4 200-250 Confirm 4 wks
CD4 250-350 Monitor PVLgt100000 HCV/HIVAN
Recommend HAART
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Baseline investigations

• Rule out all Opportunistic infections
• Treat OIs before initiating HAART
• Counsel pts regarding ARVs
• Baseline investigations CD4, Viral load, CBC,
  LFT, Lipid profile, Blood Sugar ,HBV, HCV

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When to initiate ART?
Risk of AE Adherence commitment Resistance
development Cost and readiness
Risk of progression
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First-Line Regimens for Adults
2 NRTIs are the backbone of any recommended
effective combination
Scaling-Up Antiretroviral Therapy in
Resource-Limited Settings, 2003
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Progression to AIDS/Death
No therapy
Mono-therapy
of patients progressing
Dual-therapy
Triple therapy
Months
JAMA 1998 CMAJ 1999
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What to start?
NRTI Recommended Zidovudine Tenofovir Alt
ernative Stavudine Abacavir Didanosine

• NNRTI
• Nevirapine
• Efavirenz

• NRTI
• Lamivudine

API ASI ART Guidelines 2005-2006
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What to start?
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ART not recommended for use
Reasons Resistance Less potent Less
potency Teratogenic Antagonist Additive toxicity
Drugs Mono, dual therapy 3NRTIs TDF ddI
NNRTI EFV in pregnancy d4TAZT ddC ddI/d4T
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ART strategies not recommended

• Sequential adding
• Altering doses and schedules
• Structured treatment interruptions (?)
• Induction-maintenance (?)

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Goals of Therapy
Maximum and durable suppression of viral
load Restoration and/or preservation of
immunologic function Improvement of quality of
life Reduction of HIV-related morbidity and
mortality
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Response to HAART
Ideal Response
RNA
Common Response
RNA
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Factors contributing to antiretroviral failure
Drug-resistant variants Preexisting Selected
Subinhibitory Drug Levels Limited potency or
distribution Poor adherence Poor
absorption Drug-drug interactions
Host Immune Failure CD4 cell functions Cytotoxic
T lymphocytes Chemokines
Persistient Viral Replication
Evolution of Drug Resistance
Drug Failure
Adapted from Hirach et al. JAMA.1998
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High levels of adherence required but not always
attained
Relationship of adherence (measured by MEMS) to
virologic success
100
Mean adherence rate
81
p 0.00001
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75
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Patients reaching undetectableHIV RNA LOQ 400
()
50
25
25
6
0
gt95
9095
8090
7080
lt70
Greatest danger zone for developing resistance

• ?95 adherence is required for optimal virologic
  suppression

Paterson, Ann Intern Med 200013321
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Why do patients miss doses?

0
10
20
30
40
50
60
Too busy / simply forgot
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Away from home
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Change in daily routine
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Felt depressed/overwhelmed
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Took drug holiday / medication break
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Ran out of medication
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Reasons given for missingantiretroviral
doses(structured questionnaire)
Too many pills
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Worried about becoming 'immune'
Felt drug was too toxic
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Wanted to avoid side effects
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Didn't want others to notice
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POSSIBLE INTERVENTIONS
Reminder of HIV infection
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Simplify dosing schedule
Confused about dosage direction
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Decrease pill burden
Didn't think it was improving health
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Other
To make it last longer
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Were told the medicine is no good
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Adapted from Gifford AL et al, J. AIDS
200023386-395
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Barriers and facilitators to antiretroviral
medication adherence among patients with HIV in
Chennai, India A qualitative study

• Cost
• Disclosure- Stigma
• Family members- DOT
• Kumarasamy N et al., AIDS Patient care STDs.
  2005

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ARV Toxicities

• Initial problems tolerating therapy
• Hypersensitivity reactions
• Immune-reconstitution related
• Chronic toxicities
• Drug-drug interactions

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Initial Problems Tolerating Therapy

• Zidovudine related nausea and headache
• 20 to 35
• Peak day 3, duration mean 5 days, resolution
• Rx take with food, warn, reassure, simple
  analgesics
• Efavirenz related neurotoxicty
• 2 to 15
• Follows initial dose, exacerbated by alcohol,
  mood altering therapies
• Rx warn, avoid alcohol, split dose 2 nocte 1
  mane,

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Initial Problems Tolerating Therapy

• Nelfinavir associated diarrhea
• Initial few weeks in most individuals
• Rx exclude OI, antimotility agents, calcium

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Hypersensitivity Reactions

• Nevirapine
• 15 20, usually at 14 days (1-3 weeks)
• Increased in Asian populations
• Prevention by slow increase, prednisolone
• Dont escalate with rash, 80 can dose through
  exception if hepatitis, mouth ulcers
• Very rare SJS dont reuse

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Hypersensitivity Reactions

• Abacavir
• Median day 11 (almost all within 6 weeks)
• Fever, myalgia, rash
• 3 to 12
• Redosing associated with fatality DO NOT REDOSE

Day 25
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Chronic Toxicities

• Bone marrow suppression
• Anaemia Check B12, folate, iron, other
  treatments
• Rx replacement deficiencies, change from ZDV to
  others
• Hepatitis
• Consider HCV, HBV, HDV, toxicity drugs, fatty
  liver
• Rx depends on time course early consider immune
  mediated, avoid ritonavir, DONT stop lamivudine
  if HBV

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Chronic Toxicities

• Peripheral neuropathy
• Consider nutritional, other drugs (INH), ddCgt
  D4Tgt ddI and uncontrolled HIV
• Rx switch, replace B12, folate, pain control
• Body shape changes
• Combination of PI plus stavudine
• Check metabolic complications (fasting
  cholesterol, trigs)
• Central adiposity v peripheral fat loss
• Rx change off PI or D4T (initial data small fat
  gain, imperceptible in short term)

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HAART associated physical changes

• ? abdominal girth
• Enlargement of dorsocervical fat pad (buffalo
  hump)
• Breast enlargement
• Lipoatrophy in face, arms, legs and buttocks
• Prominent leg veins
• Abby Shevitz et al. AIDS 2001,151917-1930

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Chronic Toxicities

• Pancreatitis
• Monitor amylase, consider with ddI, gt 3TC
  children, gt D4T
• Rx stop agent change to non-d
• Lactic acidosis
• Consider in increasing fatigue with acidosis and
  abnormal LFTs
• US liver, measure lactate
• Rx stop nRTIs, riboflavin, Compound Q10, carnitine

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Chronic Toxicities

• Depression
• Consider uncontrolled HIV, efavirenz
• Rx assess HIV control, switch EFV, antidepressant
  
• Metabolic
• Fasting cholesterol, trigs, BSL
• Rx Consider switch of PI or EFV to nevirapine or
  abacavir, pravastatin, fibrates

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Metabolic changes

• Dyslipidemia
• ? TGL, ? total cholesterol, ? LDL, ? HDL
• Insulin resistance
• glucose intolerance or (rarely) diabetes
• Abby Shevitz et al. AIDS 2001,151917-1930

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Chronic Toxicities

• Renal angle pain, calculi
• Indinavir crystals
• Look for and reverse dehydration
• Pain relief, if recurrent consider switch.

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Stavudine

• Most commonly used ARV in roll out
• Severe peripheral neuropathy
• Lipoatrophy- mean 20 months
• (Saghayam S,Chaguturu S, Kumarasamy N,
  et al. CID 2004)

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Prevent Lipoatrophy

• Substitute AZT after 6 -12 months with d4T
  containing HAART in ARV roll outs

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Follow up - investigations

• CD4 - Once in 3-6 months
• Viral load- Once in 6 months
• CBC- Once in 3 months
• LFT- Once in 3 months
• S.Amylase,S.Lipase,S.lactate, RFT,Blood
  sugar,Lipid profile,USG Abdomen, ARV genotyping-
  whenever needed

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Treatment Failure and Drug ResistanceVirologic,
Immunologic, and Clinical Definitions
Virologic failure
Immunologic failure
Clinical failure
CD4 Count
Drug Resistance
Viral Load
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Virologic failure

• VL gt 400 copies/ml at 24 weeks
• VL gt 50 copies/ml at 48 weeks
• VL rebound to gt400 copies/ml after viral
  suppression
• Note Single levels to 50-1000 c/ml- Blips
• 1000-5000 c/ml

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When to switch?
Definitions of treatment failure in HIV adults
and adolescents

• Clinical signs
• New OI or malignancy
• Recurrence of prior opportunistic infection
• Onset or recurrence of WHO Stage III disease
  conditions

• CD4 cell criteria
• Return of CD4 to pre-treatment level
• gt 30 decrease of CD4 during treatment without
  other concomitant infection

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What to ChangeSecond-line Treatment Regimens
for Adults

• All drugs should be replaced

ABC ddI/TDF LPV/r or SQV/r or IDV/r
d4T or ZDV 3TC NVP or EFZ
Change to
Scaling-Up Antiretroviral Therapy in
Resource-Limited Settings, 2003
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What to change?
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MTCT

• High maternal viral load
• Low maternal CD4
• Maternal Opportunistic infections
• Chorioaminionitis
• Prolonged Labor,Episiotomy
• Breast Feeding

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Mode of Delivery ZDV Prophylaxis
HIV Perinatal Transmission
The European Mode of Delivery Collab. Lancent
1999 3531035-8
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HIVNET012 (Single dose NVP)

• Kampala, Uganda
• Nevirapine 200mgs single dose PO 2 hrs before
  delivery to mother
• Nevirapine syp 2mgs/kgbodyweight within 72 hrs to
  the infant
• Nevirapine lowered the risk of HIV-1 transmission
  during the first 14-16 weeks of life by nearly
  50 in a breastfeeding population.
• LA Guay, et al. Lancet. 1999 Sep 4 354(9181)
  795-802.

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About resistance

• Develops under sub-optimal drug pressure
• Mutations in the RT and Prot gene
• Permanently archived
• Some drugs have low genetic barrier
• Class cross resistance

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ARV Resistance testing

• Phenotyping
• Genotyping
• Virtual phenotyping

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IAS-USA list
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Progressive vs. Immediate Resistance
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Progressive vs. Immediate Resistance
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NNRTI Resistance

• Resistance mutations common after virologic
  failure
• May occur as 1st mutation, preceding M184V
• The most common mutations cause resistance to all
  NNRTIs no evidence for sequencing within class
• Dont continue NNRTI in failing regimen!
• No fitness advantage
• Accumulation of NNRTI mutations may cause
  cross-resistance to 2nd generation agents in
  development

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Success of HAART

• Start therapy only when the patient is ready
• Stress the importance of adherence before
  starting at every visit thereafter
• Keep the viral load suppressed
• Identify failure and respond quickly
• Consider the likely resistance patterns

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Success of HAART

• Start therapy only when the patient is ready
• Stress the importance of adherence before
  starting at every visit thereafter
• Keep the viral load suppressed
• Identify failure and respond quickly
• Consider the likely resistance patterns

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Benefits Barriers

• Combination Therapy Today
• Benefits Barrier
• Suppression of HIV Drug - drug interactions
• If sustainable, HIV becomes Resistance
• a manageable disease Complex dosing
• Prevention of Immune system Expense
• damage
• Increase in Survival times Long term efficacy?
• Decrease in OIs

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Benefits of ART in prevention

• Preventing Mother to child transmission
• Post exposure prophylaxis (PEP)
• Occupational
• Sexual (NPEP)
• Primary prevention (PREP) ?
• Secondary prevention (?)

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YRG CARE
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