ART

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ART Current Guidelines and future options
Dr. A.K. GuptaAdditional Project Director,
Delhi State AIDS Control Society, Govt .of Delhi

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Disease Burden of HIV/AIDS- India

• Estimated number of People Living with HIV/AIDS
  2.27 million (1.82.9 million) in 2008
• Six high prevalence states contribute more than
  60 of PLHA
• Women constitute 39 and Children 3.8
• Estimated Adult HIV prevalence 0.29

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Prevalence of HIV and Estimated Infected
Population
There is evidence that current strategies have
stabilized the epidemic in the country
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HIV Prevalence India, 2007
A total of 3,58,797 samples were tested during
HIV Sentinel Surveillance 2007
Note ANC Prevalence is the standardized for
population.
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Routes of Transmission of HIV
Analysis of information from around 300,000
persons tested HIV positive at various counseling
and testing centers in 2009-10,
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Management of an HIV infected person

• Aims of Management
• Reduce sufferings because of HIV infection.
• Treat/prevent Opportunistic Infections.
• Protect patient from acquiring further infection.
• Prolongation of life, improve quality of life.
• Prevent transmission of HIV from patient to
  others.

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Basic Approaches for Management of Patients of
HIV/AIDS

• Supportive therapy
• Preventive Strategies
• Prophylaxis for different O.Is depending on
  CD4 count.
• Therapeutic Strategies
• 1. Treatment of O.Is.
• 2. ARV Therapy.

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Antiretroviral Therapy (ART)

• Combine different classes of antiretrovirals
• To achieve maximal and most durable suppression
  of viral replication
• To prevent emergence of drug resistant mutants
• To improve survival quality of life

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Goals of ART (1)

• Clinical goal
• To prolong life improve quality of life
• 2. Virological goal
• Greatest possible reduction in viral load for as
  long as possible to halt disease progression and
  to prevent or delay resistance
• 3. Immunological goal
• Immune reconstitution that is both quantitative
  (CD4 within normal range) and qualitative
  (pathogen specific immune response)

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Goals of ART (2)

• 4. Therapeutic goal
• Rational sequencing of drugs to
  achieve previous 3 goals while
• Maintaining therapeutic options
• Minimizing drug toxicities side effects
• Maximizing adherence
• 5. Epidemiological goal
• Reduce HIV transmission

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Eradication of HIV?

• Not yet
• And .
• in spite of plasma RNA below detection, there is
  evidence of genetic evolution in reservoirs.

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Issues concerning ART

• When to start treatment ?
• Which and how many agents to use ?
  Choice of optimal regimen ?
• How to monitor the therapy ?
• How long to give therapy ?
• When to change therapy and to what ?
• Drug interactions involving antiretroviral
  therapy.

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• WHEN TO START?

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Initiation of ART in Adults and Adolescents
National Guideline

• Revised National Guideline (April 2009)

WHO Clinical Staging CD4 (cells/cu.mm)
I and II Treat if CD4 Count lt 250
III Treat if CD4 Count lt 350
IV Treat irrespective of CD4 Count
Total lymphocyte count is no longer to be
usedfor initiation or monitoring of ART
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• WHAT TO START WITH?

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Classes of Antiretroviral Drugs
Four Broad Groups
A Nucleoside Reverse Transcriptase Inhibitors (NRTI)
B Non - Nucleoside Reverse Transcriptase Inhibitors (NNRIT)
C Protease Inhibitors (PI)
D Fusion Inhibitors(FI)
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ANTIRETROVIRAL DRUGSAvailable in India
NRTI NNRTI PI
Zidovudine (AZT) Nevirapine(NVP) Indinavir(IDV)
Lamivudine (3TC) Efavirenz(EFV) Nelfinavir(NFV)
Stavudine (d4T) Delavirdine(DLV) Saquinavir(SQV)
Didanosine (ddl)   Ritonavir(RTV)
Zalcitabine(ddC)   Atazanavir(ATV)
Abacavir(ABC)   Lopinavir(LPV)
Tenofovir(TFV)  
Emtricitabine(FTC)  
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Guidelines for Antiretroviral Therapy
No MONOTHERAPY or DUAL THERAPY
HAART Highly Active Antiretroviral Therapy
Human Immunodeficiency virus (HIV) infection is
currently treated with combination therapy using
at least three drugs from NRTI NNRTI/PIs over
an indefinite period.
Possible combinations
1. 2 NRTI's 1 NNRTI 2. 2 NRTI's 1 PI 3.
2 NRTI's 1 More NRTI
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HAART and Viral Load
baseline
0
AZT 3TC
-1
Change in Viral Load (log scale)
-2
AZT/3TC/Indinavir
-3
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36
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NEJM 1997337734
Time (weeks)
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HAART and CD4 Count
AZT/3TC/Indinavir
200
Rise in CD4 Count
100
AZT 3TC
0
baseline
-100
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12
36
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Time (weeks)
NEJM 1997337734
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Step 1 Clinical History
Approach to patient with HIV infection Step 1-
Clinical History

• HIV specific symptoms Present past
• Past history Jaundice, TB, coronary artery
  disease, dyslipidaemia others
• Personal history Smoking, alcohol drugs
• Family history Diabetes, hypertension, etc.
• Sensitive sexual history Genital ulcers, other
  STIs, substance use, multiple sex partners, etc.
• Treatment history ARVs, contraceptives in women,
  herbal drugs, etc.

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Step 2 Physical Examination

• Weight, height BMI
• Oral cavity, lymph nodes, skin, eyes
• Genital examination
• Vital signs
• Systemic examination all systems
• Ophthalmic fundus examination
• Quality of life assessment

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Laboratory Investigations

• For All patients
• Complete blood count.
• Urine Analysis.
• Blood Chemistry
• Transaminases, Blood Urea, Serum creatinine,
  Blood Sugar
• Serology
• Sero diagnosis for HIV
• VDRL, Toxoplasma IgG, Hepatitis B C serologies.
• Chest X-Ray PA veiw..
• Montoux test.
• PAP smear in women
• CD4/CD8 cell count
• Viral load??--not essential

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Laboratory Investigations

• If indicated
• Pregnancy test.
• Sputum Examination
• AFB
• Gram Stain
• PC
• Stool Examination for parasites Including
  modified ZN stain
• USG admomen
• Organomegaly
• Abscessess in Liver Spleen.
• Ascites, neoplasms
• L Nodes at
• Porta hepatis.
• Retroperitoneal

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Laboratory Investigations

• If indicated
• Lymph node Biopsy
• CSF Examination
• Cytology.
• Biochemistry.
• India ink staining
• CT/MRI Brain.
• Blood Culture.
• S.Amylase/S. lactic acid/S lipid profile.
• Decision to be taken on individual basis

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National ART regimen

• Zidovudine / Lamivudine / Nevirapine
• Or
• Stavudine / Lamivudine / Nevirapine
• ( Efavirenz in place of Nevarapine if coinfected
  with TB
• or side effects with NVP,
• Tenofovir under consideration for special
  situations only)

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First line FDCs

1. Stavudine (30 mg) Lamivudine (50mg)
2. Zidovudine (300mg) Lamivudine (150mg)
3. Stavudine (30mg) Lamivudine (150mg)
   Nevirapine (200 mg)
4. Zidovudine (300mg) Lamivudine (150mg)
   Nevirapine (200 mg)
5. Efavirenz (600mg).

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• HOW TO MONITOR THE PATIENTS?

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Monitoring the Therapy
1 month 3 months 6 months Every 6 months thereafter
Clinical (monthly Yes Yes Yes Yes
CD4 counts No No Yes Yes
LFTs Yes No Yes Yes
CBC Yes (AZT) No Yes Yes
Other chemistry Viral Load estimation not a part of National Guidelines for 1st line therapy, recommended by API, DHHS etc. Viral Load estimation not a part of National Guidelines for 1st line therapy, recommended by API, DHHS etc. Viral Load estimation not a part of National Guidelines for 1st line therapy, recommended by API, DHHS etc. Viral Load estimation not a part of National Guidelines for 1st line therapy, recommended by API, DHHS etc.
As clinically indicated
A 2 week follow up after initiation is strongly
recommended wherever possible
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Important side effects

• Zidovudine Haematologic toxicities ,
  Granulocytopenia, anemia, myopathy,
  pigmentation.
• Lamivudine Minimal toxicities, lactic acidosis
  and steatosis.
• Stavudine Lactic acidosis, peripheral
  neuropathy, pancreatitis.
• Nevirapine Severe, life-threatening
  hepatotoxicity, hepatic failure, severe
  life-threatening skin reactions, Stevens-Johnson
  syndrome, toxic epidermal necrolysis etc.
• A 14 day lead in dose needed.
• Efavirenz Neuro psychiatric side effects, contra
  indicated in pregnancy.
• Protease Inhibitors Metabolic complications -
  Lipid abnormalities, body fat redistribution,
  hyperglycaemia.

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SUCCESSFUL HIV THERAPY REQUIRES RIGOROUS ADHERENCE

• gt95 adherence necessary to achieve viral load
  lt400 copies/mL in 81 of HIV patients
• A 10 reduction in adherence was associated with
  a doubling of HIV RNA level
• 80 adherence may be sufficient to achieve
  therapeutic goals in other chronic disease states
  (e.g., hypertension)

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Initiating ART Patient Education

• It is not curative, but prolongs life
• Treatment is lifelong, expensive
• High level of adherence is critical (gt95)
• Short and long term adverse events
• Drug interactions
• Safer sex still essential
• Do not share drugs with friends , family members

Start ART when patient is ready
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ART in HIV and TB

• Revised Guidelines for initiation of ART
• In Adults and adolescents (April 2009)

Type of TB CD4 cell count (cells/ mm3) Timing of ART in relation to start of TB treatment ART recommendations
Pulmonary TB CD4 lt 350 Start ATT first. Start ART as soon as TB treatment is tolerated (between 2 weeks and 2 months) Recommend ART. EFV containing Regimens
Extra pulmonary TB in all patients irrespective of CD4 count. Start ATT first. Start ART as soon as TB treatment is tolerated (between 2 weeks and 2 months) Recommend ART. EFV containing regimens

• Special Attention to be paid for monitoring
  Hepato toxicity

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• WHEN TO CHANGE THE TREATMENT?

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Changing Therapy

• Due to adverse drug effects.
• Due to inconvenient regimens.
• Due to treatment failure.
• Due to occurrence of tuberculosis/ pregnancy.

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Definitions of ART failure
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Second Line ARV Drugs

• NACO survey shows that treatment failure to first
  line is nearly 2.8
• Issues with second line drugs
• Ten time costlier than the first line drugs
• More toxic to patient than the first line drugs
• Training of health care providers required
• Institutional strengthening, particularly
  laboratories for viral load and drug resistance
  testing.
• Regulatory mechanisms to be developed
• All these mechanisms have to be in place before
  second line therapy can be rolled out as third
  line drugs are not available.

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Second line ART drugs in National Programme
2nd line ARVs Dosage Dosing schedule
TDF 3TC Fixed dose combination of TDF 300 mg 3TC 300 mg ( Once daily) 1 0 0 ( One tablet in the morning)
LPV/r Heat stable co-formulation of LPV 200mg Ritonavir 50 mg (twice daily) 2 0 2 (Two tablets in the morning and Two tablets in the evening)
AZT Zidovudine 300 mg Twice daily 1 0 1 (One tablet in the morning and One tablet in the evening)
TDF-Tenofovir 3TC-LamivudineLPV-Lopinavirr-Rito
navirAZT-Zidovudine
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Before labeling failure.. ensure

• Patient had a reasonable trial of first line ART
  for at least 6 months
• Assess adherence and support patient to improve
  this (reinforce)
• Screen and treat intercurrent OIs
• Provide Cotrimoxazole as per guidelines if
  necessary
• Exclude IRIS
• If TB is present assess if this is reinfection
  or IRIS or a new infection. If the response to TB
  therapy is good, then the decision to switch
  therapy can be postponed and the patient
  re-evaluated again.
• CD4 count

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Important Practice Points

• What should not be done
• Do not start ART in a patient who is not fully
  motivated/or counselled about drugs, their side
  effects and economic factor or in whom adherence
  is doubtful.
• No monotherapy at all.
• Do not start ART without availability of minimal
  laboratory monitoring.
• Do not provide ART without capacity to meet
  patients needs on nutrition and other supportive
  therapies.

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Cumulative Outcome of PLHAs on
ART
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Cost of ART Services

• ARV Drugs
• First line ART- Rs 5000/patient/yr
• Alt First line ART- Rs- 11500/ patient/ yr
• Second line ART- Rs- 29000/ patient/ yr
• Laboratory Services
• CD4 Count Rs. 175-225 per test
• DNA-PCR for young children Rs. 1000-1200

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Second Line ART

• The rollout of second line ART began form
  Jan.2008 at 2 sites GHTM, Tambaram, Chennai and
  JJ Hospital, Mumbai on a pilot basis.
• Expanded to 10 centers of excellence from Jan
  2009.
• Presently, 2500 patients are receiving second
  line drugs at these 10 centers.

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National ART Guidelines

• FOLLOW NACO GUIDELINES AVAILABLE ON NACO
  WEBSITEwww.nacoonline.org
• Even the Supreme Court of India has mandated that
  these guidelines need to be followed by all
  doctors both in public and private sector

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PPP Model ART Centres Concept

• As a part of Govt. commitment to involve
  private sector into the national program, ART
  services through PPP model are encouraged in
• NGO/ Trust Hospitals
• PSUs
• Corporate Sector
• It includesART centers, Community Care Centres,
  STI clinics etc

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Pattern of Assistance Pattern of Assistance Pattern of Assistance
Component Existing Scheme Existing Scheme
Component Assistance from NACO Contribution of implementing partner NGO/Corporate
Land X Only for new constructions/ refurbishment
Infrastructure Development X To be provided by implementing partner
Equipment (CD4 machine) X To be provided by implementing partner
Human Resources for ART Centre X To be provided by implementing partner
Diagnostic Kits (CD4) For eligible patients from community in Corporate sector For All eligible patients in NGO sector For employees their families in corporate/ PSU centre
ARV Drugs For eligible patients from community in Corporate sector For All eligible patients in NGO sector For employees their families in corporate/ PSU centre
Drugs for Opportunistic Infections For eligible patients from community in Corporate sector For All eligible patients in NGO sector For employees their families in corporate/ PSU centre
Baseline investigations X To be provided by implementing partner
Training of key personnel v TA / DA to be borne by sponsoring agency
IEC material v X
Operational Costs as per guidelines X To be provided by implementing partner
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Thank You