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ART – Current Guidelines and future options
Dr. A.K. Gupta
Additional Project Director, Delhi State AIDS
Control Society, Govt .of Delhi
Disease Burden of HIV/AIDS- India
Estimated number of People Living with HIV/AIDS: 2.27 million
(1.8—2.9 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%
Prevalence of HIV and
Estimated Infected Population
There is evidence that current strategies have
stabilized the epidemic in the country
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.
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,
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.
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.
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
Before ART
After ART
Goals of ART (1)
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)
Goals of ART (2)
Eradication of HIV?
Not yet…
And ….
…in spite of plasma RNA below
detection, there is evidence of genetic
evolution in reservoirs.
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.
WHEN TO START?
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 < 250
III
Treat if CD4 Count < 350
IV
Treat irrespective of CD4 Count
Total lymphocyte count is no longer to be used
for initiation or monitoring of ART
WHAT TO START WITH?
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)
ANTIRETROVIRAL DRUGS
Available 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)
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
HAART and Viral Load
Change in Viral Load (log scale)
baseline
0
AZT + 3TC
-1
-2
AZT/3TC/Indinavir
-3
12
24
36
Time (weeks)
48
NEJM 1997:337:734
Rise in CD4 Count
HAART and CD4 Count
AZT/3TC/Indinavir
200
100
AZT + 3TC
0
baseline
-100
12
24
36
Time (weeks)
48
NEJM 1997:337:734
Approach to patient
with
HIV infection
Step 1:
Clinical
History
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.
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
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
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
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
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)
i. Stavudine (30 mg) + Lamivudine (50mg)
ii. Zidovudine (300mg) + Lamivudine (150mg)
iii. Stavudine (30mg) + Lamivudine (150mg) +
Nevirapine (200 mg)
iv. Zidovudine (300mg) + Lamivudine (150mg) +
Nevirapine (200 mg)
v. Efavirenz (600mg).
HOW TO MONITOR THE PATIENTS?
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
LFT’s
Yes
No
Yes
Yes
CBC
Yes (AZT)
No
Yes
Yes
Other
chemistry
As clinically indicated
Viral Load estimation not a part of National Guidelines for 1st line therapy,
recommended by API, DHHS etc.
*A 2 week follow up after initiation is strongly recommended wherever possible
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.
SUCCESSFUL HIV THERAPY REQUIRES
RIGOROUS ADHERENCE
• >95% adherence necessary to achieve viral
load <400 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)
Initiating ART:
Patient Education
•
•
•
•
•
•
•
It is not curative, but prolongs life
Treatment is lifelong, expensive
High level of adherence is critical (>95%)
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
ART in HIV and TB
Revised Guidelines for initiation of ART
In Adults and adolescents (April 2009)
Type of TB
Pulmonary
TB
CD4 cell
count
(cells/ mm3)
CD4 < 350
in all patients
Extra
irrespective
pulmonary of CD4 count.
TB
Timing of ART in relation
to start of TB treatment
ART
recommendations
Start ATT first. Start ART
as soon as TB treatment
is tolerated (between 2
weeks and 2 months)
Recommend ART.
EFV containing
Regimens
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
WHEN TO CHANGE THE TREATMENT?
Changing Therapy
•
•
•
•
Due to adverse drug effects.
Due to inconvenient regimens.
Due to treatment failure.
Due to occurrence of tuberculosis/
pregnancy.
Definitions of ART failure
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.
Second line ART drugs in National
Programme
2nd line
ARV’s
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-Lamivudine;LPV-Lopinavir;r-Ritonavir;AZTZidovudine
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
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 patient’s
needs on nutrition and other supportive therapies.
Ever Registered
No. of patient on 1st line
No. of ART centre
1400000
350
1200000
300
1000000
250
800000
200
600000
150
400000
100
200000
50
0
Mar-05
Mar-06
Ever Registered
No. of patient on 1st line
No. of ART centre
Mar-07
Mar-08
Mar-09
march.10
march.11
194,607
428,056
686,913
933,540 1253498
6845
37368
69016
140654
223223
315640
404882
25
54
107
147
211
269
300
0
ART SCALE UP IN INDIA (CLHA)
90000
Ever Registered
No. of patient
350
No. of ART centre
80000
300
70000
250
60000
50000
200
40000
150
30000
100
20000
50
10000
0
Mar-05
Mar-06
Ever Registered
Mar-07
Mar-08
Mar-09
Mar-10
Mar-11
22,462
32,900
48,721
64,661
84,987
No. of patient
269
2335
6365
9495
14303
19203
23854
No. of ART centre
25
54
107
147
211
269
300
0
Cumulative Outcome of PLHAs on ART
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
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.
National ART Guidelines
• FOLLOW NACO GUIDELINES AVAILABLE ON
NACO WEBSITE—www.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
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 includes—ART centers, Community Care
Centres, STI clinics etc
Pattern of Assistance
Existing Scheme
Contribution of
implementing partner
Assistance from NACO
NGO/Corporate
Only for new constructions/
X
refurbishment
Component
Land
Infrastructure Development
X
To be provided
implementing partner
by
Equipment (CD4 machine)
X
To
be
provided
implementing partner
by
Human Resources
Centre
X
To
be
provided
implementing partner
by
for ART
For eligible patients from For employees & their
community in Corporate families in corporate/ PSU
ARV Drugs
centre
sector
Drugs
for
Opportunistic For All eligible patients in
Infections
NGO sector
To
be
provided
by
Baseline investigations
implementing partner
X
Diagnostic Kits (CD4)
Training of key personnel
√
IEC material
√
Operational
guidelines
Costs
as
per
X
TA / DA to be borne by
sponsoring agency
X
To
be
provided
implementing partner
by