ART – Current Guidelines and future options
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Transcript of ART – Current Guidelines and future options
ART – Current Guidelines and future options
Dr. A.K. GuptaAdditional 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 goalImmune 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 GuidelineRevised National Guideline (April 2009)
WHOClinical 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 usedfor 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 DRUGSANTIRETROVIRAL DRUGSAvailable in IndiaAvailable in India
NRTI NNRTI PIZidovudine (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
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
No MONOTHERAPY or DUAL THERAPY
HAART and Viral Loadbaseline
AZT + 3TC
AZT/3TC/Indinavir
2412 36 48
Time (weeks)
Cha
nge
in V
iral L
oad
(log
scal
e)
0
-2
-3
-1
NEJM 1997:337:734
HAART and CD4 Count
AZT + 3TC
AZT/3TC/Indinavir
2412 36 48
Time (weeks)
Ris
e in
CD
4 C
ount
0
200
100
NEJM 1997:337:734
-100
baseline
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.
Approach to patient with HIV infection
Step 1- Clinical History
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 / NevirapineOr
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 Therapy1 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 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
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
Type of TBCD4 cell
count(cells/ mm3)
Timing of ART in relation to start of TB treatment
ART recommendations
Pulmonary TB
CD4 < 350Start 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
Revised Guidelines for initiation of ART In Adults and adolescents (April 2009)
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;AZT-Zidovudine
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.
Cumulative Outcome of PLHAs on ART
Cost of ART ServicesCost 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 ARTSecond 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
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 SectorIt includes—ART centers, Community Care
Centres, STI clinics etc
PPP Model ART Centres : PPP Model ART Centres : ConceptConcept
Pattern of Assistance
Component
Existing Scheme
Assistance from NACOContribution of
implementing partner NGO/Corporate
Land XOnly for new constructions/ refurbishment
Infrastructure Development X To be provided by implementing partner
Equipment (CD4 machine) XTo be provided by implementing partner
Human Resources for ART Centre
XTo 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
Drugs for Opportunistic Infections
Baseline investigationsX
To be provided by implementing partner
Training of key personnel √TA / DA to be borne by
sponsoring agencyIEC material √ XOperational Costs as per guidelines
XTo be provided by implementing partner