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