ISSUES ON ANTIRETROVIRAL THERAPY

DR.K.PRASANTHI MD

…A long WALK with HIV….

..a small Talk on ART !!

ART……. !!!.... Will it pave the way for success ..?

Months

% o

f pati

ents

pro

gres

sing

No therapy Mono-therapy

Dual-therapy

Triple therapy

Progression to AIDS / Death

Source: NEJM

Some facts about ART• 1996 - PIs were introduced - era of HAART

came in

• Then - high costs, large number of pills and side effects of these drugs

• Now cost of Therapy reduced from

Rs.30,000 in 1998 to Rs1000 per month in 2006,

no. of pills from 32 to 1 or 2 per day,

regimens simplified, fewer side effects with newer drugs

Antiretroviral Therapy (ART)

• ART is the combination of different classes of ARV drugs

– To achieve maximal and most durable suppression of viral replication

– To prevent emergence of drug resistant mutants

– To improve survival & quality of life After ART

Images Courtesy GHTM Tambaram /I-TECH

Do all Patients with HIV Infection Need ART?

Patients with higher CD4 counts e.g. >500 cells/cumm do not have additional survival benefit from ART &The risk from ART toxicities is high (especially Nevirapine) in patients with higher CD4 counts

- determine eligibility for ART - based on clinical and immunological criteria

Indications for Initiation of ART National Guidelines, April 2009

WHO

Clinical StagingCD4 (cells/cu.mm)

I and II Treat if CD4 Count <250

III Treat if CD4 Count <350

IV Treat irrespective of CD4 Count

WHO Clinical Staging I

• Asymptomatic

• Persistent generalised lymphadenopathy (PGL)

• Painless• non-contiguous sites (excluding

inguinal) • bsence of known cause • Persisting for 3 months

WHO Clinical Staging 2

• moderate weight loss (<10% of presumed or measured body weight)

Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis)

Herpes zoster

Recurrent oral ulceration

Seborrhoeic dermatitis

Fungal nail infections

WHO Clinical Staging 3 severe weight loss (>10% of presumed or

measured body weight)

chronic diarrhoea for longer than one month

persistent fever longer than one month

Persistent oral candidiasis

Oral hairy leukoplakia (OHL)

Pulmonary tuberculosis cont......

………..WHO Clinical Staging 3

Severe bacterial infections

Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

Unexplained

Anaemia (<8 g/dl)

Neutropenia (<0.5 x 109 /L) and or

Chronic thrombocytopenia (<50 X 109 /L)

WHO Clinical Staging 4

HIV wasting syndrome

Pneumocystis pneumonia (PCP)

Recurrent severe bacterial pneumonia

Oesophageal candidiasis

Extra pulmonary tuberculosis

Kaposi’s sarcoma

cont……..

………WHO Clinical Staging 4

Central nervous system toxoplasmosis

HIV encephalopathy

Extra pulmonary cryptococcosis

Disseminated non-tuberculous mycobacteria infection

Chronic cryptosporidiosis, isosporiasis

cont……

……….WHO Clinical Staging 4

Disseminated mycosis (extra pulmonary histoplasmosis, coccidiomycosis)

Lymphoma (cerebral or B cell non-Hodgkin)

Invasive cervical carcinoma

Atypical disseminated leishmaniasis

HIV associated nephropathy or cardiomyopathy

NACO ART services Three Tier model

Care & Support : Community Care Centre (CCC)

• good quality, skilled and knowledgeable healthcare providers

• in chronic patient management, including treatment failures

• Training HIV Care personnel

• Operational Research and scientific publications

• Fellowship Programmes for doctors

• Mentoring ART centres in the region / state

Centre of Excellence

Chandigarh

New Delhi

Varanasi

Imphal

Kolkata

Ahmadabad

Mumbai

Hyderabad

Bengaluru

Chennai

COE

Centres of Excellence

No COE ART Centres

1Government Hospital of Thoracic Medicine (GHTM), Tambaram , Chennai

Allotted ART centres in Tamil Nadu, Kerala, Pondicherry & ART centres of Tirupathi, Nellore & Chittoor

2 Sir J.J. Hospital, Mumbai Allotted ART centres in Maharashtra, Madhya Pradesh & Goa

3 Government Gandhi General Hospital , Hyderabad

All ART centres in Andhra Pradesh (except ART centres of Tirupathi, Nellore & Chittoor)

4 Bowring and Lady Curzon Hospital, Bangalore All ART centres in Karnataka

5 Bairamji Jijibhai Medical College (BJMC), Ahmedabad

Allotted ART centres in Gujarat & ART centres of Udaipur & Jodhpur

Centres of Excellence &ART Centres for Referrals

No COE ART Centres

6 Maulana Azad Medical College (MAMC), New Delhi

All ART centres in New Delhi, Rajasthan (except Udaipur & Jodhpur), Uttarakhand & ART centres in Meerut, Aligarh & Agra

7Post Graduate Institute of Medical Education & Research (PGIMER) , Chandigarh

All ART centres in Himachal Pradesh, Haryana, Punjab, Chandigarh, Jammu & Kashmir

8 School of Tropical Medicine, Kolkata

All ART centres in West Bengal, Orissa, Jharkhand, Chhattisgarh, Assam and Sikkim

9 BHU Varanasi All ART centres in UP (except Meerut, Agra & Aligarh) & Bihar

10 RIMS , Imphal All ART centres in North Eastern States

Centres of Excellence &ART Centres for Referrals

ART Plus Centres: Rationale

• To combat Problems - treatment failure with First Line ART are referred to the CoE for further evaluation and Second Line treatment.

• facing problems due to long distance, travel, time and costs.

• it has been decided to expand the network of ART centres that would be capacitated to start Second Line treatment

1. Govt. Medical College, Salem (Functioning)

2. Govt. Medical College, Aurangabad (Oriented)

3. Byramjee Jejeebhoy Medical College & Sasoon Hospital, Pune (Oriented)

4. Govt. Medical College, Nagpur (Oriented)

5. Govt. Medical College, Surat (Oriented)

6. KIMS, Hubli, Karnataka (Sanctioned)

7. GGH, Vijayawada, Andhra Pradesh (Sanctioned)

8. Govt. Medical College, Trichur, Kerala (Sanctioned)

ART Plus Centres

As on March 2011

Role of Link ART Centres

LAC

Back Referral to ART Centre

Screening of HIV-TB

Co infection

Psycho-Social SupportTo PLHIV

Treatment ofMinor OIs

Provide ARV Drugs to Stable PLHIV on ART

Adherence Counselling

and Monitoring PLHIV for side

effects

• LAC reduces travel from long distances to access ART Services

• Designed to enhance ART Adherence

Role of CCC in ART

• Drug Adherence and nutritional counselling

• tracing missed cases and those lost to follow-up through outreach workers

• Psycho-social support

• Home-based care for bedridden patients

ART programme: Current Scenario

Total number of patients on ART : 3,84,726

• % Adults

• % Children

: 94 %

: 6%

No. of new adult patients on ART per month

No. of new children patients on ART per month

: 7000

: 350

Updated December 2010

Treatment Outcome: Cumulative

Updated October 2010

NRTI NNRTI Protease Inhibitor OTHERS

Zidovudine (AZT)*

Nevirapine (NVP)* Lopinavir (LPV)* Integrase Inhibitors

Stavudine (d4T)* Efavirenz (EFV)* Ritonavir (RTV)* Raltegravir

Lamivudine (3TC)*

Atazanavir (ATV) Fusion Inhibitor

Emtricitabine (FTC)

Saquinavir (SQV) Enfuviritide (T-20)

Didanosine (ddI ) Indinavir (IDV) Chemokine Co Receptor (CCR5 / CXCR4) Antagonists)

Abacavir (ABC) Nelfinavir (NFV)

NtRTI Amprenavir (APV)

Tenofovir (TDF)*Fosamprenavir, (FPV), Tipranavir (TPV), Darunavir (DRV)

Maraviroc (CCR5 co receptor antagonists)

* The highlighted drugs are NOW available in the NACO ART programme

Classes of ARV Drugs

National ART Regimen

Drugs

Regimen I Zidovudine + Lamivudine + Nevirapine

Regimen I (a) Stavudine + Lamivudine + Nevirapine

Regimen II Zidovudine + Lamivudine + Efavirenz

Regimen II (a) Stavudine + Lamivudine + Efavirenz

National First line ART

Recommended First Line Drugs : 2NRTI +1 NNRTI

First line ART: Drug ToxicitiesDrugs Short term toxicities Medium term

toxicitiesLong term toxicities

Zidovudine Nausea, vomiting, Diarrhoea

Bone Marrow suppressionAnaemiaHyper pigmentationLactic Acidosis

Lipodystrophy

StavudineLactic AcidosisPancreatitisPeripheral Neuritis

LipodystrophyDyslipidemia

Lamivudine Skin Rashes

Nevirapine Skin RashesHepato toxicity

Efavirenz

Skin RashesHepato toxicity Drowsiness, dizzinessConfusion, Vivid dreams

Regimen Drug Combination Remarks

Regimen IIITenofovir + Lamivudine + Nevirapine For patients not

tolerating Zidovudine and StavudineRegimen III (a) Tenofovir +

Lamivudine + Efavirenz

Alternate to Zidovudine & Stavudine

Alternate First line ART

Regimen Drug Combination Remarks

Regimen IVZidovudine + Lamivudine + Lopinavir / Ritonavir

For patients not tolerating both NVP & EFV

Regimen IV (a)Stavudine + Lamivudine + Lopinavir / Ritonavir

For patients not tolerating both NVP & EFV and Hb <9 g%

Alternate to Nevirapine & EfavirenzIn patients with confirmed HIV 2 infection

Alternate First line ART

ART in special situations…….

Type of TBCD4 cell

count

(cells/ mm3)

Timing of ART in relation to start of TB

treatment

ART Recommendations

Pulmonary TB

CD4 <350

Start ATT first Start ART as soon

as TB treatment is tolerated

(after 2 weeks & before 2 months)

Recommend ART.

EFV containing

Regimens

Extra pulmonary

TB

irrespective of CD4 count

Start ATT first Start ART as soon as

TB treatment is tolerated

(after 2 weeks &

before 2 months)

Recommend ART.

EFV containing

regimens

Special Attention to be paid for monitoring Hepato toxicity

ART in HIV and TB

WHO

Clinical StagingCD4 (cells/cu.mm)

I and II Start ART at CD4 Count <350

III & IV Start ART irrespective of CD4 Count

Avoid Efavirenz during First Trimester of Pregnancy

Strict Monitoring for Adverse effects of Nevirapine is needed if CD4 count is >250

ART in PregnancyGuidelines for initiation of ART (2010)

Intervention Risk of Mother-to-Child HIV Transmission

No ARV, breastfeeding 30-45%

No ARV, No breastfeeding 20-25%

Short course with 1 ARV, breastfeeding 15-25%

Short course with 1 ARV, No breastfeeding 5-15%

Short course with 2 ARVs, no breastfeeding 5%

3 ARVs (ART), no breastfeeding 1%

Source: WHO

ARV / PTCT

Care of HIV Exposed Infants & Children

6 weeks10 weeks

14 weeks6 months

9 months12 months

18 months

DNA PCR for all HIV exposed infants

DNA PCRHIV Antibody test followed by DNA PCR if HIV+

Final confirmatory Antibody Test for all HIV exposed infantsirrespective of earlier testing results / treatment status

Birth

Schedule of visits at ICTC

Rapid antibody test not recommended

ART in Infants (<12 Months)

Criteria for starting ART

- All infants under 12 months of age with confirmed HIV infection irrespective of clinical or immunological stage

- Where virological testing is not available, infants under 12 months of age with clinically diagnosed presumptive severe HIV should start antiretroviral therapy

Monotherapy as Prophylaxis

• Nevirapine (NACO Guidelines)

–Mother - Single dose NVP 200mg onset of labour

–Baby - Syrup NVP 2mg/kg within 72 hours of delivery

• Revised NACO Guidelines will be in place shortly

ART & HIV-2

Primarily seen in West Africa

Less transmissibility as compared to HIV-1

Slower rate of progression

Low MTCT

No viral load assay available

NNRTI are ineffective

PI-based ART (AZT/d4T + 3TC + LPV/r)

OI ….??..... ART

1. OIs shortly after initiating ART (within 12 weeks) -

There is no change or mild increase in CD4 counts - either sub clinical infections or due to advanced disease

2. OI after 12 weeks after initiation of therapy

There is a marked raise in CD4 counts - IRIS

3. OI as the manifestation of failing ART regimen

Patients have a failing CD4 count – treatment failure

• Clinical monitoring – Monthly– Clinical Evaluation– Treatment Adherence Evaluation– For Adverse reactions of ART/OI drugs– For drug interactions– For Immune Reconstitution Inflammatory Syndrome

• Immunological monitoring– CD4 count

• Virological test (Targeted Viral load test) - PCR– (SACEP/DACEP)

Follow up of ART

• Tests are required to monitor

- Disease progression

- Staging of disease

- Response to ART

• Include - CD4 T-cell Assay

- Viral load assay

Tests for Monitoring HIV/ART

CD4 counts and CD4 %

• assess immunological status of the HIV-infected

• Varies due to diurnal change, undercurrent illness, steroid treatment, splenectomy, after immunisations

• repeated measurements are more informative than single value

• CD4 counts are higher in infants as compared to adults and fall to adult values by age 5

• CD4% varies less than CD4 counts, hence considered more valuable in children <5 years of age

When to Perform CD4 Test

• All HIV patients accessing Hospitals - immediately after their HIV status known

• Pre-ART: once in 6 months till they are being initiated on ART

• During ART: – Once in 6 months for monitoring

– As and when their clinical conditions demand

IRIS - Definition

The worsening of signs and symptoms due to known

infections or

the development of disease due to occult

infections,

that results from an inflammatory response by a

re-invigorated immune system following the initiation

of anti-retroviral therapy

Practical Definition: NACO

• “Occurrence or manifestations of new

Opportunistic Infections within six weeks to six

months after initiating ART - with increase in CD4

count”

Source: National AIDS Control Organisation, India (NACO): Antiretroviral Therapy Guidelines for HIV-infected Adults and Adolescents Including Post-exposure

Prophylaxis. May 2007

Criteria for Diagnosing IRIS

HIV positive

Receiving ART Decrease in HIV-1 RNA level from baseline Increase in CD4 cells from baseline

Clinical symptoms consistent with inflammatory process

Clinical course NOT consistent with OI

Source: Samuel A. Shelburne, Martin Montes and Richard J. Hamill Journal of Antimicrobial Chemotherapy, Source: (2006) 57, 167-170.

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Can happen with any ART initiation, especially in PLHIV presenting with very low CD4 count

• “ manifestations of new OIs within six weeks to six months after initiating ART; with increase in CD4 count”

• Common conditions associated with:

Tuberculosis - 68.8%, Herpes zoster - 12.5%, Cryptococcal Meningitis - 9.4%, Toxoplasmosis- 6.3%, Bacterial Pneumonia- 3.1%

Infectious Causes of IRISMycobacteria

Mycobacterium tuberculosis

MAIC

Cytomegalovirus

Herpes viruses

Cryptococcus neoformans

Pneumocystis jirovecii pneumonia

Histoplasmosis capsulatum

Toxoplasmosis

Hepatitis B Virus

Hepatitis C Virus

Progressive multifocal leukoencephalopathy

Parvovirus B 19

Molluscum contagiosum & genital warts

Sinusistis

Folliculitis

Strongyloides stercoralis & other parasitic infections

Non-Infectious Causes of IRIS

Autoimmune IRIS

Rheumatoid arthritisSLEGraves diseaseAutoimmune thyroid disease

Sarcoid IRISGranulomatous reactions

Other Rare Manifestations

AIDS-related lymphoma

Guillain-Barre’ syndrome

Interstitial lymphoid pneumonitis

Pathogenesis of IRIS

Improved Cell Mediated Immunity with restoration of both memory and naïve CD4 cells

Increased CD4/CD8 cells detect hidden pathogens which were ignored with deficiency of immunity previously

Result in inflammatory process at the area of occult / sub-clinical infections

Usually improves with control of inflammation and specific treatment

IRIS: Differential Diagnosis

Failure of ART

ART Toxicity

Active Opportunistic Infections

Failure of Antimicrobial Therapy

Management

Mild form (with ongoing ART)

Observation

Localised IRIS (with ongoing ART)

Local therapy such as minor surgical procedures for lymph node abscesses

Severe IRIS - Temporary cessation of ART has to be considered

Prevention of IRIS

Keeping high vigilance in patients who are at risk of developing IRIS during the introduction phase of ART

Measures taken to reduce pathogen load

Delay initiation of ART few weeks until pathogen load is decreased by using appropriate anti- microbial agents

Second line ART

and

SACEP / DACEP

• Second line regimen is “the next regimen used in sequence

immediately after first-line therapy has failed”

• Treatment Failure

refers to the loss of antiviral efficacy

identified by clinical, immunological and/or virological monitoring.

Treatment Failure: Time of detection

Treatment Failure

Virologic detection Immunologic detection

Time

Viral Load

Clinical Status

CD4 Count

Clinical detection

High index of suspicion is the key

patients on first line ART for at least 6 months:• New OIs/recurrence/clinical events after 6

months on first line ART (after ruling out IRIS)• Clinical deterioration in spite of good

adherence to therapy• Progressive CD4 count decline• Viral load testing to confirm treatment failureReview by the SACEP / DACEP

Identifying Treatment Failure

Clinical failure

New or recurrent WHO stage 4 condition, after at least 6 months of 1st line ART

Immunological failure

• Fall of CD4 count to pre-therapy

• 50% fall from the on-treatment peak value

• Persistent CD4 levels below 100 cells/mm

Virological Failure

Plasma viral load >5,000 copies/ml after at least 6 months of 1st line ART

Defining Treatment Failure

Source: National Second line ART guidelines, Nov 2008

State AIDS Clinical Expert Panel(SACEP)

The SACEP consists of Nodal Officer of Centre of Excellence One more ART expert (from the names provided by

NACO)

Joint Director (CST) / Regional Coordinator / Consultant (CST) at SACS where SACEP is located

Paediatrician from CoE if there are paediatric patients on that particular day

observers from central level for monitoring purposes

District AIDS Clinical Expert Panel(DACEP)

The DACEP consists of Nodal Officer of ART Plus Centre One more ART expert (from the names provided by NACO) Designated representative from SACS/DPM/DAPCU /

Regional Coordinator

Paediatrician from ART Plus Centre shall be present if there are paediatric patients on that particular day

observers from central / state level for monitoring purposes

• SACEP / DACEP meets at the Centre of Excellence (CoE) or ART Plus Centre to review cases weekly or fortnightly on a designated week day (for e.g. Tuesday)

• It meets next working day in case designated week day happens to be a holiday (for e.g. Wednesday)

• A maximum of 20 new patients shall be reviewed at each meeting

SACEP / DACEP meetings

04/08/23

CD4 & Viral load

Monitoringonce

in 6 months

Repeat CD4& viral loadIn 3 months

InitiateSecond line

ART

Confirming Virological Failure

Preferred Second line regimen:

• Lopinavir / Ritonavir + Tenofovir + Lamivudine +

Zidovudine (Patients with Hb >9 g/dl)

Alternate Second line regimen:

• Lopinavir / Ritonavir + Tenofovir + Lamivudine

(Patients with Hb <9 g/dl)

Second line ART Regimens

Updated December 2010

PLHIV on Second line ART

• second line ART now available to all those in need of it because of treatment failure - whether they underwent first line treatment in the government sector or private sector, in a phased manner.

• In the first phase - started at four Centres of Excellence (JJ Hospital in Mumbai, GHTM Tambaram, MAMC, New Delhi and STM, Kolkata) with immediate effect. This will be open to patients from any part of the country.

Universal access to second line ART

New Recommendations

• - increase the CD4 cut off point to 350 cells/mm3 in India

• - initiate ART in all HIV-TB co-infected patients, irrespective of CD4 count.

Issues and Challenges

• Low referrals from ICTC to ART centres

• Pre-ART care and Follow up

• Ensuring optimal (> 95%) adherence to ART

• Timely and Early initiation of ART

• Tracking patients Lost to follow up (LFU)

• Second line ART

• Linkages with RNTCP and other local networks

• Irrational ART Prescriptions outside National Programme

HIV…ART…WE…

walk together for success but

mind the gaps

• Created by Dr. K.Prasanthi MD for e learning resources for Medical

Professionals in the Developing World• Email

• bebold_p@yahoo.co.in