ISSUES ON ANTIRETROVIRAL THERAPY DR.K.PRASANTHI MD
Nov 02, 2014
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