Transcript More or Less Laboratory monitoring for ART

ART Scale-up
Where to go in the next decade?
Prof Charles Gilks
Head of School of Public Health
University of Queensland
Outline of talk
• ART scale-up: a decade of progress
• Advances in ARVs and ART
• Laboratory monitoring of ART
• The next decade – where to go?
The global treatment gap
The treatment gap was declared a global health emergency on
Sept 22nd, 2003 at UNGASS (UN General Assembly Special Session)
Global activism around increasing access to
ART as a basic human right in resourcelimited settings
GFATM and PEPFAR established and
resourced for ART scale-up
JW Lee pledges to address global HIV
inequity and close the treatment gap
JW Lee Director General WHO 2003-2006
‘The right of everyone to the enjoyment of
HOW?? Target-driven Public Health
the highest attainable standard of health’
“Three by Five”
The target: three million people on
treatment by the end of 2005
need
The goal : universal access to ART as a
basic human right to health to all in
Public Health ART strategy
WHO guidelines
•
Public Health ART Strategy
Aim:
Prolong survival
Increase Quality of Life
Core Elements of PHA
Chronic disease management
• Practical case records and registers
• Decentralised care
• Task shifting
Simplified and standardised approaches
• First-line and second line ART
• When to start; substitute; switch; stop/salvage
• Parsimonious laboratory monitoring
• Population-level HIV DR monitoring
Users: Public sector planners & policy makers
Guidelines and Guidelines
WHO guidelines for Public Sector ART
• Simple standard care packages
• First then second line regimens
• CD4 testing available; clinical monitoring
• Population level impact – survival; QOL
US DHHS; IAS USA; BHIVA; ASHM; etc
• Physician/specialist-led ART
• Initial regimen then multiple options
• Access to all lab services
• Individual outcome – viral suppression
Global Access to Treatment
Actual and projected numbers of people
receiving antiretroviral therapy in low-and
middle-income countries, and by WHO
Region, 2003–2015
WHO, Global Treatment Report 2013
• Nearly 10 million people
on ART by end of 2012
• 1.6 million in one year
• African region shows the
greatest rate of increase
• Coverage 68% for adults
but only 34% for children
• Coverage not uniform certain regions and
populations left behind
(Eastern Europe, IDUs)
Impact of ART on survival
Cumulative Life-Years Gained from
Antiretroviral Therapy, 1996–2011
25
total
High-income
countries
(in millions)
Cumulative life-years gained
— Global
Low- and
middle income
countries
0
1996
2011
Source: Joint United Nations Programme on HIV/AIDS, 2012.
1st and 2nd line ARVs for adults
1st Line
Start
2nd line
Substitute
AZT, d4T,
3TC,
NVP; EFV
Recommended 1st Line ARV
Drugs
Switch
ABC,
TDF
Frequently
Recommended as 2nd
line drugs, but also as
alternative drugs in 1st
line regimens
Stop
ddI
PI/r
Recommended as 2nd Line
Drugs
Ceiling Prices of Major 1st and 2nd Line ARV Regimens
2nd Line Regimens
1200
1000
1090
800
886
749
600
1st Line Regimens
709
400
669
349
200
299
100
0
d 4 T / 3 T C / N VP
159
212
d 4 T / 3 T C + EF V
269
T D F / 3 T C / EF V
A Z T / 3 T C + L P Vr
T D F / F T C + L P Vr
A B C + d d I + L P Vr
Clinton Foundation, April 2008
Evolution of ARV drugs: Moving towards
better and safer options
11
Use of TDF in 1st line Regimens
Market share of NRTIs (except 3TC and FTC) in lowand middle-income countries, 2004 – 2013
Market share of APIs in %
100%
Regional variation in 1st line ART
containing TDF (2013)
90%
Percentage of Countries with TDF for Adults and Adolescents
80%
Percentage of Countries with TDF for Pregnant Women
TDF
70%
100%
60%
81%
71%
50%
40%
AZT
30%
20%
d4T
10%
0%
63%
56%
43%43%
31%
30%30%
10%
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
d4T
66%
77%
68%
45%
52%
32%
38%
23%
12%
2%
AZT
34%
22%
29%
52%
39%
52%
42%
51%
46%
38%
TDF
0%
1%
3%
4%
9%
15%
20%
26%
42%
61%
ddI
2%
1%
1%
1%
1%
1%
0%
0%
0%
0%
ABC
1%
1%
1%
1%
1%
1%
2%
2%
1%
2%
AMDS, 2013
0%
Changes in NVP and EFV use
(2007-2013)
Between 4.6 to 5.8 million
people using NVP containing
regimen in 2012
90%
Market share of APIs in %
80%
70%
60%
51%
50%
49%
40%
30%
20%
10%
0%
2007
2008
2009
EFV
2010
2011
NVP
2012
2013
WHO AMDS database, 2014
(preliminary data)
Relative market share (% of PYR) of protease inhibitors
(2003-2013)
100%
90%
LPV/r
80%
Market share of APIs in %
70%
60%
50%
40%
30%
20%
ATV
10%
DRV
0%
2003
2004
2005
2006
ATV
AMDS, 2013
2007
DRV
2008
FPV
IDV
2009
LPV
2010
SQV
2011
2012
2013
Public Health ART scale-up
Provision of laboratory services
Limited access and high cost
of high technology hospital
Laboratory Services
Universal access to
ART predicated on
decentralised care
HIV disease and AIDS
WHO CLINICAL STAGING OF HIV FOR ADULTS AND CHILDREN
PRIMARY HIV INFECTION
Unrecognized
Acute retroviral syndrome
CLINICAL STAGE 1
Asymptomatic
Persistent generalized lymphadenopathy (PGL)
CLINICAL STAGE 2
M oderate unexplained weight loss (<10% of presumed or measured body weight)
Recurrent upper respiratory tract infections (sinusitis, bronchitis, otitis media, pharyngitis)
Herpes zoster
Angular cheilitis
Recurrent oral ulcerations
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections of fingers
CLINICAL STAGE 3
Conditions where a presumptive diagnosis can be made using clinical signs or simple investigations
Severe weight loss (>10%presumed or measured body weight)
Unexplained chronic diarrhoea for longer than one month
Unexplained persistent fever (intermittent or constant for longer than 1month)
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (diagnosed in last two years)
Severe presumed bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint
infection, meningitis, bacteremia )
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Conditions where confirmatory diagnostic testing is necessary
Unexplained Anaemia (<8gm/dl), neutropenia (<1,000/mm3) or thrombocytopenia (<50,000/ mm3)
for more than 1 month
CLINICAL STAGE 4
Conditions where a presumptive diagnosis can be made using clinical signs or simple investigations:
HIV wasting syndrome
Pneumocystis p neumonia
Recurrent severe or radiological bacterial pneumonia
Chronic Herpes simplex infection;
(orolabial, genital, or anorectal of more than 1 month duration, or visceral any duration )
Oesophageal Candidiasis
Extrapulmonary tuberculosis
Kaposi's sarcoma
CNS toxoplasmosis
HIV encephalopathy
Conditions where confirmatory diagnostic testing is necessary:
Extrapulmonary Cryptococcsis including meningitis
Disseminated non-tuberculous mycobacteria infection
Progressive multifocal leukoencephalopathy (PM L)
Candida of trachea, bronchi, or lungs
Cryptosporidiosis
Isosporiasis
Cytomegalovirus infection (retinitis or of an organ other than liver, spleen, or lymph nodes)
Any disseminated mycosis (e.g. Histoplasmosis, Coccidiomycosis, Penicilliosis)
Recurrent non-typhoidal salmonella septicaemia
Lymphoma (Cerebral or B cell non-Hodgkin's)
Invasive cervical carcinoma
Visceral Leishmaniasis,
CLINICAL STAGE ON ART
STAGE 1
Asymptomatic
Persistent generalized lymphadenopathy (PGL)
Hepatosplenomegaly
STAGE 2
Recurrent or chronic upper respiratory tract infections
(otitis media, otorrhoea, sinusitis,)
Papular pruritic eruptions
Seborrhoeic dermatitis
Extensive Human papilloma virus infection
Extensive Molluscum infection
Herpes zoster
Fungal nail infections
Recurrent oral ulcerations
Lineal Gingival Erythema (LGE)
Angular chelitis
Parotid enlargement
STAGE 3
Conditions where a presumptive diagnosis can be made using clinical signs or simple investigations
Unexplained moderate malnutrition not adequately responding to standard therapy
Unexplained persistent diarrhoea (14 days or more )
Unexplained persistent fever (intermittent or constant, for longer than 1month)
Oral candidiasis (outside neonatal period )
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis/periodontitis
Pulmonary tuberculosis
Severe recurrent presumed bacterial pneumonia
Conditions where confirmatory diagnostic testing is necessary
Lymphoid interstitial pneumonitis (LIP)
Unexplained Anaemia (<8gm/dl), neutropenia (<1,000/mm 3) or thrombocytopenia (<50,000/ mm3) for more than 1 month
Chronic HIV associated lung disease including brochiectasis
STAGE 4
Conditions where a presumptive diagnosis can be made using clinical signs or simple investigations:
Unexplained severe wasting or severe malnutrition not adequately responding to standard therapy
Pneumocystis pneumonia
Recurrent severe presumed bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding
pneumonia)
Chronic Herpes simplex infection; (orolabial or cutaneous of more 1 month duration, visceral of any duration)
Extrapulmonary tuberculosis
Kaposi's sarcoma
Oesophageal Candidias
CNS Toxoplasmosis (outside the neonatal period)
HIV encephalopathy
Conditions where confirmatory diagnostic testing is necessary:
CMV infection (CMV retinitis or infection of organ other than liver, spleen, or lymph nodes onset at age 1 month or more)
Cryptococcal meningitis (or other extrapulmonary disease)
Any disseminated endemic mycosis(e.g. extra-pulmonary Histoplasmosis, Coccidiomycosis, Penicilliosis)
Cryptosporidiosis
Isosporiasis
Disseminated non-tuberculous mycobacteria infection
Candida of trachea, bronchi or lungs
Acquired HIV related rectal fistula
Cerebral or B cell non-Hodgkin's Lymphoma
Progressive multifocal leukoencephalopathy (PML)
HIV related cardiomyopathy or HIV related nephropathy
STAGE ON ART
Patient monitoring of ART
• When to switch first-line
therapy to second-line
– Clinical monitoring alone
– Immunological (CD4)
– Detectable virus (vl)
• Routine toxicity monitoring
– Haematology
– Liver Function
– Renal function
Failure / When to Switch
The three failure domains are all different
Viral load
Virologic
$$$ Costs /access
Early Switch
Clinical
criteria
CD4 count
Immunologic
Clinical
universal coverage
Late Switch
DART Trial design
3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease,
CD4<200 cells/mm3 (median 86 cells/mm3) initiating triple drug ART
Laboratory and Clinical
Monitoring (LCM)
12 weekly biochemistry,
FBC & CD4
randomise
5 year follow-up
Clinically Driven
Monitoring (CDM)
12 weekly biochemistry,
FBC & CD4;
FBC & biochemistry only returned
if clinically indicated (or grade 4
toxicity);
CD4 never returned
Other investigations &
concomitant medications if
clinically indicated
Other investigations (not CD4) &
concomitant medications if
clinically indicated
Switch to second-line for
•new/recurrent WHO 4
(or multiple WHO 3)
•CD4<100 cells/mm3
Switch to second-line for
•new/recurrent WHO 4
(or multiple WHO 3)
As per WHO guidelines, switching before 48 weeks discouraged in both arms
Survival
0.95
Proportion alive
1.0
0.94
0.8
0.92
0.90
0.90
0.87
0.18
Entebbe Cohort:
pre-ART, median
0.08
CD4 75 at study
enrolment
LCM
CDM
0.55
0.6
0.4
0.2
0.0
0
1
2
3
4
5
Years from randomisation (ART initiation)
Adverse events
Proportion event-free
1.0
SAE p=0.20
0.8
ART-modifying
AE p=0.85
0.6
Grade 4 AE
p=0.18
0.4
Grade 3/4 AE
p=0.52
0.2
LCM
CDM
0.0
0
1
2
3
4
Years from randomisation (ART initiation)
IAS July 2009
21
5
Durability of first-line ART
1.0
HR(CDM:LCM, stratified by randomisation factors)=
0.84 (95% CI 0.72-0.98), log-rank p=0.03
Still on
first-line
Proportion
0.8
0.6
CDM
LCM
0.4
Ever
substituted
in first-line
0.2
HR(CDM:LCM, stratified by randomisation factors)=
1.05 (95% CI 0.91-1.22), log-rank p=0.51
0.0
0
1
2
3
4
5
Years from randomisation (ART initiation)
Number alive in follow-up on first-line
LCM
1656
1546
1422
CDM
1660
1538
1459
1286
1334
1169
1216
609
578
Note: Estimating the proportion still on first-line and ever substituted in first-line by cumulative
incidences treating deaths on first-line as competing risks (and switch to second-line as a
competing risks for first-line substitutions). Hazard ratios are from cause-specific models censoring
deaths (and switch to second-line for first-line substitutions).
The DART trial
Runner-up
Lancet paper of the Year, 2009
The ARROW trial (babyDART)
Published Lancet March 2013
HBAC trial: results
Randomised 1000 Ugandan patients
to clinical alone, clinical with CD4, or
clinical with CD4 and vl monitoring
In patients on ART routine laboratory
monitoring associated with improved
health and survival compared with
clinical monitoring alone …
There was no significant difference
(p=0.31) between CD4 and vl arms
Stratall ANRS 12110/Esther trial: results
256 African patients were
randomised to clinical or
laboratory (CD4 and VL)
monitoring and followed
for two years
Clinical monitoring was not
non-inferior; supports
WHO recommendations
and suggests clinical
monitoring alone useful
PHPT-3 study: results *
• 716 Thai patients on ART randomised to either
CD4 or vl monitoring and followed for 3 years
• Rate of clinical failure was very low and did
not differ between arms
• Viral load monitoring may be less important
than regular safety, tolerability, adherence and
immunological monitoring
* Presented at 18th CROI Boston 2011 abstract 44
CEA laboratory monitoring
• Routine laboratory monitoring for toxicity is
particularly expensive and with the standard
first-line regimens used in DART provided no
measurable clinical benefit. Using routine
haematology and biochemistry tests in ART rollout needs to be questioned by policy makers
• CD4 monitoring provides clinical and survival
benefit but the ICER remains high ($ 8313; 3867
– dominated) under most scenarios
• Threshold analysis suggests costs of CD4 tests
need to drop below $3.78 to be cost effective in
Uganda and Zimbabwe at 3-monthly frequency
IAS July 2009
27
The future is looking good for
low-cost CD4 POC devices
Estill et al: CEA of POC viral load
monitoring vs CD4 or clinical
• VL monitoring is not cost-effective primarily due to the large number of
unnecessary switches to second-line
• CEA of POC VL is improved by higher
detection limit; by taking reduction
in new HIV infections into account;
and by assuming the failure of firstline ART is reduced by targeted
adherence counselling
Hamers et al: modelling clinical, CD4 or vl monitoring
Additional costs of laboratory
monitoring balanced by costsavings from unnecessary
switches - but massive failure
rates and many unnecessary
switches ascribed to clinical
monitoring strategy.
Routine vl monitoring may be
preferred as a replacement for
CD4 counts – but no start-up
costs to set up of vl network
were included.
Gilks et al: DART re-analysis - single CD4 test tiebreaker
>250 with clinical failure predicts vl suppression
• Multiple but not single WHO3
events and WHO4 events
predict first-line failure
• A single CD4 threshold tiebreak
of 250 for clinically monitored
patients failing first-line would
identify 80% with vl<400 who
do not need to switch to
second-line and thus avoids
premature use of second-line
The next decade: WHO 2013 Guidelines
•
•
•
•
•
Much earlier start (CD4 500)
Routine toxicity monitoring
Viral load monitoring is preferred
Provision for Third-line ART
More individualised; convergenge with
DHHS approach
• Moving away from PHA: Decentralisation
& task shifting
• Fourth guideline in a Decade; more are
planned
• Aspirational when budgets flatlined and
competing health priorities like NCDs
• Consolidate gains and achievements
Figure 1
If implement 2013 guidelines fully as
compared to 2010 guidelines:
•
•
•
•
•
Figure 2
28 m eligible by 2025
Avert 3.0 m deaths (↓ 59%)
Avert 3.1 m new infections (↓ 23%)
Cost 1.8 B more in 2015, peaks at 3.3 B
in 2020, 1.7 B in 2025
Highly cost effective at QALY 350 USD
Figure 3
Paul Revill, Miqdad Asaria, Andrew Phillips, Di Gibb, Charles Gilks
What approach – who decides?
•
•
•
•
Ministry of Health convene committee
Donors and funders (PEPFAR, GFATM); WHO
National experts (physicians)
Community representatives; on ART
• Public Health professionals
• Health economists
Thank you