Transcript Benefits and Risks of ART Dr Paula Munderi WHO Training Course for Introducing Pharmacovigilance of HIV Medicines 23 - 28 November 2009, Dar Es.

Benefits and Risks of ART
Dr Paula Munderi
WHO Training Course for Introducing
Pharmacovigilance of HIV Medicines
23 - 28 November 2009, Dar Es Salaam
Summary
Progress in ART coverage - WHO Progress
Report
Benefits of ART
Survival
Decreased Morbidity
Decreased Transmission
Vertical & Horizontal
Principles of ART
Measurement of efficacy
Risks of ART linked to AEs and Toxicities
Adherence : determinant of ART efficacy
Special Populations : Women & Children
Epidemiology of Paediatric HIV
Pregnancy and ART
Co-morbidities of specific concern : TB,
HepB, Hep C, (Malaria)
Programme implications
Selection of ARVs in the PH approach
ART principles & recommendations
Current ART practice in LMIC
What this means for countries
Acknowledgements
Sources of Slide Material
Published data
WHO progress report on access 2009
Jens Lundgren
Lynne Moffenson
WHO HQ - HIV Dept (ATC team)
DART study group
I
Benefits of ART
•Improved Survival
•Reduced morbidity
•Reduced vertical transmission of HIV
•Possibly – reduced horizontal transmission of HIV
Number of people receiving antiretroviral therapy in low- and
middle-income countries, by region, 2002–2008
4.5
North Africa and the Middle East
4.0
Europe and Central Asia
3.5
East, South and South-East Asia
Latin America and the Caribbean
3.0
Millions
Sub-Saharan Africa
2.5
2.0
1.5
1.0
0.5
0.0
End 2002
End 2003
End 2004
End 2005
End 2006
End 2007
End 2008
Reduced Death
rates over time
on ART
Rate per 100 person years
0-1 years 17.9
[14.5 – 22.1]
1-2 years 2.3
[14.5 – 22.1]
2-3 years 1.2
[0.5-3.3]
Castelnuovo B, Manabe YC, Kiragga A et al CID 2009; 49:965–72
Survival impact of ART
Proportion alive
1.0
0.8
0.95
0.92
0.90
0.94
0.90
0.87
DART cohort
ART: 2003 - 2008
LCM: 2.2/100 PY
CDM: 2.9/100 PY
median CD4 86 at
enrolment
0.55
0.6
-----------------0.4
Entebbe Cohort
(same community)
0.18
0.2
0.08
NO ART available
1996-2000
0.0
0
1
2
3
4
Years from enrolment into cohort
5
median CD4 75
at enrolment
57.7/100 PY
DART Study Group. IAS July 2009
Impact of ART on causes of death
Specific HIV-related causes
Pre-ART cohort: EC
n = 516 PYO = 658
Post-ART cohort: DART
n = 1015 PYO = 1819
Oct 95 - Dec 00
Feb 03 - Jan 06
Deaths (rate/100PY)
Deaths (rate/100PY)
118
(17.9)
27
(1.5)
Cryptococcus
64
(9.7)
4
(0.2)
Cryptosporidium
18
(2.7)
2
(0.1)
Tuberculosis
16
(2.4)
10
(0.5)
HIV-related malignancy
11
(1.7)
6
(0.3)
Bacteraemia
3
(0.5)
5
(0.3)
CMV
4
(0.6)
0
(0)
Severe anaemia
2
(0.3)
0
(0)
Syndrome likely HIV related
176
(26.7)
18
(1.0)
Wasting (+/- diarrhoea)
111
(16.9)
1
(0.1)
Febrile event
48
(7.3)
12
(0.7)
Neurological event
17
(2.6)
5
(0.3)
4
(0.6)
6
(0.3)
82
(12.6)
11
(0.6)
380
(57.7)
62
(0.3)
Cause not HIV-related
Unknown cause
Total deaths
DART Study Group: XVI INTERNATIONAL AIDS CONFERENCE 2006
Malaria – DART cohort
Vertical Transmission – Maternal Viral Load
in absence of ART
% Transmission
40
32%
30
21%
20
11%
10
6%
1%
0
<400
4003000
300040000
40000100000
>100000
Delivery Plasma HIV RNA
Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4) WITS study, 1990-1999
Timing of vertical transmission for 30%
15 %
10%
5%
Pregnancy
Pre-natal
DE
LIV
ER
Y
Breast-feeding
Post-natal
Vertical Transmission at 6 weeks postpartum by ARV Regimen
Botswana National Data Oct 2006-Nov 2007
Tlale J et al. IAS Mexico City Aug 2008 (Abs ThAC04)
15%
Most Women Formula Feed Their Infants
12.3%
10%
5%
7.0%
4.7%
3.3%
0.7%
2.3%
cART
pre-preg
cART
during
preg
0%
sdNVP
AZT
AZT
>4 wk
<4 wk
+sdNVP +sdNVP
No
ART
Vertical transmission of HIV
15-35%
<1%
Antenatal screen
Maternal ART
Neonatal ART
C. section
No breastfeeding
« Les personnes séropositives ne souffrant d’aucune autre MST et suivant un
traitement antirétroviral efficace ne transmettent pas le VIH par voie sexuelle »
Commission fédérale pour les problèmes liés au sida (CFS),
Commission d’experts clinique et thérapie VIH et sida de l’Office fédéral de la santé publique (OFSP)
P Vernazza, B Hirschel, E Bernasconi, M Flepp. Bulletin des médecins suisses 2008;89: 5
Scientific basis: Effective ART → undetectable HIV - RNA
Epidemiologic basis :
vertical transmission
is related to plasma HIV-RNA
• e.g PMTCT
Longitudinal studies
in HIV sero-discordant couples
Rwanda & Zambia
393 couples followed for 14 years
no transmission from person on cART
8.6 % transmission with no cART 1
--------------------------------------------------93 couples; in 41 +ve partner on cART
6 infections – all in non treated 2
--------------------------------------------------62 couples; Males +ve
pregnancy desired
no infection in female partner3
•
•
•
•
•
•
2, 993 couples
followed from 2002 – 2008
HIV testing every 3 months
5’609 person years
4 HIV infections from partners on cART
171 infections partners not on cART
Incidence density of HIV transmission 4
0.7% on cART vs 3.4% off cART
[RR = 0.21, CI: 0.08, 0.59]
NB: HIV persists in semen and cervicovaginal fluid during effective cART
ARVs for Prevention
• PEP & PMTCT
• Universal Test & Treat
– combination ART
• Pre- Exposure prophylaxis (PrEP)
– Tenofovir
• ARVs as “ vaginal microbicides”
– Tenofovir
– Maraviroc
II
Principles of ART
•Combination therapy
•Avoidance of resistance
•Importance of adherence
For sustained efficacy of ART ...
• synergistic combinations of  3 active drugs usually
from 2 different classes
–
single or dual drug therapy only in PMTCT; low risk PEP
• the large number of possible combinations is only
apparent
–
–
cross resistance develops within classes
Cross resistance may occur between NRTIs and NNRTIs
• preserving future treatment options is critical
– choice of initial regimen
–
rational sequencing of combinations thereafter
Measurement of efficacy of ART
When is treatment working?
• Absence of clinical disease
– WHO clinical staging
• Immune restoration
– Rise in CD4 count
• Viral suppression
– Undetectable VL
When has treatment failed
• Recurrence of clinical illness
– WHO stage II/III/IV
• Fall in CD4 count
– to below 100 cells/mm3
• Detectable VL
– to >5000 copies/ml
Resistant virus
10-20%
Wild-type virus
Resistant virus
10-20%
Wild-type virus
Drug
pressure
Adherence – Efficacy
Nachega et al, Ann Intern Med, 2007
III
Risks of ART
Mainly related to toxicities
NB: Most ART Toxicities are ...
- Predictable
- Clinically detectable
- Can be managed
The key is patient and provider education !
Italian
Cohort
I
C O
N A
Naive
Antiretroviral
Main reasons of discontinuation
of first cART regimen within
1st year: ICONA cohort
Toxicity
Failure
Non-adherence
Other
Continued
Monforte et al. AIDS 1999
Reasons for change of a first combination ART regimen
Reason
N
CD4
VL
Unknown
49
312
2.26
Other
112 391
2.60
Choice
189 364
2.60
Toxicities 190 386
2.28
Failure
3.78
86 328
p=0.27 p<0.0001
N
Median CD4
Median VL
107
300
3.26
87
326
2.81
133
382
2.60
161
363
2.46
138
418
2.60
p=0.0013
p=0.0022
EuroSIDA: Mocroft et al, AIDS Research Hum Retro, 2005
ART Toxicity related deaths:
1st year - 1 Hepatotoxicity, 2 Lactic acidosis
2nd year - 1 Hepatotoxicity; 2 lactic acidosis; 1 pancreatitis
Castelnuovo B, Manabe YC, Kiragga A et al CID 2009; 49:965–72
NB: Most ART Toxicities are ...
- Predictable
- Clinically detectable
- Can be managed
The key is patient and provider education !
IV
Women & Children
•Pregnancy
• In utero & Perinatal exposure to ARVs
• cART in children
Incidence of Seroconversion in Pregnancy:
Prevention of HIV in Pregnant Women is Critical
Country
Reference
Incidence per 100 Pt-Yrs
Pregnancy
Uganda
Gray R et al. Lancet
2005;366:1182
2.3
Botswana
Lu L et al. 2009 CROI Abs.94LB
1.3 (0.5-3.1)
Zimbabwe,
Uganda
Morrison CS et al. AIDS
2007;21:1027
1.6
South Africa
Rehle T et al. S Afr Med J
2007;97:194
5.2 (0-12.9)
South Africa
Moodley D et al. AIDS
2009;23:1255
10.7 (8.2-13.1)
43% of New Infant Infections in Botswana
May be Due to Maternal Seroconversion in Pregnancy/PP
Lu L et al . 16th CROI, Montreal, Canada Feb 2009 Abs 94LB
# HIV+
women
Estimated
MTCT rate
# infected
infants
HIV diagnosed
before or
during ANC
New maternal
infection late
pregnancy
New maternal
infection 1 yr
postpartum
13,952
378
450
(incidence 1.3%)
(incidence 1.8%)
73%
36%
276
186
4.7%
(with PMTCT ARV)
620
Of the estimated 1,082 infant HIV infections in
Botswana in 2007, 462 (43%) were due to
incident cases of maternal HIV in pregnancy/PP
Prevention
of HIV in
Women,
(Especially
Young
Women)
Prevention
of
Unintended
Pregnancies
in
HIV-Infected
Women
Prevention
of
Transmissio
n from an
HIV-Infected
Woman
to Her Infant
Support for
HIV-Infected
Mother and
Family
Unintended Pregnancy Among
HIV-Infected Women
• 51% unintended pregnancies among women with HIV in
Cote d’Ivoire.
• 74% unintended pregnancies among women in HIV care
in Rwanda.
• 84% unintended pregnancies among PMTCT clients in
South Africa.
• 93% unintended pregnancies among women in HIV-ART
Desgrees-du-Lou A et al. Int J STD AIDS 2002
care in Uganda.
Bangendanye, 3rd Ped CLS 2007
Rochet T et al. JAMA 2006
Homsy J et al. PLosOne 2009
Incident pregnancy on ART – DART cohort
Age at enrolment
18-29 yrs
30-34 yrs
35-39 yrs
40-44 yrs
All women <45
18
16
Incidence rate per
100 woman years
14
12
10
8
6
4
2
0
<1 year
1-2 years
2-3 years
3-4 years
Time since enrolment in DART
>4 years
Physiologic Changes During Pregnancy
Can Affect Therapeutic Drug Administration
• Increased plasma volume
– dilution effect
• Decreased in serum albumin
– increase in free fraction of drug
• Increased GFR 20-60% starting 1st trimester
– change in drug clearance
• Changes in hepatic enzyme activity
– increase CYP34A, 2D6 = change in drug metabolism
• Decreased gastric acid secretion, prolonged gastric emptying and
intestinal transit time
– decreased oral drug absorption
Pregnancy & Antiretroviral Pharmacokinetics
NRTIs
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zidovudine
No ∆
No ∆
No ∆
No ∆
No ∆
No ∆
NNRTIs
Efavirenz No data
Etravirine No data
Nevirapine No ∆
NUCLEOTIDES
Tenofovir AUC
PIs
Atazanavir
AUC 
Darunavir
No data
Fosamprenavir AUC ?
Indinavir
AUC 
Lopinavir/rit
AUC 
Nelfinavir
AUC 
Ritonavir
AUC 
Saquinavir
AUC 
Tipranavir
No data
FUSION INHIBITORS
Enfuvirtide No data
CCR5 CO-RECEPTOR ANTAGONISTS
Maraviroc
No data
INTEGRASE INHIBITORS
Raltegravir
No data
Toxicity - associations in pregnancy
Maternal
Foetal
• d4T / ddI
– lactic acidosis
• EFAVIRENZ
– neural tube defects
• NEVIRAPINE
– hepatic toxicity
• TENOFOVIR
– bone growth defects
• ZIDOVUDINE
– anaemia
Antiretroviral Pregnancy Registry
1/89- 1/09
Prospective Cases (http://www.APRegistry.com)
% Birth Defect
CDC general birth defect surveillance
1st trimester any ARV exposure
Atazanavir sulfate-containing (7/292)
ABC-containing (18/608)
AZT-containing (95/3108)
3TC-containing (93/3226)
d4T-containing (19/754)
Indinavir-containing (6/276)
Nelfinavir-containing (37/1074)
Nevirapine-containing (18/817)
Ritonavir-containing (20/883)
Lopinavir-containing (8/470)
Tenofovir-containing (16/678)
ddI-containing (16/365)
2.7% (2.7-2.8%)
2.9% (2.4 - 3.4%)
2.4% (1.0 - 4.9%)
3.0% (1.8 – 4.6%)
3.1% (2.5 - 3.7%)
2.9% (2.3 - 3.5%)
2.5% (1.5 – 3.9%)
2.2% (0.8 - 4.7%)
3.4% (2.4 – 4.7%)
2.2% (1.3 – 3.5%)
2.3% (1.4 – 3.5%)
1.7% (0.7 – 3.3%)
2.4% (1.4 – 3.8%)
4.4% (2.5 – 7.0%)
HIV negative but exposed children
following in utero exposure to ARVs
Clinically symptomatic mitochondrial dysfunction
– rare 0.3% - 3 per 1,000
– very rarely (0.07% - 7 per 10,000) can be fatal
Mild, clinically asymptomatic, but persistent hematologic abnormalities
– anaemia, neutropenia
Transient elevations in lactic acid
– common with in utero exposure
– usually asymptomatic
– resolve within months
ARV toxicities in treated children
similar spectrum to adults
Of particular importance in children:
Metabolic abnormalities
– hyperlipidaemia
– glucose intolerance
Fat redistribution
Bone density & growth