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 ARTSurvivalDecreased MorbidityDecreased Transmission

Vertical & Horizontal Principles of ART

Measurement of efficacyRisks of ART linked to AEs and Toxicities

Adherence : determinant of ART efficacy

Special Populations : Women & ChildrenEpidemiology of Paediatric HIV Pregnancy and ART

Co-morbidities of specific concern : TB, HepB, Hep C, (Malaria)

Programme implications Selection of ARVs in the PH approachART principles & recommendations Current ART practice in LMICWhat this means for countries

AcknowledgementsSources of Slide Material

Published dataWHO progress report on access 2009

Jens LundgrenLynne Moffenson

WHO HQ - HIV Dept (ATC team)DART study group

IBenefits 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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

End 2002 End 2003 End 2004 End 2005 End 2006 End 2007 End 2008

Mil

lio

ns

North Africa and the Middle East

Europe and Central Asia

East, South and South-East Asia

Latin America and the Caribbean

Sub-Saharan Africa

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

DART Study Group. IAS July 2009

Survival impact of ART

0.90

0.87

0.08

0.92

0.90

0.18

0.95

0.94

0.55

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n al

ive

Years from enrolment into cohort

Entebbe Cohort(same community)

NO ART available1996-2000

median CD4 75 at enrolment

57.7/100 PY

LCM: 2.2/100 PYCDM: 2.9/100 PY

median CD4 86 at enrolment

DART cohortART: 2003 - 2008

------------------

DART Study Group: XVI INTERNATIONAL AIDS CONFERENCE 2006

Impact of ART on causes of death Pre-ART cohort: ECn = 516 PYO = 658

Oct 95 - Dec 00

Post-ART cohort: DARTn = 1015 PYO = 1819

Feb 03 - Jan 06Deaths (rate/100PY) Deaths (rate/100PY)

Specific HIV-related causes 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)

Cause not HIV-related 4 (0.6) 6 (0.3)

Unknown cause 82 (12.6) 11 (0.6)

Total deaths 380 (57.7) 62 (0.3)

Malaria – DART cohort

1%6%

11%

21%

32%

0

10

20

30

40

% T

ran

smis

sio

n

<400 400-3000

3000-40000

40000-100000

>100000

Delivery Plasma HIV RNA

Vertical Transmission – Maternal Viral Load

in absence of ART

Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4) WITS study, 1990-1999

PregnancyPre-natal

15 %

5% 10%

Breast-feedingPost-natal

Timing of vertical transmission for 30%

DE LIVERY

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)

0.7% 2.3%3.3%

4.7%

7.0%

12.3%

0%

5%

10%

15%

cARTpre-preg

cARTduringpreg

AZT>4 wk

+sdNVP

AZT <4 wk

+sdNVP

sdNVP No ART

Most Women Formula Feed Their Infants

Vertical transmission of HIV

15-35%

<1% Antenatal screenMaternal ARTNeonatal ARTC. sectionNo 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

393 couples followed for 14 yearsno transmission from person on cART8.6 % transmission with no cART 1

---------------------------------------------------93 couples; in 41 +ve partner on cART6 infections – all in non treated 2

---------------------------------------------------62 couples; Males +vepregnancy desiredno infection in female partner3

Rwanda & Zambia

• 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

IIPrinciples 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

Wild-type virus

10-2

0%

Drug pressure

Resistant virus

Wild-type virus

10-2

0%

Adherence – Efficacy

Nachega et al, Ann Intern Med, 2007Nachega et al, Ann Intern Med, 2007

IIIRisks of ART

Mainly related to toxicities

NB: Most ART Toxicities are ...

- Predictable- Clinically detectable

- Can be managed

The key is patient and provider education !

Main reasons of discontinuation of first cART regimen within

1st year: ICONA cohort

I C ON A

ItalianCohort

NaiveAntiretroviral

Monforte et al. AIDS 1999

Toxicity

Failure

Non-adherence

Other

Continued

Reasons for change of a first combination ART regimen

N 107 87 133 161 138 Median CD4 300 326 382 363 418 p=0.0013Median VL 3.26 2.81 2.60 2.46 2.60 p=0.0022

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 86 328 3.78

p=0.27 p<0.0001

EuroSIDA: Mocroft et al, AIDS Research Hum Retro, 2005

Castelnuovo B, Manabe YC, Kiragga A et al CID 2009; 49:965–72

ART Toxicity related deaths:1st year - 1 Hepatotoxicity, 2 Lactic acidosis2nd year - 1 Hepatotoxicity; 2 lactic acidosis; 1 pancreatitis

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-YrsPregnancy

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 diagnosed before or

during ANC

New maternal infection late pregnancy

New maternal infection 1 yr postpartum

# HIV+ women

13,952 378 (incidence 1.3%)

450(incidence 1.8%)

Estimated MTCT rate

4.7%(with PMTCT ARV)

73% 36%

# infected infants

620 276 186

Of the estimated 1,082 infant HIV infections inBotswana in 2007, 462 (43%) were due to

incident cases of maternal HIV in pregnancy/PP

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 care in Uganda. Desgrees-du-Lou A et al. Int J STD AIDS 2002

Bangendanye, 3rd Ped CLS 2007Rochet T et al. JAMA 2006Homsy J et al. PLosOne 2009

Prevention of HIV in Women,

(Especially Young

Women)

Prevention of

Unintended Pregnancies in HIV-Infected

Women

Prevention of

Transmission from an HIV-Infected Woman

to Her Infant

Support for HIV-Infected Mother and

Family

<1 year 1-2 years 2-3 years 3-4 years >4 years

Time since enrolment in DART

Inci

denc

e ra

te p

er

100

wom

an y

ears

0

2

4

6

8

10

12

14

16

18

Age at enrolment

18-29 yrs30-34 yrs35-39 yrs40-44 yrs

All women <45

Incident pregnancy on ART – DART cohort

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 PharmacokineticsNRTIs Abacavir No ∆Didanosine No ∆Emtricitabine No ∆Lamivudine No ∆ Stavudine No ∆ Zidovudine No ∆

NUCLEOTIDES Tenofovir AUC

NNRTIsEfavirenz No data Etravirine No data Nevirapine No ∆

PIsAtazanavir AUC

Darunavir No dataFosamprenavir AUC ?Indinavir AUC

Lopinavir/rit AUC Nelfinavir AUC Ritonavir AUC Saquinavir AUC Tipranavir No data

FUSION INHIBITORS Enfuvirtide No data

CCR5 CO-RECEPTOR ANTAGONISTSMaraviroc No data INTEGRASE INHIBITORS

Raltegravir No data

Toxicity - associations in pregnancy

Maternal

• d4T / ddI– lactic acidosis

• NEVIRAPINE– hepatic toxicity

• ZIDOVUDINE– anaemia

Foetal

• EFAVIRENZ– neural tube defects

• TENOFOVIR– bone growth defects

Antiretroviral Pregnancy Registry 1/89- 1/09 Prospective Cases (http://www.APRegistry.com)

% Birth Defect

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)

2.4% (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%)

CDC general birth defect surveillance 2.7% (2.7-2.8%)

1st trimester any ARV exposure 2.9% (2.4 - 3.4%)

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 childrensimilar spectrum to adults

Of particular importance in children:

Metabolic abnormalities– hyperlipidaemia– glucose intolerance

Fat redistribution

Bone density & growth