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Long Term Side Effects of ART in Africa: Third Millenium

Dr Cissy Kityo Mutuluuza

Joint Clinical Research Centre

IAS Conference 17-20 July 2011- Rome, Italy

www.ias2011.org

Number of people receiving ART in low and middle income countries by region 2002–2009

5,25 million on ART by end of 2009 30% rise from end of 2008

13 fold increase in six years

5,25 million on ART by end of 2009 30% rise from end of 2008

13 fold increase in six years

Source: WHO, 2010

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"Treatment 2.0": Re-energizing the Public Health Approach to ART

TREATMENT2.0

Strengthen delivery systems

Mobilize communities

Provide point of care diagnostics

Optimize drug

regimens

Reduce costs

TREATMENT2.0

Strengthen delivery systems

Mobilize communities

Provide point of care diagnostics

Optimize drug

regimens

Reduce costs

www.ias2011.org

Benefits of ART

A. voluntary testing/counselingB. awareness of HIVC. motivation of health care workersD. expenses for palliative and OI careE. number of orphansF. Keeps households and businesses intactG. access to health facilitiesH. Potential to enhance prevention

a. Behavioral: access to prevention education during care encounters

b. Biological: decreased transmission due to lowered viral load

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Impact of ART on mortality in

Impact of ART on mortality in

Northwest Province, South Africa

Northwest Province, South Africa

Data source: Ministry of Health, South Africa

0

2000

4000

6000

8000

10000

12000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

dea

ths

0

5000

10000

15000

20000

25000

30000

35000

40000

Eve

r o

n A

RT

cum on

ART15-24

25-34

35-44

45-54

65+

data sources: Stats SA: SA

MOH South Africa

Impact of ART on TB incidence in

Impact of ART on TB incidence in Botswana Botswana

0

100

200

300

400

500

600

700

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

inci

den

ce/1

00,0

00

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

ARTTB

Sources: NASA data reported to WHO and UNAIDS by Ministry of Health, Botswana;

TB Program, Ministry of Health, Botswana

Impact of ART in Resource-Limited Settings

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Relative rate of MI according to PI exposure

D:A:D NEJM 2007

Adjusted RR* per year of PI: 1.16 [1.10-1.23]

None <1 1-2 2-3 3-4 4-5 5-6 >60.5

1

2

4

8

PI-exposure (yrs)

RR

(95

% C

I)

However, there are complications: no such a thing as a free lunch….

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Many organ systems are affected by ART

• Cardivascular system• Kidneys• Liver• Pancreas• Bone• Perpheral Nervous System• Muco-cutaneous membranes• Lypodystrophy• Lactiacidosis

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0.1 1 10

Are you better off with ART : Serious Non-AIDS Outcomes in SMART

No. of Patients with EventsEndpoints

Major CVD+, hepatic or renal disease 104 1.8 1.1CVD+ 79 1.3 0.8

Relative Risk (95% CI)

RateDC VS

Renal (ESRD) 11 0.2 0.1

1.4Hepatic (Cirrhosis) 17 0.3 0.2

1.4

4.5

1.7

NADM++ 47 0.8 0.5

1.8

1.6

Favors DC Favors VS

Other non-OD death 51 0.9 0.5

Any of the above 186 3.2 2.0

1.6

+ MI (clinical or silent), stroke, surgery for CAD++ Except non-melanoma skin

NEJM 2006; 355:22838-96

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SMART Results for START Endpoints

No. of Patients with EventsEndpoint

Serious AIDS 59 1.3 0.4

Favors VS ►

►

Favors DC

Hazard Ratio (DC/VS) (95% CI)Rate*

DC VS

3.6

1.9

Serious non-AIDS 186 3.2 2.01.6

* Per 100 person-years

Serious AIDS or 239 4.4 2.4non-AIDS

Curr Opin HIV AIDS 2008;3:112-117

0.1 1 10

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ART Treatment for AfricaWhere are we now?

• Priorities now:– Roll-out to rural areas, near health centres where

most people live– Integrate with other services– Strengthen systems

• WHO 2010 Guidelines?:– Alternative first-line ART (replacing stavudine)– Moving CD4 threshold for ART initiation up– Increased efficacy (CD4? Viral load?) monitoring

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Monitoring Long Term Side Effects• Few studies conducted to optimise long term ART

outcomes in adults and children

• Data from African ART programs and cohorts is mainly limited to initial short term utility of ART

• Data from Developed countries cannot always be extrapolated to Africa

• Factors in Africa that may affect long term effects of ART include:– Prevalence of co-infections is high– Nutritional status is poor– Use of herbal medicines is widespread– Treatment is started in advanced stage of disease

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The Development of AntiRetroviral Therapy in

Africa(DART) trial

Routine vs clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa:

a randomised non-inferiority trial

(www.ctu.mrc.ac.uk/dart)

Trial Design3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease,

CD4<200 cells/mm3 initating ART

Laboratory and ClinicalMonitoring (LCM)

12 weekly biochemistry,FBC & CD4

Other investigations & concomitant

medications if clinically indicated

Switch to second-line for

• new/recurrent WHO 4 (or multiple WHO 3)

• CD4<100 cells/mm3

Clinically Driven Monitoring (CDM)

12 weekly biochemistry,FBC & CD4;

FBC & biochemistry only returned if clinically

indicated (or grade 4 toxicity);

CD4 never returnedOther investigations &

concomitant medications if clinically indicated

Switch to second-line for• new/recurrent WHO 4

(or multiple WHO 3)

randomise

As per WHO guidelines, switching before 48 weeks discouraged in both arms

Main objectives of DART

• To evaluate the need for routine laboratory monitoring of ART in African adults starting ART having fulfilled clinical and CD4 criteria for ART initiation

• To evaluate 12 week cycles of structured treatment interruptions (STIs) in patients with CD4 300 cells/mm3 at 48/72 weeks (stopped March 20061)

• Primary endpoints

– Efficacy: new WHO stage 4 HIV event (AIDS) or death

– Safety: any Serious Adverse Event which is not only HIV-related

• Cost-effectiveness analysis1 DART Trial Team AIDS 2008;22(2):237-47

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Toxicity monitoring

Routine laboratory monitoring for toxicity did not impact adverse events or substitutions in first-line

• Differences between arms are driven by HIV events

• More tests done in LCM

– routine monitoring does not prevent extra tests being requested

• Routine laboratory tests for toxicity were the most costly part of ART provision in DART

• Laboratories are still needed– eg screening; diagnosis and management of acute

illnesses

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0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n e

ve

nt-

fre

e

0 1 2 3 4 5

Years from randomisation (ART initiation)

LCM CDM

Grade 4 AEp=0.18

SAE p=0.20

ART-modifying AE

p=0.85

Adverse events

Grade 3/4 AEp=0.52

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Data on longer term toxicities of ART

• Needed to understand how to prevent, diagnose and manage these complications in order to provide optimal long-term care in Africa

• Use of existing good quality cohorts in Africa to obtain data

• Targeted lower intensity monitoring approaches – non-invasive portable techniques for measuring cardiac

and vascular function– Bioelectrical Impedance Analysis (BIA)– ? Role of immune activation markers (D Dimer, IL-6, CRP)

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Need to invest in ART Pharmacovigilance

• Long-term use of ARTon such a large scale, could potentially lead to a significant number of adverse drug reactions especially for highly-vulnerable groups like pregnant women and young children

• Few countries have an effectively functioning pharmacovigilance system for monitoring the appropriate use and collection of drug safety data.

• Establishing