Long Term Side Effects of ART in Africa: Third Millenium Dr Cissy Kityo Mutuluuza Joint Clinical Research Centre IAS Conference July Rome, Italy

Number of people receiving ART in low and middle income countries by region 2002–2009 5,25 million on ART by end of % rise from end of fold increase in six years 5,25 million on ART by end of % rise from end of fold increase in six years Source: WHO, 2010

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

Benefits of ART A.  voluntary testing/counseling B.  awareness of HIV C.  motivation of health care workers D.  expenses for palliative and OI care E.  number of orphans F.Keeps households and businesses intact G.  access to health facilities H.Potential to enhance prevention a.Behavioral: access to prevention education during care encounters b.Biological: decreased transmission due to lowered viral load

Impact of ART in Resource-Limited Settings

Relative rate of MI according to PI exposure D:A:D NEJM 2007 However, there are complications: no such a thing as a free lunch….

Many organ systems are affected by ART Cardivascular system Kidneys Liver Pancreas Bone Perpheral Nervous System Muco-cutaneous membranes Lypodystrophy Lactiacidosis

Are you better off with ART : Serious Non-AIDS Outcomes in SMART No. of Patients with Events Endpoints Major CVD +, hepatic or renal disease CVD Relative Risk (95% CI) Rate DCVS Renal (ESRD) Hepatic (Cirrhosis) NADM Favors DCFavors VS Other non-OD death Any of the above MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin NEJM 2006; 355:

SMART Results for START Endpoints No. of Patients with Events Endpoint Serious AIDS Favors VS ► ► Favors DC Hazard Ratio (DC/VS) (95% CI) Rate* DCVS Serious non-AIDS * Per 100 person-years Serious AIDS or non-AIDS Curr Opin HIV AIDS 2008;3:

ART Treatment for Africa Where 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

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

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 (

Trial Design 3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease, CD4<200 cells/mm 3 initating ART Laboratory and Clinical Monitoring (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/mm 3 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 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/mm 3 at 48/72 weeks (stopped March ) 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 analysis 1 DART Trial Team AIDS 2008;22(2):237-47

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

Proportion event-free Years from randomisation (ART initiation) LCMCDM Grade 4 AE p=0.18 SAE p=0.20 ART- modifying AE p=0.85 Adverse events Grade 3/4 AE p=0.52

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)

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