Long Term Side Effects of ART in Africa: Third Millenium

1. 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

2. 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 Source: WHO, 2010

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

4. Benefits of ART •  voluntary testing/counseling •  awareness of HIV •  motivation of health care workers •  expenses for palliative and OI care •  number of orphans • Keeps households and businesses intact •  access to health facilities • Potential to enhance prevention • Behavioral: access to prevention education during care encounters • Biological: decreased transmission due to lowered viral load

5. Impact of ART in Resource-Limited Settings

6. However, there are complications: no such a thing as a free lunch…. 8 Adjusted RR* per yearof PI: 1.16 [1.10-1.23] 4 2 RR (95% CI) 1 0.5 None <1 1-2 2-3 3-4 4-5 5-6 >6 PI-exposure (yrs) Relative rate of MI according toPI exposure D:A:D NEJM 2007

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

8. Are you better off with ART : Serious Non-AIDS Outcomes in SMART Relative Risk (95% CI) No. of Patients with Events Rate Endpoints DC VS Major CVD+, hepatic or renal disease 1041.81.1 1.7 CVD+ 791.30.8 1.6 Hepatic (Cirrhosis)170.30.2 1.4 Renal (ESRD) 110.20.1 4.5 NADM++ 470.80.5 1.4 Other non-OD death 510.90.5 1.8 Any of the above 1863.22.0 1.6 + MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin Favors DC Favors VS NEJM 2006; 355:22838-96

9. SMART Results for START Endpoints Hazard Ratio (DC/VS) (95% CI) No. of Patients with Events Rate* Endpoint DC VS Serious AIDS 59 1.30.4 3.6 1.6 Serious non-AIDS 186 3.22.0 1.9 Serious AIDS or 239 4.42.4non-AIDS 0.1 1 10 Favors VS ► Favors DC ► * Per 100 person-years Curr Opin HIV AIDS 2008;3:112-117

10. 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

11. 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

12. 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)

13. Trial Design 3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease, CD4<200 cells/mm3 initating ART randomise • 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 returned • Other investigations & concomitant medications if clinically indicated • Switch to second-line for • new/recurrent WHO 4 (ormultiple WHO 3) As per WHO guidelines, switching before 48 weeks discouraged in both arms

14. 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 analysis 1 DART Trial Team AIDS 2008;22(2):237-47

15. 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

16. LCM CDM Adverse events 1.0 SAE p=0.20 0.8 ART- modifying AE p=0.85 0.6 Grade 4 AE p=0.18 Proportion event-free 0.4 Grade 3/4 AE p=0.52 0.2 0.0 0 1 2 3 4 5 Years from randomisation (ART initiation)

17. 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)

18. 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