Starting HAART: When to Take the First Step?

Tuesday 20 July from 11:00 – 12:30Session Room 1

Dr. Peter Mugyenyi Joint Clinical Research Centre

Kampala, Uganda

Staring HAART: When to Take the First Step?

Scientific Perspectives from a developing country

Peter Mugyenyi FRCPJoint Clinical Research CentreKampala, Uganda

Number of people receiving antiretroviral therapy in low- and middle-income countries, by region, 2002–2008

Source UNAIDS progress report 2009

Source UNAIDS progress report 2009

5

BackgroundHigher mortality has been observed in the first 2-3 months on ART in adults initiating ART in low-income compared to high income settings

unadjusted (LMIC:HIC)adjusted for age, sex, baseline CD4, stage, regimen

HAART started being scaled up in 2004 at a peak of the crisis

• Priority given to the very sick• Starting CD4 was < 200• Mortality and morbidity was high especially

within the first 1 year• Resource-constrained countries still faced a

dilemma of choosing between providing HIV treatment to more patients and focusing on more severely ill patients.

Evidence for late ART initiation from DART study

LCMN=1656

CDMN=1660

CD4 count (cells/mm3) median<50 cells/mm3

86(0-

199)55433%

86(1-

199)55533%

HIV-1 RNA (log10 copies/ml) mean (SD) (N=968)

5.4(0.7)

5.4(0.7)

WHO stage 234

36322%91655%37723%

31019%94857%40224%

Morbidity and mortality observed in DART study was mainly due to late start of HAART

New WHO4/death DeathsLCM CDM LCM CDM

Events (% of participants)35621%

45928%

16410%

21813%

Cause-specific rate/100PYoesophageal candida 1.09 1.65 - -tuberculosis (ex pulm for

WHO 4)0.87 0.92 0.09 0.32

cryptococcosis 0.69 1.09 0.17 0.26diarrhoea/wasting 0.17 0.48 0.09 0.15HSV or CMV 0.13 0.38 0.00 0.03neurological event 0.18 0.20 0.23 0.30lung event 0.24 0.12 0.15 0.20cancer 0.13 0.14 0.29 0.15septicaemia/neutropenia - - 0.19 0.41renal/hepatic/CVD/lactic

acidosis- - 0.20 0.28

gastrointestinal - - 0.11 0.09trauma/suicide/malaria/

cholera- - 0.12 0.12

other - - 0.08 0.04died without new WHO 4

event/NK1.75 1.97 0.46 0.59

9

Deaths among DART study participants

Deaths in 1st year / Initiated ART (%)

CD4 0-49 50-99 100-149 150-199*DART, 18+ years

103/1106(9%)

36/784(5%)

23/759(3%)

17/661(3%)

Adapted from Sarah Walker’s CROI presentation

Late initiation of HAART after eligibility determination in South Africa

• Study conducted in two outpatients government-subsidised hospitals in Kwazul-Natal South Africa (2008)

Total enrolled 1474

Had CD4 cell count testing dome within 90 days 1012/1474 (69%)

Median [IQR] CD4 cell counts in cells/µl 159 [65, 299]

CD4 cell counts done, and ART-Eligible 538/1012 (53%)

ART-Eligible and did not initiate ART within 12 months 328/538 (61%)

Deaths among ART-eligible subjects before ART initiation or with unknown ART initiation status

89/108 (82%)

Bassett IV. et. al. Who starts antiretroviral therapy in Durban, South Africa?... not everyone who should. AIDS 2010

Late initiation of HAART after eligibility determination in South Africa

Fig: Mortality among antiretroviral therapy-eligible subjects, based on ART initiation status (N = 108 deaths among 536 ART-eligible subjects).

(White) On ART; (Gray) unknown ART status; (Black) pre-ART.

Bassett IV. et. al. Who starts antiretroviral therapy in Durban, South Africa?... not everyone who should. AIDS 2010

The Preventive role of HAART

• Results from the study involving 3381 discordant couples in Africa: – Transmission rate

Initiated HAART: • 0.37 per 100 person years

– HAART not initiated: • 2.24 per 100 person years

92% risk reduction with HAART

Donnell D et al hetrosexual HIV-1 transmission after initiating antiretroviral therapy: A prospective cohort analysis. Lancet 2010 June 12/18

The Preventive role of HAART• Among HIV infected individuals not on

HAART, rate of HIV transmission highest :

• CD4 < 200

• Viral load > 50,000 copies/ml

Donnell D et al

When to Take the First Step?• Evidence for starting ART early is abundant

and clear: Interim review led to early end of Clinical Trial known as CIPRA HT 001 in Haiti: starting ART at CD4 between 200 and 350 mm3 improves survival compared with deferring treatment until CD4 drops below 200 cells/mm3.

When to start

• Optimum time to start is dependant on– Resources—these need to increase to cope

with the rising numbers and as an “investment” for eventual control

– continuing ART roll out – Success requires commitment to Universal

access.

Is early start of ART cost effective?• Early start and sustained viral suppression:

– Restores and preserves immune function– Role in “control of immune activation linked to chronic

inflammation, end organ failure and comorbid conditions previously not thought to be linked to HIV” –from US new recommendation

– decreases incidence of Malaria and debilitating OIs including TB :

– HIV transmission

• It ultimately delivers the best possible treatment outcome

Implication of DART results to Africa

• Treatment can be scaled up to rural and hard to reach areas in Africa. (80% Ugandans live in rural areas)

• Treatment may start and successfully scaled up while capacity building is going on.

• Priority is to train health care providers in good clinical practice to ensure adherence.

• With good clinical monitoring, the vast majority of patients can be maintained on first line therapy for many years (projected beyond 10 years)

Initiating HAART: Current practice in Resource limited countries - a mixed picture

• Uganda: Start ART at CD4 250 as a “compromise because of resource constraints”.

• A few countries in Africa use the current level of CD4 350

• Some donor programs and countries have come up with “priority patients” including pregnant women and HIV-TB co-infected people to be started on ART at CD4 350

• The reality is that many still use CD4 200 level but are not able to providing treatment to all.

AIDS crisis in Africa is getting worse in both treatment and prevention

• The majority of patients in dire need of ART are not accessing it and the numbers in need are growing. – In SSA people on ART rose from 2.1 million in 2007 to 3.2 million

by end of 2009– Over 7 million in immediate need of ART but are not accessing it.– In less than a decade numbers in need of treatment are projected

to double • Implication of raising thresholds for initiating treatment from CD4 200

to CD4 350:– “need for adults could be substantial – up to two times more than

those currently estimated” (UNAIDS). .

ART programs are facing uncertain future.The main threats are:

• Inadequate funding: – PEPFAR which implemented a highly successful treatment

program showed what can be achieved if resources were availed.

– Funds from Global fund for AIDS, TB and Malaria are grossly insufficient.

– Clinton Foundation which supplements the programs is soon winding up, with no sign of replacement

• Funder’s changed policies and priorities:– Donors are emphasizing “strengthening Health Systems”

above treatment– Plans to transition AIDS programs to the mainly

unprepared Ministries of health for integration into the continuum of care

Conclusion

• Current WHO recommendation of starting ART 350 CD4 should be considered only the minimum interim start level, while awaiting further evidence from ongoing trials evaluating the benefits of starting earlier and the “Test and Treat” model

World Leaders made commitment to “Universal access” by the year 2010

Acknowledgements

• DART and ARROW Trial Teams• Sarah Walker for providing the data and

graphic illustrations• Others recognised on individual slides

End

WHO Recommendations for initiating ART in HIV infected infants and children according to clinical stage and

immunological markers (May 2010)

Age Clinical Stage

Immunological

<24months Treat all

>24months Stage 4 Treat all

Stage 3 Treat all

Stage 2 No CD4 available: Don’t treatOrCD4 below age-adjusted threshold: Treat

Stage 1

WHO Recommendations for initiating ART in infants and children (May 2010)

Age Infants and Children <24months

24months through 59months

Five years or older

% CD4 All <25% NA

Absolute CD4

≤ 750 mm3 ≤ 350 mm3 As in adults