Clinical differences between younger & older adults with HIV starting antiretroviral therapy in Uganda &

Zimbabwe: A secondary analysis of the DART trial

1,3Sujal M. PARIKH, 1Ekwaro A. OBUKU, 2Sarah A. WALKER, 6Aggrey S. SEMEERE, 6,7Brandon J. AUEBERCH, 8John G. HAKIM,

5Harriet MAYANJA-KIZZA, 1Peter N. MUGYENYI, 4Robert A. SALATA, 1Cissy M. KITYO on behalf of the DART Trial Team*

Joint Clinical Research Centre, Kampala, Uganda

4th International Conference on HIV & Aging,

30th October, 2013 Marriot Inner Harbor, Baltimore, USA

1

Virologically controlled PLHIV • Patients who have achieved long-term viral load control on HAART are now

increasingly experiencing premature onset of diseases associated with aging, such as

– cardiovascular (CV) disease

– non-AIDS cancers

– liver disease

– renal disease

• These serious non-AIDS diseases are being observed at an excess rate compared to the general population

• Persistent HIV-induced immune dysfunction/activation appears to be associated with this excess

Engels EA. AIDS 2009; 23:875-885. 2

HIV and the aging population in the US – The number of persons 65 years of age and

older at AIDS diagnosis has grown 10-fold in the last 10 years1,2 (50% by 2015)3.

1. Stoff D M et al. AIDS 2004;18(suppl 1):S1-S2 2. Centers for Disease Control and Prevention. Cases of HIV and AIDS in the United States and Dependent Areas. HIV/AIDS Surveillance Report 2005.

Available at http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2005report/pdf/2005SurveillanceReport.pdf; accessed October 2009.

Num

ber o

f pat

ient

s

Age (years)

Adapted from HIV/AIDS Surveillance Report 20052

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SSA will triple from 3.1 million in 2011 to 9.1 million by 2040 or 1 in 4 (Hontelez et al, 2013)

0

5

10

15

20

25

15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 45 - 49 50 - 59

S.04/05

S.11/12

Cen. '02

Age group (years)

Prop

ortio

n (%

) Uganda: Age distribution for 2004/05 vs. 2011/12 HIV prevalence surveys

Source: MoH 2006; MoH 2012; UBoS 2004

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Age group (years)

Prop

ortio

n (%

) Uganda: HIV prevalence by age group 2004/05 vs. 2011/12

0

2

4

6

8

10

12

15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 45 - 49 50 - 59 Mean

S.04/05

S.11/12

Source: MoH, 2012

Kenya, 50 – 54: 5.7% to 9.1% (2003 – 2008) Uganda, 50 – 59: 5.8% to 6.4% (2004 – 2011) South Africa, 50 – 59: 6.4% (Negin, 2012)

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Previous work on Aging & HIV/AIDS

• Bulk of data from High Income Settings – § Differences unique to older adults

• Multiple co-morbidities – NCDs & Infectious Diseases

• Poly-pharmacy – Adherence

• Immunological/Virological – Risk of HIV acquisition – Response to ART

• Social – Support mechanisms

The few studies from Africa* miss mainly laboratory information: - Gender - Hypertension, BMI - Hep B, Hep C, CMV - Hb, ALT, AST, Creatinine - CD4+ - VL

* Negin 2010; Negin 2011; Bakanda, 2011; Negin 2012; Greig 2012; Hirschhorn 2012 Pathai 2013; Hontelez, 2013

§ High KP et al, 2012 6

Objective

• We aimed to describe differences between younger and older adults with HIV starting antiretroviral therapy in two low–income African countries.

• Differences: – Clinical – Laboratory measures

• Age groups: – 18 to 49 years (younger) – ≥ 50 years (older)

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Methods

• Secondary analysis – exploratory – cross–sectional, start of ART – *DART randomized

controlled trial data.

• DART had two arms – CDM

• Clinically driven monitoring • No CD4, (Heam. & Biochem.)

– LCM • Laboratory & clinical monitoring • CD4, Heam. & Biochem./12 wks

*Development of AntiRetroviral Therapy in Africa

Setting: - HIV/AIDS care clinics - Zimbabwe, Uganda - Jan 2003, Oct 2008

Eligibility: - WHO stage 2 – 4 - HIV+; >18 years - CD4+ <200 cells/ml - No previous ART (PMTCT) Viral loads: - N = 968 at baseline - Retrospective, stored samples

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THE JOINT CLINICAL RESEARCH CENTRE, KAMPALA, UGANDA

JCRC 1990 JCRC 2012 VISION

Pioneer in HIV/AIDS research and care for PLWHA - First African ART trial: AZT (Zidovudine), 1992 - First ever HIV vaccine trial: (ALVAC), 1999* - >100,000 PLWHAs have accessed ART by 2010

Infrastructure: - Certified Laboratories - 6 country-wide Regional Centres of Excellence

* Cao et al. 2003 JID Mar 15;187(6):887-95.

www.jcrc.org.ug/research

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Analysis • Aim: Identify variables that differed significantly between

the younger and older adults with HIV (18 – 49 versus >50 years) at enrollment into *ART care. – Stata 11.2 software – Logistic regression

• adjusted Odds Ratios (aOR)

– *WHO cut offs for hypertension, overweight and obesity – Excluded creatinine & body mass index (BMI) from adjusted

analyses due to their significant correlation with creatinine clearance (r2 = – 0.6 & r2=0.33, respectively, both p<0.0001).

– Not all participants had HIV-1 RNA measures taken, we thus employed two adjusted regression models (+/- VL).

– NS: P>0.05

*Antiretroviral Therapy; *World Health Organization 10

Variable Overall population N = 3316

18 – 50 years ≥ 50 years P-Value

n (%) 3097 (93) 219 (7) Age (years, mean, SD) 37.6 (7.8) 36.3 (6.3) 55.1 (4.4) P<0.001 Sex Male (%) 1160 (35) 1054 (90.9) 106 (9.1) P<0.001 Female (%) 2156 (65) 2043 (94.8) 113 (5.2) BMI mean (SD) 21.7 (3.8) 21.6 (3.8) 22.5 (3.9) P<0.001 Blood Pressure (mm Hg) Systolic, mean (SD) 110.6 (14.7) 109.9 (13.9) 120.9 (20.2) P<0.001 Diastolic, mean (SD) 72.3 (11.1) 71.9 (10.8) 77.9 (13.6) P<0.001 WHO Clinical Stage (%) II 673 (20) 620 (92) 53 (8) P=0.077 III 1864 (56) 1737 (93) 127 (7) IV 779 (24) 740 (95) 39 (5)

Table 1: Characteristics at ART initiation stratified by age < 50 years & age ≥ 50 years

11 NB: (Parentheses) are either % or S.D.

CD4+ (cells/µL) median (IQR) 86 (81–139) 85 (30–138) 92 (45–147) P=0.222 Viral Load (log10 cp/mL) mean (SD) 5.4 (0.7) 5.4 (0.7) 5.7 (0.5) P=0.003 Hemoglobin (g/dL) mean (SD) 11.5 (1.7) 11.5 (1.8) 11.7 (1.5) P=0.078 Creatinine (mg/dL) mean (SD) 0.91 (0.27) 0.90 (0.27) 0.98 (0.26) P<0.001 ALT (mmol/L) median (IQR) 25 (18–36) 25 (18–36) 23 (17–33) P=0.008 AST (mmol/L) median (IQR) 34 (26–48) 34 (26–48) 34 (25–44) P=0.895 Hepatitis B virus pos (%) 302 (9.3) 290 (96) 12 (4) P=0.053 neg (%) 2,950 (90.7) 2,747 (93.1) 203 (6.9) Hepatitis C virus pos (%) 77 (2.4) 69 (89.6) 8 (10.4) P=0.177 neg (%) 3,176 (97.6) 2,969 (93.5) 207 (6.5)

Variable N = 3316 18 – 50 years ≥ 50 years P-Value

Table 1: Characteristics at ART initiation stratified by age < 50 years & age ≥ 50 years

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Co-morbidity <50 years (%) >50 years (%) P-Value

Systolic Hypertension 9.2 21.3 <0.001 Diastolic Hypertension 3.5 19.0 <0.001 Overweight or Obese 14.8 24.0 <0.001 Hepatitis C 2.3 3.7 0.17 Hepatitis B 9.6 5.6 <0.05 >2 comorbidities 5.1 11.4 <0.001 >2 comorbidities in South African cohort*

8.8% 29.6% <0.0001

Table 2: Prevalence of comorbidities

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N=3316; 219 (>50 years); 3097 (<50 years)

*Negin, 2012

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Parikh SM, Obuku EA, Walker SA, Semeere AS, Auerbach BJ, et al. (2013) Clinical Differences between Younger and Older Adults with HIV/ AIDS Starting Antiretroviral Therapy in Uganda and Zimbabwe: A Secondary Analysis of the DART Trial. PLoS ONE 8(10): e76158. doi:10.1371/ journal.pone.0076158

Adjusted analysis

Adjusted analysis • Fewer females among older adults *

– (aOR: 0.03, 95% CI: 0.00 – 0.19, p<0.001)

• Higher systolic blood pressure – (aOR: 1.05, 95% CI: 1.03 – 1.06, p<0.001)

• Higher CD4+ cell counts – (aOR: 1.00, 95% CI: 1.00 – 1.01, p=0.009)

• Lower creatinine clearance † – (aOR: 0.97, 95% CI: 0.96 – 0.97, p<0.001).

• Higher VL – (aOR: 2.51, 95% CI: 1.07 – 5.87, p=0.034)

15 *Negin, 2012; †Cooper, 2010

Summary: • HIV cohorts in sub-Sahara Africa are Aging:

– Health system adjustments: • Resources (financial & human); services (integration of care);

knowledge and skills of care providers (NCDs, complications of ART)

• There are differences between age groups: – Younger cf. Older adults PLWHAs

• Laboratory findings (Haem., Biochem., VL); co-morbidities; gender

• Next steps/future research: – equity/access to care (older adults, women); differences in

clinical outcomes (VACS index); other biomarkers; establishing cohorts in sub-Sahara Africa (HIV uninfected).

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Qualitative analysis: opportunities

• Training courses in HIV/AIDS centers of excellence – Advanced course – Complications of chronic

ART

• CSO network (URAA)

• Affirmative action – Mukono district model – SAGE

Obuku EA, Parikh SM, Nankabirwa V, Kakande NI, Mafigiri DK, et al. (2013) Determinants of Clinician Knowledge on Aging and HIV/AIDS: A Survey of Practitioners and Policy Makers in Kampala District, Uganda. PLoS ONE 8(2): e57028. doi:10.1371/journal.pone.0057028

Acknowledgement Mentors: Prof. P. Mugyenyi Prof. R. Salata Dr. C. Kityo Dr. S. Walker Prof. H. Mayanja

Co-authors: Dr. B. Auerbach Dr. A. Semeere

Admin support: CWRU, USA JCRC, Uganda VIGH/FICRSF, USA

National Institutes of Health, Fogarty International Centre:

Grant no: R24 TW007988 18