Experience with first-line ARV regimens in Lusaka

Jeff Stringer, MDProfessor, Obstetrics and Gynecology, UAB

Director, Centre for Infectious Disease Research in Zambia

The University of Alabama atBirmingham

Why MOH is changing to Tenofovir

• Tolerability• Once daily dosing• ARV sequencing• Better outcomes as first-line

Patients enrolled at Project HEART-supported sites thru Aug ‘07

113,561Enrolled

70,624On ART

0

20000

40000

60000

80000

100000

120000

May-0

4

Aug-0

4

Nov-0

4

Feb-05

May-0

5

Aug-0

5

Nov-0

5

Feb-06

May-0

6

Aug-0

6

Nov-0

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Feb-07

May-0

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Aug-0

7

Background

• Patient data captured on forms• Entered in real time into SmartCare EMR• Every pharmacy prescription and dispensation

captured (n=789,541)– Switching very well captured– Reasons for switching not well captured

• D4T and AZT commingled in every clinic• Prescription by availability; anemia

Methods• Comparison of D4T vs. AZT- containing

regimens• Outcome = Mortality

– Post 90-days• Cox Proportional Hazards Regression

– Exposure categorized by initial regimen in crude analyses (ITT)

– Adjusted analyses treat drug exposure as time-varying covariate

23,253on NVP ART > 1

month

45,,492Returned for further

care

59,512 ART NaïveHIV+ AdultsEvaluated

14,020Did not return

12,635AZT

9,962D4T

1,985Late

673Withdrew

748Died

1,804Late

542Withdrew

946Died

6,670Active

9,229Active

656Missing Initial

Regimens

14,506did not start ART146 uncertain start

dates

5,955Initiated with EFV

(TB)

1,632< 30 days on ART

22,597Dispensed

AZT(n=12,635)

D4T(n=9,962)

Age, median (IQR) 35 (30, 41) 34 (29, 40)

Female 58% 70%

CD4 count, median (IQR) 139 (77, 199) 119 (58, 191)

< 50 cells/l 15% 21%

WHO I or II 39% 30%

III 54% 60%

IV 7% 10%

Hemoglobin, median (IQR) 11.6 (10.6, 12.8) 9.6 (8.5, 10.7)

< 8 g/dL 1.8% 17%

BMI, median (IQR) 20.4 (18.5, 22.8) 19.4 (17.4, 21.6)

<16 kg/m2 5.0% 12%

Active TB 0.3% 0.5%

*p < 0.001 for all comparisons (except TB, p = 0.14)

Comparison of patients by initial regimen

Switching from D4T and from AZT: 22,597 Adults in Lusaka

AZT → D4T rate: 27.1 / 100 pt-yrsMedian time to switch: 84 days

D4T → AZT rate: 13 / 100 pt-yrsMedian time to switch: 148 days

Post 90-Day MortalityCrude

WHO I/II 1.0

III 1.97 (1.74 - 2.23)

IV 3.48 (2.96 - 4.09)

CD4 >200 1.0

50-200 0.94 (0.82 - 1.07)

<50 1.90 (1.65 - 2.19)

Age >35 1.0

< 35 1.15 (1.04 - 1.26)

Weight (continuous) 0.95 (0.95 - 0.96)

HgB >10 1.0

8-9.99 2.29 (2.04 - 2.57)

<8.0 3.18 (2.73 - 3.70)

Female 1.0

Male 1.43 (1.30 - 1.58)

AZT 1.0

D4T 1.83 (1.66 - 2.02)

Post 90-Day MortalityCrude Adjusted

WHO I/II 1.0 1.0

III 1.97 (1.74 - 2.23) 1.46 (1.27 - 1.69)

IV 3.48 (2.96 - 4.09) 2.13 (1.76 - 2.58)

CD4 >200 1.0 1.0

50-200 0.94 (0.82 - 1.07) 0.90 (0.78 - 1.05)

<50 1.90 (1.65 - 2.19) 1.35 (1.15 - 1.59)

Age >35 1.0 1.0

< 35 1.15 (1.04 - 1.26) 1.20 (1.07 - 1.34)

Weight (continuous) 0.95 (0.95 - 0.96) 0.96 (0.95 - 0.97)

HgB >10 1.0 1.0

8-9.99 2.29 (2.04 - 2.57) 1.91 (1.67 - 2.19)

<8.0 3.18 (2.73 - 3.70) 2.21 (1.84 - 2.65)

Female 1.0 1.0

Male 1.43 (1.30 - 1.58) 1.80 (1.60 - 2.02)

AZT 1.0 1.0

D4T 1.83 (1.66 - 2.02) 1.15 (1.01 - 1.31)

Post 90-Day MortalityCrude Adjusted Time-varying

WHO I/II 1.0 1.0 1.0

III 1.97 (1.74 - 2.23) 1.46 (1.27 - 1.69) 1.44 (1.25 - 1.66)

IV 3.48 (2.96 - 4.09) 2.13 (1.76 - 2.58) 2.11 (1.74 - 2.55)

CD4 >200 1.0 1.0 1.0

50-200 0.94 (0.82 - 1.07) 0.90 (0.78 - 1.05) 0.90 (0.78 - 1.04)

<50 1.90 (1.65 - 2.19) 1.35 (1.15 - 1.59) 1.33 (1.14 - 1.56)

Age >35 1.0 1.0 1.0

< 35 1.15 (1.04 - 1.26) 1.20 (1.07 - 1.34) 1.19 (1.07 - 1.33)

Weight (continuous) 0.95 (0.95 - 0.96) 0.96 (0.95 - 0.97) 0.96 (0.95 - 0.97)

HgB >10 1.0 1.0 1.0

8-9.99 2.29 (2.04 - 2.57) 1.91 (1.67 - 2.19) 1.72 (1.51 - 1.97)

<8.0 3.18 (2.73 - 3.70) 2.21 (1.84 - 2.65) 1.96 (1.64 - 2.33)

Female 1.0 1.0 1.0

Male 1.43 (1.30 - 1.58) 1.80 (1.60 - 2.02) 1.83 (1.63 - 2.05)

AZT 1.0 1.0 1.0

D4T 1.83 (1.66 - 2.02) 1.15 (1.01 - 1.31) 1.48 (1.30 - 1.69)

1%

9%

26%

64%

Normal (n=13,111)

Mild insufficiency (n=5,249)

Moderate insufficiency (n=1,752)

Severe insufficiency (n=227)

Baseline renal function20,339 patients initiating ART in Lusaka, Zambia

Creatinine clearance calculated by Cockroft-Gault equation

(Mild = 61 – 90 mL/min; Moderate = 31 – 60 mL/min; Severe = < 30 mL/min)

Mortality by baseline renal function20,339 patients initiating ART in Lusaka, Zambia

Creatinine clearance calculated by Cockroft-Gault equation

Mortality risk according to baseline renal function

Crude HR (95% CI)n=16,646

Adjusted HR *(95% CI)n=15,051

Normal renal function Ref Ref

Renal Insufficiency

Mild 1.7 (1.5, 1.9) 1.5 (1.3, 1.7)

Moderate 3.0 (2.7, 3.5) 2.3 (2.0, 2.7)

Severe 6.2 (4.8, 8.0) 4.4 (3.4, 5.8)

* Adjusted for baseline CD4 count, WHO stage, hemoglobin and adherence to antiretroviral drugs

Summary

• Why we’re switching to Tenofovir DF– Truvada is better than combivir

• Gallant et al NEJM 2006

– D4T ass’d with worse outcomes than AZT in our data

• Why we’re worried– Many patients have underlying renal disease– Monitoring of renal function can be difficult in

some settings

End

Study 934

Preliminary 48 week analyses

February 25, 2005

Study 934 Study Design

ART-naïve patients

(n = 517)

randomized 1:1

96 wks

96 wks

Any CD4 cell count

HIV RNA > 10,000 c/mL

TDF QD

FTC QD

Efavirenz QD

AZT/3TC BID

Efavirenz QD

Adequate Renal and Hepatic Function at baselineFTC/TDF Fixed dose combination tablet was not used

Study 934

Statistical Analysis

• Non inferiority Trial

• 85% power to detect a 13% difference between arms

• Primary Endpoint-Time to Loss Virologic Response (TLOVR)

– FDA-required endpoint

– Similar to ITT Missing = Failure, Switch = Failure

– Requires confirmation for success

– Used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals

a. Median values

Study 934

Baseline Characteristics (ITT)

FTC/TDF (n = 255)

CBV (n = 254)

Agea 36 37

% Female 14% 13%

% White 56% 61%

% Black 25% 20%

% Hispanic 15% 16%

HIV RNA (log10 copies/mL)a 5.0 5.0

% HIV RNA > 100,000 52% 50%

CD4+ (cells/mm3)a 233 241

% < 200 42% 41%

% < 50 15% 11%

Study 934

Baseline NNRTI Resistance (ITT)

• 22 patients (11 FTC/TDF vs. 11 CBV)

• Investigators notified if affected

• FDA recommended excluding these patients for Week 48 primary endpoint analysis (n = 487)

• Primary Efficacy Endpoint (HIV RNA < 400 c/mL) at Week 48 analyzed for both populations, excluding NNRTI-R (n = 487) and ITT (n = 509)

Study 934Proportion with HIV-RNA <400 c/mL (TLOVR) ITT (n = 509)

0

20

40

60

80

100

BL 8 16 24 32 40 48

Weeks

% R

esp

on

der

FTC/TDF 81%*CBV 71%*

*95% CI: (+3.4%, +18.1%)

p = 0.005

Exclude NNRTI-R (n=487): FTC/TDF 84%, CBV 73%, p=0.002 (+4.3%,18.6%)

a. p value 0.016b. p value 0.021

Study 934 Summary Outcomes Wk 48 TLOVR < 400 c/mL

FTC/TDF(N = 255)

CBV(N = 254)

Permanent Study Regimen Discontinuation 19% 29%

Adverse Event 4% 9%a

Lost to Follow Up 5% 7%

Withdrawal Consent/Non Compliance 3% 4%

Other 3% 3%

Virologic Rebound <1% 4%b

Insufficient Virologic Response 2% 1%

Pregnancy 2% 1%

Death <1% <1%

Study 934

Proportion with HIV-RNA <400 c/mL (TLOVR)by Baseline HIV-RNA

FTC/TDF (n=255)

CBV (n=254)

P value

95% CI

HIV RNA (c/ml) at Week 48

100K 80% 71% 0.083 -1.1 to 19.9% > 100K 82% 70% 0.016 +3.0 to 22.7%

Study 934Proportion with HIV-RNA <50 c/mL (TLOVR) ITT (n = 509)

0102030405060708090

BL 8 16 24 32 40 48

Weeks

% R

esp

on

der

FTC/TDF 77%*CBV 69%*

*95% CI: (+0.5%, +15.8%)

p = 0.042

Exclude NNRTI-R (n=487): FTC/TDF 80%, CBV 71%, p=0.027 (+1.2%,16.1%)

Study 934

CD4 Mean Absolute Change from BaselineAs Treated

FTC/TDF 189CBV 158

FTC+TDF+EFV 238 234 223 218 209 198CBV+EFV 222 216 199 188 175 164

0

75

125

175

225

BL 8 16 24 32 40 48

Weeks

Mea

n C

han

ge

(cel

ls/m

m3)

p = 0.002 at Week 48p < 0.001 by AAUCMB

Study 934Resistance Development at Week 48 (mITT)

1. All patients with confirmed >400 copies/mL of HIV RNA at Week 48 or early discontinuation analyzed. Patients with baseline NNRTI-resistance excluded (n = 22).

2. Genotyping of 1 additional Combivir patient failed due to technical reasons.3. K103N developed in 21/25 patients; other NNRTI mutations that developed included K101E, K103E,

V108I, V179D, G190A/S, P225H, M230L

FTC/TDF, n=244 N, (% mITT, % VF)

CBV, n=243N (% mITT, % VF)

Virologic Failure 12 232

Any EFV-R3 9 (4%, 75%)

16 (7%, 73%)

Any M184V/I2

(0.8%, 17%)7

(3%, 32%)

Any TAMs 01

(0.4%, 5%)

K65R 0 0

Wild-type3

(1%, 25%)5

(2%, 23%)

Rates of K65R in TDF Clinical Trials

Study 934TDF/FTC/EFV

n=255

n (%)

Study 418TDF/FTC/LPV

n=190

n (%)

Week 48-96 1 (3%) pending pending

Week 24-48 2 (2%) 0 0

Week 0-24 5 (2%) 0 0

Study 903TDF/3TC/EFV

n=299

n ( %)

Time Period

Week 96-144 0

a. Occurring in more than 1 patient in either arm; patients may have > 1 eventb. p = 0.016

Study 934Adverse Events Leading to Study Drug Discontinuation Through Week 48

Safety PopulationFTC/TDF(n = 257)

CBV(n = 254)

No. w/ any Adverse Eventa 10 (4%) 23 (9%)b

Adverse Event

Anemia/ ↓ Hgb 0 14 (6%)

Nausea 1(<1%) 4 (2%)

Fatigue 0 3 (1%)

Vomiting 0 2 (<1%)

Dermatitis (NNRTI) 2 (<1%) 0

Neutropenia 0 2 (<1%)

Study 934Median (Range) Hemoglobin and Hematocrit ValuesDiscontinuations due to Anemia on CBV arm (n=14)

Hem

ato

crit

%

05

10

15202530

35404550

5560

Baseline Nadir

40

47

31

22

33

11

0

2

4

6

8

10

12

14

16

18

20

Baseline Nadir

Hem

og

lob

in (

g/d

L) 13.8

16.0

10.8

6.9

3.7

9.3

0

2

4

6

8

10

12

14

16

18

20

Baseline Nadir

Hem

og

lob

in (

g/d

L) 13.8

16.0

10.8

6.9

3.7

9.3

Study 934 Calculated Creatinine Clearance (CLcr)

CBV(n=254)

FTC/TDF (n=257)

Baseline CLcr, Mean (ml/min) 129 126

CLcr at week 48, Mean 127 134

Study 934 Serum Creatinine

Maximum Confirmed Toxicity Grade (mg/dL)a

FTC/TDF(n = 257)

CBV(n = 254)

1 (>1.5 - 2.0) 0 1 (<1%)

2 (2.1 - 3.0) 0 1 (<1%)

3 (3.1 - 6.0) 0 0

4 (>6.0) 0 0

a. Confirmed toxicity grade = two consecutive visits

Study 934 Serum Phosphorus

Maximum Confirmed Toxicity Grade (mg/dL)a

FTC/TDF(n = 257)

CBV(n = 254)

1 (2.0-<2.2) 0 0

2 (1.5-1.9) 0 1 (<1%)

3 (1.0-1.4) 0 0

4 (<1.0) 0 0

a. Confirmed toxicity grade = two consecutive visits

• Superior overall response in the FTC/TDF arm compared to CBV arm

• No patient developed K65R• M184V developed less frequently in the TDF/FTC arm than in the

Combivir arm.

• Significantly more CBV patients discontinued due to adverse events

• Similar renal safety profile• No confirmed abnormalities serum creatinine or phosphorus in

FTC/TDF arm

Study 934 Week 48 Summary

AZT Brand (initial)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

D4T Generic

D4T Brand

AZT Generic

AZT Brand

AZT Generic (initial)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

D4T Generic

D4T Brand

AZT Brand

AZT Generic

AZT (initial)

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2000

4000

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14000

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

D4T

AZT

D4T Brand (initial)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

AZT Generic

AZT Brand

D4T Generic

D4T Brand

D4T Generic (initial)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

AZT Generic

AZT Brand

D4T Brand

D4T Generic

D4T (initial)

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2000

4000

6000

8000

10000

12000

14000

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

AZT

D4T

D4T (initial)

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2000

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10000

12000

14000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

AZT Generic

AZT Brand

D4T Brand

D4T Generic

AZT (initial)

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2000

4000

6000

8000

10000

12000

14000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

D4T Generic

D4T Brand

AZT Generic

AZT Brand

All (initial)

0

5000

10000

15000

20000

25000

1 4 7 10 13 16 19 22 25 28 31 34 37 40

D4T Generic

D4T Brand

AZT Generic

AZT Brand