Supplementary Table 1: Prevalence at Baseline

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December2014

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second line ARTin the EARNEST trial: Supplementary material

Supplementary Table 1: Prevalence at baseline

n/total n (%)
Symptomatic neuropathy / 279/1251 (22%)
Grading
Grade 1 / 108/279 (39%)
Grade 2 / 86/279 (31%)
Grade 3 / 85/279 (30%)
Asymptomatic neuropathy / 266/1246 (21%)
Signs / 546/1244 (44%)
Symptoms / 484/1251 (39%)

Supplementary Table 2: Centre effect

Centre / Symptomatic Peripheral Neuropathy
n/total n (%) / Signs / Bilateral symptoms
n/total n (%)
Bilateral Reduced Ankle jerk
n/total n (%) / Bilateral Reduced Vibration Sense
n/total n (%)
Uganda (Kampala JCRC) / 60/231 (26%) / 36/230 (16%) / 164/230 (71%) / 73/231 (32%)
Uganda (Kampala IDI) / 54/215 (25%) / 129/215 (60%) / 34/215 (16%) / 81/215 (38%)
Uganda (Kampala Nsambya) / 13/47 (28%) / 20/44 (45%) / 7/48 (15%) / 20/48 (42%)
Zimbabwe (Harare) / 117/263 (44%) / 137/263 (52%) / 65/264 (25%) / 159/264 (60%)
Uganda (Fort Portal) / 6/65 (9%) / 8/65 (12%) / 3/66 (5%) / 27/63 (43%)
Uganda (Gulu) / 4/43 (9%) / 2/41 (5%) / 3/43 (7%) / 15/43 (35%)
Uganda (Mbale) / 4/46 (9%) / 10/47 (21%) / 6/47 (13%) / 13/47 (28%)
Uganda (Mbarara) / 6/97 (6%) / 5/97 (5%) / 3/97 (3%) / 34/97 (35%)
Uganda (Kabale) / 1/31 (3%) / 1/33 (3%) / 2/29 (7%) / 5/31 (16%)
Uganda (Kakira) / 1/31 (3%) / 1/31 (3%) / 4 /31(13%) / 1/31 (3%)
Malawi (Blantyre) / 10/92 (11%) / 4/92 (4%) / 13/92 (14%) / 43/92 (47%)
Zambia / 3/37 (8%) / 4/37 (11%) / 4/37 (11%) / 7/37 (19%)
Kenya (Eldoret) / 0/52 (0%) / 2/52 (4%) / 2/52 (4%) / 6/52 (12%)
Malawi (Mzuzu) / 10/17 (59%) / 1/19 (5%) / 17/17 (100%) / 12/19 (63%)

Supplementary Table 3: D4T effect

Adjusted Odds ratio (95% CI)a / P value
D4T only
D4T / 1.19 (0.79, 1.78) / 0.41
Years exposed to D4T
No D4T / 1 / 0.007
2 years / 1.44 (0.94, 2.20)
3 years / 1.23 (0.82, 1.85)
4 years / 1.05 (0.69, 1.41)

a Adjusted for all variables in final model ie centre, age, sex, CD4, , smoking, alcohol use, CVD family history, creatinine, glucose, centre, viral load, tenofovir exposure, nevirapine exposure, and job status

Supplementary Table 4: TB and Isoniazid effects

Adjusted Odds ratio (95% CI)a / P value
TB in model
TB history / 1.86 (1.33, 2.60) / <0.0001
Isoniazidb in model
Isoniazid within 10 weeks / 2.22 (1.33, 3.70) / 0.002
TB and Isoniazidb in model
TB history / 1.63 (1.11, 2.39) / 0.01
Isoniazid in 10 weeks / 1.54 (0.85, 2.76) / 0.15
TB and Isoniazidb interaction c
No history of TB or isoniazid / 1
TB with no isoniazid in 10 weeks / 1.66 (1.13, 2.44) / 0.01
TB and isoniazid within 10 weeks / 2.41 (1.42, 4.07) / 0.001

a Adjusted for all variables in final model ie centre, age, sex, CD4, , smoking, alcohol use, CVD family history, creatinine, glucose, centre, viral load, tenofovir exposure, nevirapine exposure, and job status

bIsoniazid in last 10 weeks only.Only one patient used isoniazid as prophylaxis, all other patients taking isoniazid in the last 10 weeks were treating TB

c Testing equality for TB with no isoniazid and TB with isoniazid p=0.22

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Supplementary Table 5: Baseline analysis Sensitivity Analyses

Characteristic / Symptomatic
Peripheral Neuropathy
(Complete cases)
N=841a / All sites
Symptomatic
Peripheral Neuropathy
(with Imputations)
N=1275 / Bilateral symptoms plus either reduced vibration sense or absent ankle reflex (with imputations)
N=1256 / Signs of Peripheral Neuropathy
(with Imputations)
N=1256 b / Symptoms of Peripheral Neuropathy (with imputations)
N=1256c
Odds ratio (95% CI) / P value / Odds ratio (95% CI) / P value / Odds ratio (95% CI) / P value / Odds ratio (95% CI) / P value / Odds ratio (95% CI) / P value
Sex- female / 1.78 (1.12, 2.82) / 0.02 / 1.63 (1.12, 2.37) / 0.01 / 1.25 (0.82, 0.98) / 0.04 / 0.82 (0.60, 1.14) / 0.24 / 1.60 (1.18, 2.16) / 0.002
Age -years / 1.04 (1.02, 1.07) / <0.0001 / 1.04 (1.02, 1.06) / <0.0001 / 1.04 (1.02, 1.06) / <0.0001 / 1.03 (1.01, 1.05) / <0.0001 / 1.03 (1.01, 1.04) / <0.0001
CD4 (per doubling) / 0.83 (0.74, 0.93) / 0.002 / 0.85 (0.77, 0.94) / 0.001 / 0.87 (0.78, 0.97) / 0.01 / 0.94 (0.86, 1.02) / 0.14 / 0.83 (0.77, 0.91) / <0.0001
TB / 1.86 (1.25, 2.77) / 0.002 / 1.89 (1.35, 2.64) / <0.0001 / 1.97 (1.38, 2.83) / <0.0001 / 1.43 (1.04, 1.95) / 0.03 / 1.42 (1.07, 1.89) / 0.02
Ever smoked / 1.83 (1.06, 3.18) / 0.03 / 1.65 (1.05, 2.57) / 0.03 / 1.47 (0.90, 2.38) / 0.12 / 1.27 (0.83, 1.94) / 0.27 / 1.34 (0.91, 1.97) / 0.14
Alcohol use / 0.57 (0.30, 1.10) / 0.09 / 0.54 (0.30, 0.98) / 0.04 / 0.44 (0.22, 0.87) / 0.02 / 1.16 (0.73, 1.84) / 0.54 / 0.75 (0.47, 1.21) / 0.24
Creatinine (per 0.1mg/dl) / 1.09 (1.01, 1.18) / 0.03 / 1.09 (1.03, 1.16) / 0.007 / 1.03 (0.96, 1.11) / 0.37 / 1.06 (1.00, 1.12) / 0.04 / 1.03 (0.98, 1.09) / 0.21
Centre (vs Kampala JCRC)
Kampala (IDI) / 0.72 (0.40, 1.28) / <0.0001 / 0.83 (0.51, 1.34) / <0.0001 / 0.30 (0.17, 0.53) / <0.0001 / 0.62 (0.40, 0.96) / <0.0001 / 1.05 (0.68, 1.61) / 0.005
Kampala (Nsambya) / 1.08 (0.44, 2.65) / 1.05 (0.47, 2.33) / 0.36 (0.13, 0.97) / 0.24 (0.12, 0.49) / 1.48 (0.74, 2.97)
Zimbabwe / 0.93 (0.55, 1.55) / 1.08 (0.68, 1.72) / 0.60 (0.37, 0.98) / 0.33 (0.21, 0.51) / 1.79 (1.16, 2.74)
Others † / 0.19 (0.10, 0.34) / 0.20 (0.12, 0.33) / 0.16 (0.10, 0.27) / 0.05 (0.04, 0.08) / 0.93 (0.64, 1.34)
Mzuzu / (excluded) / 3.98 (1.36, 11.63) / (excluded) / (excluded) / (excluded)
Viral Load (per doubling) / 1.08 (0.99, 1.18) / 0.07 / 1.08 (1.00, 1.16) / 0.04 / 1.06 (0.98, 1.15) / 0.15 / 1.05 (0.98, 1.12) / 0.15 / 1.08 (1.01, 1.14) / 0.02
Glucose (per doubling) / 1.85 (0.89, 3.85) / 0.10 / 1.56 (0.88, 2.75) / 0.13 / 1.38 (0.74, 2.57) / 0.31 / 1.06 (0.62, 1.81) / 0.83 / 1.71 (1.03, 2.84) / 0.04
Family history of CVD / 1.54 (1.00, 2.37) / 0.05 / 1.50 (0.97, 2.31) / 0.07 / 1.63 (1.04, 2.54) / 0.03 / 1.20 (0.82, 1.78) / 0.35 / 1.87 (1.30, 2.70) / 0.001
Tenofovir / 0.62 (0.34, 1.13) / 0.12 / 0.66 (0.41, 1.07) / 0.10 / 0.78 (0.46, 1.06) / 0.35 / 1.00 (0.66, 1.51) / 1.00 / 0.70 (0.48, 1.03) / 0.07
Nevirapine / 1.62 (0.90, 2.92) / 0.11 / 1.51 (0.92, 2.48) / 0.10 / 1.52 (0.88, 2.63) / 0.14 / 1.35 (0.89, 2.04) / 0.16 / 1.54 (1.04, 2.27) / 0.03
Student / 0.23 (0.03, 1.80) / 0.19 / 0.31 (0.07, 1.39) / 0.04 / 0.25 (0.03, 1.88) / 0.11 / 0.84 (0.41, 1.70) / 0.06 / 1.05 (0.56, 1.97) / 0.07
Unemployed- too ill / 1.47 (0.90, 2.39) / 1.54 (1.02, 2.31) / 1.53 (0.99, 2.38) / 1.19 (0.79, 1.78) / 1.61 (1.11, 2.34)
Unemployed- no jobs / 1.17 (0.71, 1.94) / 1.36 (0.90, 2.06) / 0.96 (0.59, 1.56) / 1.65 (1.12, 2.43) / 0.95 (0.67, 1.36)
D4T / 1.78 (1.08, 2.96) / 0.03 / 1.45 (1.02, 2.06) / 0.04
Height / 1.03 (1.01, 1.05) / 0.001
Ethambutol / 1.95 (1.12, 3.40)c / 0.02

a Model selection performed on complete cases selects D4T instead of TDF and NVP. When included instead of TDF and NVP D4T OR=1.96 (1.22, 3.16) p=0.005. When including everyone, centre and age explains d4t effect, when restricting the sample to complete cases it does not, data not MCAR.

b CD4 effect when viral load excluded OR=0.92 (95% CI 0.85, 1.01) p=0.07 Viral load effect when CD4 excluded: OR=1.06 (95% CI 1.00, 1.13) p=0.07

c Similar effects were seen with pyrazinamide and rifampicin (p<0.02). TB p>0.2 when these are included

Supplementary Table 6: Symptomatic neuropathy arm comparison week 48 to 96

Change from baseline to week 96: p=0.0002

Change from week 48 to week 96: p<0.0001

Difference between the arms (week 48 to 96) p=0.55

Supplementary table 7: Asymptomatic Peripheral Neuropathy arm comparison
Total / PI/ NRTI / PI/ RAL / PI mono / Global p value / PI/RAL vs PI/NRTI / PI mono vs PI/NRTI
n/total n (%) / n/total n (%) / n/total n (%) / n/total n (%) / Risk difference / p value / Risk difference / p value
(95% CI) / (95% CI)
Week 0 / 266/1246 (21%) / 88/415 (21%) / 85/422 (20%) / 93/409 (23%)
Week 48 / 284/1172 (24%) / 90/391 (23%) / 93/393 (24%) / 101/388 (26%) / 0.59 / +0.6% (-5.3%, +6.6%) / 0.83 / +3.0% (-3.0%, +9.1%) / 0.33
Week 96 / 235/1133(29%) / 117/377 (31%) / 103/380 (27%) / 105/376 (28%) / 0.45 / -3.9% (-10.4%, +2.5%) / 0.23 / -3.1% (-9.6%, +3.4%) / 0.35
Supplementary Table 8: Bilateral Signs arm comparison
Total / PI/ NRTI / PI/ RAL / PI mono / Global p value / PI/RAL vs PI/NRTI / PI mono vs PI/NRTI
n/total n (%) / n/total n (%) / n/total n (%) / n/total n (%) / Risk difference / p value / Risk difference / p value
(95% CI) / (95% CI)
Week 0 / 546/1244 (44%) / 184/415 (44%) / 180/420 (43%) / 182/409 (45%)
Week 48 / 419/1172 (36%) / 128/391 (33%) / 145/398 (37%) / 146/388 (38%) / 0.30 / +4.2% (-2.5%, +10.8%) / 0.22 / +4.9% (-1.8%, +11.6%) / 0.15
Week 96 / 520/1132 (46%) / 169/376 (45%) / 173/380 (46%) / 178/3756(47%) / 0.79 / +0.6% (-6.5%, +7.7%) / 0.87 / +2.4% (-4.7%, +9.5%) / 0.51
Supplementary Table 9: Bilateral Symptoms arm comparison
Total / PI/ NRTI / PI/ RAL / PI mono / Global p value / PI/RAL vs PI/NRTI / PI mono vs PI/NRTI
n/total n (%) / n/total n (%) / n/total n (%) / n/total n (%) / Risk difference / p value / Risk difference / p value
(95% CI) / (95% CI)
Week 0 / 484/1251 (39%) / 154/420 (37%) / 175/422 (41%) / 155/409 (38%)
Week 48 / 221/1176 (19%) / 77/392 (20%) / 73/395 (18%) / 71/389 (18%) / 0.87 / -1.2% (-6.6%, +4.3%) / 0.68 / -1.4% (-6.9%, +4.1%) / 0.62
Week 96 / 278/1148 (24%) / 82/379 (22%) / 96/389 (25%) / 100/380 (26%) / 0.31 / +3.0% (-2.9%, +9.0%) / 0.32 / +4.7% (-1.4%, +10.7%) / 0.13

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Supplementary Table 10:

Factors affect PN status at week 48 and week 96

Characteristic / Symptomatic
Peripheral Neuropathy
(complete cases N=775)
Adjusted Odds ratio (95% CI) / P value
Time
Week 96 / 2.04 (1.42, 2.95) / 0.0001
Age -years / 1.05 (1.03, 1.07) / <0.0001
TB / 2.04(1.43, 2.91) / <0.0001
Centre
Kampala (JCRC) / 1 / 0.0001
Kampala (IDI) / 1.44 (0.79, 2.64)
Kampala (Nsambya) / 0.19 (0.04, 0.84)
Zimbabwe / 2.01 (1.12, 3.59)
Others † / 0.35 (0.19, 0.67)
Employment status (vs employed)
Student / 0.54 (0.12, 2.37) / 0.01
Unemployed- too ill / 2.88 (1.47, 5.64)
Unemployed- no jobs / 1.02 (0.65, 1.60)
CD4 (per doubling)
Baseline CD4 / 0.91 (0.81, 1.01) / 0.08
Current CD4 / 1.24 (0.96, 1.59) / 0.10
Viral load (per doubling)
Baseline Viral load / 1.01 (0.94, 1.09) / 0.79
Current Viral load / 1.00 (0.94, 1.06) / 0.97
Sex- female / 1.26 (0.85, 1.88) / 0.25
Ever smoked / 0.82 (0.22, 3.08) / 0.76
Alcohol use / 1.31 (0.66, 2.60) / 0.44
Family history of CVD / 1.32 (0.91, 1.91) / 0.14
Current Creatinine (per 0.1mg/dl) / 0.96 (0.90, 1.03) / 0.29
Glucose at 2nd line switch (per doubling) / 1.38 (0.70, 2.70) / 0.35
TDF exposure / 0.78 (0.54, 1.13) / 0.22
NVP in first line / 1.25 (0.70, 2.24) / 0.46

Supplementary Figure 1: Patient flow

Supplementary Figure 3a: Viral Load over time (Viral load<1,000)

Supplementary Figure 3b: Viral Load over time (Viral load<50)

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