Factors affecting virological failure in patients receiving antiretroviral therapy: a prospective HIV Clinical cohort in rural Uganda. Patrick Kazooba1, Billy Mayanja1, Jonathan Levin1, Ben Masiira1, Nassim Kyakuwa1, Heiner Grosskurth1, 2, Dermot Maher1, Pontiano Kaleebu1, 2 1. MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda 2. London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E, 7HT 3. International Rescue Committee, Tanzania Office, P.O. Box 106048, Dar es Salaam, Tanzania

Background 1 Virological failure is the incomplete viral suppression, or viral rebound after complete suppression while on antiretroviral therapy (ART) for 6 months or more Patients with virological failure require a switch of their ART regimen to a more effective second line ART regimen In resource limited settings, second line ART has cost implications that a pragmatic approach to virological failure is essential before switching to second line ART

Background 2 - several factors are associated with virological failure Justification - several factors are associated with virological failure - a pragmatic approach to virological failure helps avoid unnecessary switching of individuals with conventionally defined virological failure to second line regimen Objectives (a) determine factors affecting virological failure (b) compare pragmatically with conventionally defined virological failure (c) justify the need to use pragmatically defined virological failure to switch patients to second line regimen

Methods Prospective open HIV clinical cohort in rural southwest Uganda ART and contrimoxazole prophylaxis introduced in 2004 All HIV infected participants in the cohort receiving ART were included in the study Between 2004 - 2010 participants were seen quarterly and collected data on: - socio-demographic factors, sexual behavior and ART adherence - medical history and clinical examination - CD4 cell counts measured quarterly -viral load measured 6 monthly

Methods: case definitions Conventional virological failure: a patient with a single viral load greater than 1000 copies/ml or two successive viral load measurements greater than 400 copies/ml, at any time after 6 months on ART Pragmatic virological failures: a patient identified with conventional virological failure, and received intensified adherence counselling and continued on first line ART but still had a viral load of greater than 1000 copies/ml after 6 more months

Methods – statistical analysis For both conventional and pragmatic virological failures: -we calculated failure rates and their 95% CI -examined their explanatory factors separately. Cox proportional hazards regression models were fitted to identify independent predictors of two virological failure definitions Proportion of conventional failures which were also pragmatic failures was calculated for each explanatory variables Logistic regression models were fitted to determine factors associated with being a pragmatic failure among the conventional failures

Results: Baseline characteristics 1 Factor Level N (%) Gender Male Female 115 (36.4%) 201 (63.6%) Age (years) Mean (SD) 37.7 (11.3) Age group (years) 14 – 29 30 – 39 40 – 49 50 + 67 (21.2%) 129 (40.8%) 79 (25.0%) 41 (18.0%) Education Level None or incomplete primary Complete primary or some Secondary Complete secondary or Higher 213 (67.4%) 48 (15.2%) 55 (17.4%) Number of steady partners at enrollment None One Two or More 135 (42.7%) 166 (52.5%) 15 (4.8%) Drink alcohol No Yes 223 (70.6%) 93 (29.4%)

Results: Baseline characteristics 2 Factor Level N (%) Occupation Farmer Trader / Seller Semi-skilled / Skilled Other / missing 192 (60.8%) 42 (13.3%) 18 (5.7%) 64 (20.2%) Weight (kg) Mean (SD) 52.6 (9.5) Weight group (kg) <40 40 - 55 55 - 70 70 + 25 (7.9%) 167 (52.8%) 109 (34.5%) 15 (4.8%) BMI kg /m2 20.1 (2.9) CD4 at ART initiation (cells/µl) Median (IQR) 156 ( 73 – 200) CD4 group at ART initiation (cells/µl) <50 50 – 99 100 – 149 150 – 199 200 + 36 (11.4%) 51 (16.1%) 86 (27.2%) 79 (25.0%)

Results: Baseline characteristics 3 Factor Level N (%) Baseline viral load (copies/ml) Median (IQR) 81,758 (26,721 – 193,814) Baseline viral load group (copies/ml) <400 400 – 999 1000 – 9999 10000 – 99999 100000 – 999999 1000000+ 15 (5.5%) 1 (0.4%) 21 (7.8%) 115 (42.3%) 112 (41.2%) 8 (2.9%) Proportion of visits at which adherence achieved 97 (92 – 100) Adherence achieved in at least 95% of visits No Yes 106 (33.8%) 208 (66.2%)

Summary of conventional virological failure rate broken down by explanatory factors The overall conventional failure rate was 8.6 per 100 pyar, and the rate was: -much higher among participants aged below 30 years -higher among participants who were married or had a steady partner -higher among those who drank alcohol -was almost twice as high among those who reported full adherence at fewer than 95% of visits than amongst those who reported full adherence on 95% or more of visits.

Summary of pragmatic failure rate broken down by explanatory factors Overall the pragmatic failure rate was 2.7 per 100 pyar, and the rate was: - higher among participants aged below 30 years. - higher among those who had one steady partner than for those without a steady partner - higher in those who drank alcohol - was 3 times higher among patients who reported full adherence at fewer than 95% of visits than those who reported full adherence on 95% or more of visits.

Adherence: per 10% decrease in proportion of visits Factors associated with virological failure – Results from fitting Cox models Factor Conventional virological failure ( 84 participants) Pragmatic virological failure (28 Participants) Adjusted HR* (95% CI) P-value Adjusted HR* (95% CI) Aged under 30 years No Yes 1 1.47 (0.90 – 2.39) 0.12 2.83 (1.32 – 6.08) 0.008 Adherence: per 10% decrease in proportion of visits 1.37 (1.22 – 1.55) <0.001 1.42 (1.19 – 1.69) Drinks alcohol 1.38 (0.88 – 2.17) 0.16 2.00 (0.93 – 4.31) 0.076

Proportion of conventional failures who failed pragmatically. 1/3 of the conventional failures also failed pragmatically (28/84). Similar proportions for males and females More than half of the conventional failures aged below 30 also failed pragmatically The proportion failing pragmatically was higher among those who did not achieve adherence on at least 95% of visits Those who drank alcohol were also more likely to fail pragmatically than those who did not drink

Factors associated with Pragmatic Failure among individuals with conventional failure –results from logistic regression Cox models Factor Level Adjusted OR* 95% confidence limits P-value Aged under 30 years No Yes 1 4.67 Reference (1.43 – 15.2) 0.011 Proportion of Adherent visits Per 10% decrease in proportion of visits 1.15 (0.87 – 1.51) <0.001 Drinks alcohol 3.15 (1.01 – 9.81) 0.048

Discussion 1 The pragmatic definition reduced the numbers to be switched to second line ART by 67%, from 84 conventional failures to 28 This supports the conservative approach not to immediately switch patients to second line ART on evidence of conventional virological failure alone Intensified adherence counseling of these patients will keep them on first line ART regimen which is cost effective and safe in resource limited settings and preserve second line ART regimen for as long as possible.

Discussion 2 The finding that lower adherence was associated with failure is not surprising, but in a sense validates our self-reported adherence measurements. The fact that younger patients are at greater risk of failure is important, since some of these may be vertically infected, thus warranting special attention and intensive ART adherence counseling.

Discussion 3 Strengths -Prospective cohort enabled long time regular follow up of participants on ART -Routine laboratory virological assessment of participants on ART enabled assessment of virological failure of treatment Weaknesses -Small numbers of patients in the younger age group did not allow us to explore the age effect more closely -We did not consider other factors e.g. viral subtypes to examine the other factors affecting virological failure

Conclusion In resource limited settings, the pragmatic definition should be used to switch second line ART as this preserves second line ART for longer periods and is also cost effective and safe Using the conventional approach, patients may be incorrectly classified as having treatment failure and unnecessarily switched to second-line therapy. Patient tailored adherence counselling approaches especially for the young patients should be applied to keep them on first line ART regimen for as long as possible.

Acknowledgements Study participants Study clinicians, laboratory and statistics staff for their help and input Medical Research Council (UK) for funding