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Peripartum Hair Levels of Antiretrovirals Predict Viral Suppression in
Ugandan Women
Catherine Koss, Peter Bacchetti, Deborah Cohan, Paul Natureeba, Howard Horng, Tamara Clark, Edwin Charlebois,
Moses Kamya, Diane Havlir, Monica Gandhi
Makerere University-University of California, San Francisco Research Collaboration
Disclosures
AbbVie Pharmaceuticals provided lopinavir/ritonavir (Aluvia) but had no other role in study design, data accrual and analysis, or abstract preparation.
Background
• During pregnancy and breastfeeding, barriers to drug adherence and fluctuations in ARV pharmacokinetics may reduce drug exposure – risk for virologic failure in women – risk for HIV acquisition in infants
• Objective, quantifiable measure of ARV adherence and exposure may be useful
Hair Concentrations of ARVs
• Non-invasive, quantitative measure of cumulative ARV exposure that integrate adherence and pharmacokinetics
• Predict viral suppression
• Not yet studied among pregnant and breastfeeding women • Hair concentrations
– Reflect uptake from circulation over weeks to months – Less susceptible to transient improvements in adherence – No specialized training; stored/shipped at room
temperature Gandhi et al. Clin Infect Dis 2011. Van Zyl et al. J Acquir Immune Defic Syndr 2011.
Objective
Evaluate hair concentrations of ARVs among pregnant and breastfeeding women in relation to virologic outcomes
Study Design PROMOTE-Pregnant Women and Infants
• Open-label, randomized trial to test whether lopinavir reduces rates of placental malaria
• Tororo, Uganda
• HIV-infected ART-naïve pregnant women at 12-28 weeks gestation
• Randomized to zidovudine/lamivudine and: – Efavirenz or – Lopinavir/ritonavir
• Dose increased from 400/100 mg BID to 600/150 mg BID from 30 weeks gestation to delivery
• Infants received AZT or NVP prophylaxis during breastfeeding
Natureeba et al. J Infect Dis 2014. Cohan et al. AIDS 2015.
Measurements • HIV-1 RNA
– Screening, delivery, and 24 weeks postpartum – Primary outcome: Viral suppression (HIV-1 RNA ≤400 copies/
ml) at delivery and 24 weeks postpartum
• Adherence – Self-reported recall over the 3 days prior to each study visit
(every 4 weeks)
• Hair samples – 30-34 weeks gestation and 10-25 weeks postpartum among
women on ARVs ≥4 weeks – ARV hair concentrations measured via liquid chromatography/
tandem mass spectrometry using validated assays
Analysis
• Multivariate logistic regression models examined predictors of viral suppression – Delivery (among women on ART ≥6 weeks) – 24 weeks postpartum
Results
593 Screened
389 Randomized
204 Excluded • 79 gestational age <12 or >28 weeks • 57 prior ARVs • 25 did not return for lab results • 43 other
195 Efavirenz
162 Efavirenz
194 Lopinavir
163 Lopinavir
Started on ART
Hair collected
Baseline Characteristics
Efavirenz N = 162
Lopinavir N = 163
Maternal age, years Mean (SD)
30.3 (5.5)
29.3 (5.3)
Gestational age, weeks Median (min-max)
21.8 (13.6-28)
20.7 (13-29.3)
CD4 cell count Median (min-max)
373 (14-1080)
358 (81-1030)
Log10 HIV-1 RNA Median (min-max)
4.3 (2.6-5.9)
4.1 (2.6-5.9)
HIV-1 RNA <100,000 copies/ml n (%)
125 (78.6%)
138 (85.2%)
Results: Delivery
Efavirenz N = 162
Lopinavir N = 163
HIV-1 RNA ≤400 c/ml * 98.0% (149/152)
87.4% (139/159)
Weeks since ART initiation ** Median (min-max)
16.9 (4.6-27.9)
17.7 (3.9-27.1)
Self-reported adherence Median (min-max)
100% (33.3-100)
100% (77.8-100)
* Cohan et al. CROI 2014 & AIDS 2015 ** Women on ART <6 weeks were excluded from models of viral suppression at delivery.
Results: 24 Weeks Postpartum
Efavirenz N = 149
Lopinavir N = 151
HIV-1 RNA ≤400 c/ml 92.5% (124/134)
90.6% (126/139)
Self-reported adherence Median (min-max)
100% (80-100)
100% (80.6-100)
88% of women were breastfeeding at 24 weeks postpartum. One infant (lopinavir arm) acquired HIV.
05
1015
2025
Hair Concentrations of Efavirenz H
air c
once
ntra
tion
(ng/
mg)
Viral Suppression No No Yes Yes
24 Weeks Postpartum Delivery +
05
1015
2025
Hair Concentrations of Lopinavir H
air c
once
ntra
tion
(ng/
mg)
Viral Suppression
No No Yes Yes
24 Weeks Postpartum Delivery +
Predictors of viral suppression at delivery
Efavirenz OR (95% CI)
Lopinavir OR (95% CI)
ARV hair concentration per doubling
1.86 (1.14-3.1) 1.62 (1.19-2.2)
Pretreatment HIV-1 RNA per 10-fold increase
0.54 (0.12-2.3) 0.31 (0.16-0.62)
Self-reported adherence per 10% of prescribed dose
1.17 (0.32-4.3) 3.69 (1.10-12.4)
Maternal age per decade
3.24 (0.34-31) 1.90 (0.75-4.8)
Gestational age at enrollment per week
0.89 (0.65-1.21) 0.94 (0.84-1.05)
ART duration per week
1.17 (0.89-1.53) 1.02 (0.93-1.12)
Predictors of viral suppression at 24 weeks postpartum
Efavirenz OR (95% CI)
Lopinavir OR (95% CI)
ARV hair concentration per doubling
1.58 (1.18-2.1) 1.51 (1.05-2.2)
Pretreatment HIV-1 RNA per 10-fold increase
0.46 (0.20-1.09) 0.70 (0.36-1.35)
Self-reported adherence per 10% of prescribed dose
* 3.1 (0.94-10.0)
Maternal age per decade
1.93 (0.55-6.7) 1.34 (0.49-3.7)
Gestational age at enrollment per week
1.01 (0.87-1.18) 1.04 (0.91-1.17)
ART duration per week
0.97 (0.85-1.11) 0.96 (0.86-1.07)
*Too little variation in self-reported adherence to permit a meaningful estimate.
Multivariate analysis: Predictors of viral suppression
0.1 1.0 10.0 Adjusted Odds Ratio (aOR)
Delivery
24 Weeks Postpartum
ARV Predictor aOR (95% CI)
EFV Self-reported adherence 1.00 (0.29-3.4)
ARV hair concentration 1.86 (1.14-3.1)
LPV Pretreatment HIV RNA 0.25 (0.11-0.54)
Self-reported adherence 2.20 (0.53-8.9)
ARV hair concentration 1.90 (1.33-2.7)
EFV Pretreatment HIV RNA 0.38 (0.14-1.05)
ARV hair concentration 1.81 (1.22-2.7)
LPV Self-reported adherence 3.3 (0.88-12.4)
ARV hair concentration 1.53 (1.05-2.2)
Viral suppression
Multivariate analysis: Predictors of viral suppression
0.1 1.0 10.0 Adjusted Odds Ratio (aOR)
Delivery
24 Weeks Postpartum
ARV Predictor aOR (95% CI)
EFV Self-reported adherence 1.00 (0.29-3.4)
ARV hair concentration 1.86 (1.14-3.1)
LPV Pretreatment HIV RNA 0.25 (0.11-0.54)
Self-reported adherence 2.20 (0.53-8.9)
ARV hair concentration 1.90 (1.33-2.7)
EFV Pretreatment HIV RNA 0.38 (0.14-1.05)
ARV hair concentration 1.81 (1.22-2.7)
LPV Self-reported adherence 3.3 (0.88-12.4)
ARV hair concentration 1.53 (1.05-2.2)
Viral suppression
Summary
• Hair concentrations of efavirenz and lopinavir predicted viral suppression at delivery and 24 weeks postpartum in this cohort of pregnant and breastfeeding women in Uganda
• Hair collection was highly acceptable (84%)
• Higher rate of viral suppression at delivery in the efavirenz arm is consistent with published results from PROMOTE trial
Discussion
• Measuring ARV exposure during pregnancy and breastfeeding, when pharmacokinetic parameters can vary, may be important for predicting and influencing viral suppression
• ARV hair concentrations could serve as an innovative
tool to explain virologic outcomes in research studies
• Widespread applicability, especially in clinical settings, will depend on – defining thresholds for ARV hair concentrations – availability of lower-cost assays, under development
Acknowledgements • PROMOTE study participants and study staff • Practitioners at Tororo District Hospital • The National Institutes Health: NICHD, P01 HD059454;
NIAID R01 AI098472, T32 AI060530. • AbbVie Pharmaceuticals for donation of lopinavir/
ritonavir (Aluvia) • The Makerere University-UCSF Research Collaboration
Questions about Hair Analysis Laboratory at UCSF: [email protected] and [email protected]