peripartum hair levels of antiretrovirals predict viral...

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)


EFV Pretreatment HIV RNA 0.38 (0.14-1.05)


LPV Self-reported adherence 3.3 (0.88-12.4)


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]

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