Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension

Abstract

Background: Blinded clinical trials have reported a modest and transient "start-up syndrome" with initiation of tenofovir-based pre-exposure prophylaxis (PrEP). We evaluate this phenomenon and its effect on adherence in an open-label PrEP study.

Methods: In the iPrEx open-label extension (OLE) study, an 18-month open-label, multi-site PrEP cohort taking daily oral co-formulated tenofovir/emtricitabine, we examined the prevalence and duration of PrEP-associated symptoms and their effect on adherence, assessed by drug levels in dried blood spots tested monthly for the first 3 months.

Results: Symptom reports peaked within the first month, with 39% reporting potentially PrEP-related symptoms compared to 22% at baseline. Symptoms largely resolved to pre-PrEP levels by 3 months.Symptoms varied substantially in frequency by study site (range in 1-month symptoms: 11% to 70%). Nongastrointestinal (GI) symptoms were not associated with adherence (odds ratio [OR] = 1.2, 95% confidence interval [CI], .4-3.7); however, GI-associated symptoms in the first 4 weeks were inversely associated with adherence at 4 weeks (OR = 0.47, 95% CI, .23-.96). Reports of GI symptoms were associated with 7% (95% CI, 4%-11%) of suboptimal adherence in this cohort.

Conclusions: PrEP-associated symptoms in the open-label setting occur in a minority of users and largely resolve within 3 months. GI symptoms are associated with a modest reduction in PrEP adherence, but good adherence is possible even in the presence of frequent symptom reports.

Clinical trials registration: Clinicaltrials.govNCT00458393.

Keywords: HIV prevention; PrEP; pre-exposure prophylaxis; tenofovir/emtricitabine.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Percentage of participants reporting any of the targeted symptoms prior and in the 6 months following initiation of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis (PrEP). Data below the axis gives the number of participants with available symptom interviews at each visit. Abbreviation: GI, gastrointestinal.

Figure 2.

Percentage of participants reporting symptoms at 1 and 3 months following initiation of pre-exposure prophylaxis (PrEP) by specific symptom and all gastrointestinal (GI) symptoms (any report of abdominal pain, diarrhea, flatulence, nausea, or vomiting) and non-GI symptoms (any report of arthralgia, fatigue, headache). Calculated among 1092 participants with symptom data at both visits. The solid line represents equal reports at month 1 and month 3. Values below the line are less frequent at month 3 compared to month 1. Symbol legend: x: P < .0001, +: P < .01, triangle P < .05, diamond: P > .05.

Figure 3.

Proportion of participants reporting any symptom prior to pre-exposure prophylaxis (PrEP) initiation and 1 month following PrEP initiation by enrolling site. There are 11 sites in 6 countries (Peru: 2 sites, Brazil: 3 sites, United States of America: 3 sites; Ecuador, Thailand, and South Africa: 1 site each). Reference lines of equal reports and an absolute increase of 15% from pre-PrEP to 1 month after are plotted.

Figure 4.

Relative odds (and 95% confidence intervals) of higher tenofovir diphosphate levels (