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  Glasgow HIV
28 - 31 October 2018
Glasgow, UK
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Meta-analysis of the risk of Grade 3/4 or serious
clinical adverse events in 12 randomised trials of PrEP

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TDF/FTC PrEP as Safe as Placebo in Meta-analysis of 13 Trials Across Globe
HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow
Mark Mascolini
Meta-analysis of 13 randomized placebo-controlled trials of preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) determined that TDF/emtricitabine (FTC) or TDF alone is as safe as placebo by several measures, including overall grade 3 or 4 adverse events [1]. The findings raise questions about the value of more expensive PrEP alternatives.
In 2018 more than 300,000 people across the world are taking PrEP to prevent HIV infection. The safety of PrEP with TDF/FTC or TDF alone remains a troubling question because clinical trials and cohort studies in people with HIV link TDF to higher rates of kidney and bone toxicity. Yoking HIV-negative PrEP takers with a similar burden would weigh against taking TDF to avert HIV infection.
To get a broad perspective on toxicity with TDF-based PrEP, researchers at Imperial College London and colleagues at other centers conducted this systematic review and meta-analysis. They searched electronic databases and major HIV meeting abstracts for randomized placebo-controlled trials comparing TDF-based PrEP with placebo. They extracted safety data and used standard meta-analysis methods to pool data. Primary safety endpoints were grade 3 or 4 adverse events, protocol-defined serious adverse events, grade 3 or 4 creatinine elevations, and bone fractures.
The analysis included 13 randomized controlled trials, 7 in men who have sex with men (MSM), 3 in women, 2 in HIV-different couples, and 1 in injection drug users. Trials took place in Africa, Europe, North and South America, and Asia. Three trials tested TDF alone, and 1 asked MSM to take PrEP only before and after sex. All told, the trials had 22,250 person-years of follow-up involving 15,678 participants. Follow-up ranged from 4 months to 4 years.
Percentage of events per trial arm and pooled risk difference (RD) varied hardly at all for any major endpoint:
-- Grade 3/4 adverse events: 17.4% PrEP and 16.8% control; RD 0%, P = 0.53
-- Serious adverse events: 9.4% PrEP and 10.1% control; RD 0%, P = 0.80
-- Bone fractures: 3.7% PrEP and 3.3% control; RD 0%, P = 0.50
-- Grade 3+ creatinine elevations: 0.1% PrEP and 0.1% control; RD 0%, P = 0.68
When the researchers considered grade 1 through 4 creatinine elevations, percentage of events proved higher in PrEP arms and the pooled risk difference was statistically significant:
-- Grade 1-4 creatinine elevations: 4.3% PrEP and 2.3% control; RD 2% (0% to 3%), P = 0.04
Sensitivity analyses considering daily versus intermittent PrEP, number of events versus number of people experiencing events, and studies in males, females, or both had no impact on overall significance of any outcome. Trials with more than 1 year of follow-up had a statistically significant decrease in serious adverse event risk with PrEP than with placebo (RD -0.01, P = 0.02).
The investigators noted their study is limited by low baseline risk of participants and low adherence by some participants. They concluded that their review "found no evidence of any increased risk of severe adverse events on TDF/FTC as PrEP." If TDF-based PrEP is safe, they asked, is spending more money on tenofovir alafenamide (TAF) justified? Generic TDF is now available for many PrEP candidates.
1. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A. Meta-analysis of the risk of Grade 3/4 or serious clinical adverse events in 12 randomised trials of PrEP. HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow. Abstract O143.
Study published, published pdf attached which says this in Strengths & Limitations section: Trials have inherent limitations in that participants may have been excluded if they showed a higher baseline risk of renal or bone disease, biasing potential findings. An important limitation may be low adherence in several of the trials, which could dilute the rate of drug-related adverse events. Jules
Full article:
from Jules: a few points: some recent studies over past few years have reported in abstracts at conferences increased kidney marker dysfunction for some on PrEP and risk factors include older age - those with older age may be more likely to have kidney dysfunction markers on PrEP; those with a baseline predisposition for kidney dysfunction, markers; those with high adherence may be more at risk to have adverse kidney affects, and increased condomless sex may be resulting in increased STIs, perhaps longer duration of time on PrEP may be a factor. Perhaps non-daily use but use for selected brief times just for events like before sex or over a weekend may be safer but this needs a better look. This meta analysis does not look at these factors.
Changes in Kidney Function Associated With Daily Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Preexposure Prophylaxis Use in the United States Demonstration Project
Higher cumulative TFV/FTC levels in PrEP associated with decline in renal function - (02/26/16)
talk pdf attached