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GLASGOW, Scotland -- There was no significant difference in grade 3/4 adverse events among people at high risk of HIV infection who took pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) compared with controls, a researcher said here.

In a meta-analysis of almost 16,000 participants, there were also no significant differences in the rates of serious adverse events, bone fractures, and severe renal outcomes among those taking PrEP, reported Victoria Pilkington, MD, of Imperial College London in England.

The results were presented at the International Conference on Drug Therapy in HIV Infection (HIV Glasgow), but the International AIDS Society also released a separate statement.

"The World Health Organization updated its official guidelines in 2015 to include the use of PrEP as a prevention method. The data is clear and it's time to globally implement this recommendation," International AIDS Society President Anton Pozniak, MD, said. "Clearly, to have a significant effect on the HIV epidemic, we need to scale up PrEP to reach tens of millions of people worldwide."

At the presentation, Pilkington reviewed the facts -- about 300,000 people are taking PrEP globally, most of them in the U.S. But with 1.8 million new HIV infections a year worldwide, a number she said has been "stagnant" over the years, "prevention is vital to sustainably addressing the challenge of HIV," she said.

However, barriers to adoption have been significant. Cost is one issue, Pilkington added, saying that cost is "hugely variable, depending on the availability of low-cost generics." Uptake and adherence have also been issues, but there have also been concerns around the safety of the drug itself.

"Safety concerns are something it's vital to address in order to advocate giving such a huge number of people PrEP," she said.

For the study, the researchers performed a meta-analysis of 13 randomized trials in a variety of populations that compared treatment with TDF or TDF/FTC (tenofovir disoproxil fumarate) with placebo or no treatment. These included some of the more well-known PrEP trials, such as IPERGAY, PARTNERS, and iPREX -- as well as those focusing on women, such as FEM-PrEP. Pilkington said the trials spanned from 4 months to 4 years, across various countries, including those in Africa, the U.S., the U.K., and Thailand.

The team found that overall, there were no significant differences in any of the following:

• Grade 3/4 adverse events (16.8% controls versus 17.4% PrEP, P=0.53)
• Serious adverse events (10.1% versus 9.4%, respectively, P=0.80)
• Bone fractures (3.3% versus 3.7%, P=0.50)
• Creatinine elevations ≥grade 3 (0.1% versus 0.1%, P=0.68)

Pilkington said that because there were only 12 grade 3 of higher creatinine elevations, the researchers widened their analysis to examine creatinine elevations of all grades. In this analysis, the group did find a statistically significant difference (2.3% controls versus 4.3% PrEP, P=0.04). However, she contextualized these findings, saying that of these elevations, 97% were grades 1 and 2, and 94% were grade 1 -- which was defined as "long-term, non-progressive" and "totally reversible."

Pilkington said that when examining studies with long-term follow-up (i.e., >1 year) versus short-term follow-up (<1 year), there was a statistically significant decrease in serious adverse events for people on PrEP compared with those on placebo.

"This is hugely unexpected, highly counterintuitive, and highlights that perceived risk of adverse events occurring on PrEP is nothing more than baseline risk," she said, adding that the results were "applicable not only to doctors and patients, but also to policy-makers in informing the widespread roll-out of PrEP."

She also suggested that the results could have implications about use of tenofovir alafenamide (TAF), a newer drug, "which is sold as having a better safety profile," she said.

"Our results say that TDF is already safe, and that calls into question whether TAF is justified," Pilkington added.

But one audience member, who was a member of , suggested that it is not the serious adverse events that may deter PrEP use.

"Going through social media sites, the biggest concern are the acute [adverse events, such as nausea], which are not so serious in terms of health, but may be a considerable disincentive to adherence," he said.

Pilkington said that the analysis was limited to severe adverse events, and not lower-level adverse events "that affect people's lives every day."

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