PrEP and kidney function: who really needs screening and can event-based dosing reduce side-effects?

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Two studies confirm kidney side-effects are rare when taking PrEP. One of the studies, led by the World Health Organization (WHO), also indicates that people under the age of 30 taking PrEP may need less frequent kidney screening. A separate group of researchers say that people who experience kidney side-effects might benefit from switching from taking daily pills to event-based dosing instead of stopping the medicine altogether.

Both studies looked specifically at tenofovir disoproxil fumarate (TDF)-based PrEP, which affects kidney function in a small number of people, especially in those above the age of 50 and those with baseline kidney values already below normal. While declines in kidney function are small and reversible after stopping PrEP, concerns over them can be a barrier to taking it. Another barrier is having to make frequent clinic visits to monitor kidney function; currently many guidelines recommend measuring blood creatinine every six months.

Gay and bisexual men can use event-based dosing (also known as on-demand PrEP) instead of a daily pill. Event-based dosing requires planning ahead because it involves taking a double dose (two pills) between 2 and 24 hours before sex, a single dose (one pill) 24 hours later, and another single dose 24 hours after that. Event-based dosing is not recommended for people at risk of acquiring HIV through vaginal sex because there aren’t enough data on how this approach affects levels of drugs in vaginal tissues.



Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

event based

In relation to pre-exposure prophylaxis (PrEP), this dosing schedule involves taking PrEP just before and after having sex. It is an alternative to daily dosing that is only recommended for people having anal sex, not vaginal sex. A double dose of PrEP should be taken 2-24 hours before anticipated sex, and then, if sex happens, additional pills 24 hours and 48 hours after the double dose. In the event of sex on several days in a row, one pill should be taken each day until 48 hours after the last sexual intercourse.


The presence of one or more additional health conditions at the same time as a primary condition (such as HIV).

cisgender (cis)

A person whose gender identity and expression matches the biological sex they were assigned when they were born. A cisgender person is not transgender.


When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

In the study led by WHO, researchers conducted two separate meta-analyses to identify populations of people who might require less frequent monitoring of kidney function. The first meta-analysis used summary data from eleven randomised clinical trials to evaluate the relative risks of people on PrEP experiencing grade 1 and higher adverse kidney events (blood creatinine levels of 1.1 to 1.3 times the typical values) and grade 2 and higher adverse kidney events (blood creatinine levels of 1.3 to 1.8 times the typical values). 

This analysis involved 13,523 study participants across 13 countries with diverse genders and sexual orientations, although the percentages within each group were not reported. The analysis found people taking PrEP had about 1.5 times higher risk of developing grade 1 or higher kidney events (272 out of 6764 people taking PrEP compared to 183 out of 6769 people in the control group). The odds ratio of people on PrEP experiencing grade 2 or higher kidney events was 1.75, but it was not statistically significant (13 out of 6764 people taking PrEP compared to six of 6782 people in the control group).

The second meta-analysis used individual participant data from 19 PrEP programmes and studies (most of which had not previously published their data) that responded to a request for data issued by WHO. The researchers defined clinically significant declines in kidney function associated with PrEP use as estimated creatinine clearance levels that decreased to below 60 mL/min, which is considered abnormal (greater than 90 mL/min is normal, and between 60 and 90 mL/min is moderate kidney function).

This analysis looked at data from 18,676 people from 15 countries, including about 40% from high income countries and about 60% from low- and middle-income countries. The participants were mostly men (76%), but 22% of the participants were cisgender female and 2% were transgender female. About half (48%) were under the age of 30 and most (78%) had normal kidney function —only 0.4% had abnormal estimated creatinine clearance levels during PrEP screening.

PrEP users who had at least one clinical follow-up (14,368) were included in the detailed analysis, and 349 (2.4%) of them experienced clinically significant declines in kidney function. Of 263 people who had follow up measurements, 217 (83%) returned to moderate or normal values without stopping PrEP. People older than 50 years of age had a six-fold increase in risk of experiencing clinically significant declines. People whose kidney functions before starting PrEP were in the moderate range had an eight-fold higher risk of experiencing clinically significant declines compared to those with normal kidney function.

This analysis showed a slightly higher risk of decline in kidney function in cisgender female PrEP users compared to cisgender male, but the result was not statistically significant, perhaps because too few of the projects followed females. Similarly, too few transgender and nonbinary people were included to draw any conclusions about these populations.

The London-based study included 13,980 people who received PrEP from nurses during a two-year period from a single healthcare facility (56 Dean Street). It evaluated 220 people (1.6%) who needed additional consultations with physicians because of medical issues they experienced while taking PrEP. Most of the 220 people were male (98%) and White (75%). The majority of this group (52%) experienced declines in kidney function, measured in one of several ways, including high creatinine levels and abnormal estimated glomerular filtration rates.

"Both studies confirmed previous results that kidney effects were rare, didn’t progress, and resolved after stopping PrEP."

Declines in kidney function prompted more frequent monitoring and, if they persisted, were managed in two ways. About half of the people with moderate declines in kidney function reduced protein intake, including through dietary changes and stopping protein supplements (often used by bodybuilders). Others with more severe declines in kidney function were switched from a daily PrEP dosage to either an event-based dosage or four tablets a week on Tuesday, Thursday, Saturday, Sunday (called 2Ts 2Ss). However, a few had to discontinue taking PrEP after trying these lower-dose approaches.

The WHO researchers recommend reducing the barrier of frequent kidney monitoring for younger people. As a result, WHO updated their guidelines to say that creatinine screening can be optional for people taking PrEP who are less than 30 years old and don’t have other co-morbidities. For those older than 30 years or with co-morbidities, WHO recommends screening once within three months of starting PrEP. Screening every six to twelve months is only recommended for people who have co-morbidities, for those older than 50 years regardless of co-morbidities, and for anyone with a previous creatinine clearance result of less than 90 mL/min.

Both studies confirmed previous results that kidney effects were rare, didn’t progress, and resolved after stopping PrEP. Furthermore, the second analysis showed that the vast majority of people’s kidney function values returned to normal without having to stop PrEP.

Stopping PrEP in the face of ongoing kidney-related side-effects may not be the only option. If available, both tenofovir alafenamide-based PrEP or injectable cabotegravir have fewer kidney-related side-effects. The London researchers say that moving people to an event-based approach may be a valid way to keep people on TDF-based PrEP while minimising adverse kidney effects. Furthermore, they said, this approach can be tried if other types of adverse side-effects are experienced while taking PrEP.


Schaefer R et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. The Lancet HIV, online ahead of print 7 March 2022 (open access).

DOI: 10.1016/S2352-3018(22)00004-2

Tittle V et al. Complex PrEP: the factors requiring consultant-led review of PrEP users. Sexually Transmitted Infections, online ahead of print, 15 February 2022 (open access).

DOI: 10.1136/sextrans-2021-055277