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Open-Label Oral PrEP at 4 Doses a Week: Why Zero Infections Does Not Equal 100% Efficacy

August 1, 2014

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PrEP do you swallow?

One of the most important advances at AIDS 2014 was a late-breaker study on open label use of oral PrEP, presented by Robert Grant from UCSF.1

The results were important for two reasons. Firstly, participants knew they were receiving active treatment. Secondly, they knew that PrEP had not only been proven to be highly effective but that efficacy was also dependent on good adherence. A more detailed review of the large and complex dataset were published in Lancet Infectious Diseases to coincide with the conference.2

The open label study included 72 weeks follow-up and involved monthly clinic visits for the first 3 months and quarterly visits thereafter. Of note, PrEP was not prescribed as continuous treatment: participants were actively encouraged to use PrEP during periods that they thought it was appropriate. This tested a more likely real-world use of PrEP.

The initial iPrEX study was an NIH-funded, international, placebo-controlled randomised trial that enrolled 2470 MSM and 29 transgender women. Intent-to-treat analysis reported a 44% reduction in the primary endpoint of new HIV infections in the active (tenofovir/FTC) arm compared to the placebo group. In a post hoc analysis, the relative risk reduction increased to 73% based on self-reported adherence (defined as taking PrEP 90% doses). The level of efficacy increased to 92% in a sub-study that evaluated adherence based on the presence of active drug levels which nudged up to 95% after adjustment for highest risk behaviour (receptive anal intercourse without a condom [UAI]).3

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Although the iPrEX data contributed to US FDA approval in 2012 of a PrEP indication for daily tenofovir/FTC, uptake was very slow, with use by fewer than 2400 people in the 18 months post-approval (roughly half of whom were women).4

Modelling studies in a later pharmacokinetic analysis that included iPrEX data, suggested that either alternate day or daily adherence would provide levels of protection of 96% and 99%, respectively.5 This assumed previously reaching steady-state drug levels, which are estimated to take one week of daily dosing.6

Uptake and acceptability of PrEP is the first step in the "PrEP cascade". The first important result from iPrEX-OLE was that 62% of eligible people (1678/2680) enrolled in the open-label study. As the study only recruited from June 2011 (rather than being an immediate roll-over from the end of the initial study), a second important result was that 75 of these people were found to already be HIV positive, suggesting a concern for the time to open label access. However, uptake was similar for the iPrEX (65%: 1526/2336) and ATN 082 (68%; 46/68) studies but lower for the US Safety Study (39%; 106/271). The third notable result was that of the 1603 people eligible for open label PrEP, only 72% (n=1128) chose to start at enrolment, 6% (n=97) started at a later date and 23% (n=378) declined PrEP (but were still followed).

Although this second step reduced overall uptake to about 45% of previous study participants, this could be a positive result. Interpreting the PrEP cascade is dependent on whether each step results in an increasingly higher risk group that is using PrEP. Low risk loss is a good thing. This is fundamentally different to the treatment cascade where every loss is clinically important.

It is helpful that there were some statistically significant differences between people choosing or declining PrEP, and that some of these choices were related to higher background risk for HIV. For example, uptake was 81% vs 75% in people with vs without recent receptive anal sex without a condom (p=0.003) and was 77% vs 75% in those who were HSV positive vs HSV negative (p=0.03). However, although statistically significant, these differences are modest. They also didn't showed a consistent relationship to HIV risk as there were no differences by age, education, use of alcohol (high usage) or recreational drugs (cocaine or methamphetamine, both low usage), gender identity, known HIV positive partner, other STI infections (syphilis or gonorrhoea), or previous trial experience (active vs control), all p >0.05, NS.

Reasons given for declining PrEP (obtained from a computer-assisted self assessment) included a concern for side effects (50%), not wanting to take a daily pill (16%), not liking pills (13%) preference for other options (14%) and concern for stigma about either HIV (7%) or assumed sexuality (3%).

Drug levels were measured for all new cases of HIV infection, and in an additional randomly selected control group who remained HIV negative. Measurements were performed with a newly developed dried blood spot assay for tenofovir diphosphate (TDF-DP) that was able to detect a single dose taken in the previous four weeks. This was considerably more sensitive than the previous plasma test. The long intracellular half life of TDF-DP results in relatively wide target levels of detectable drug: with LLOQ-350, 350-699, 700-1249 and >1250 fmol/punch correlating with adherence levels of <2, 2-3, 4-6 and 7 doses/week, respectively. If no drug was detected adherence was assumed to be zero.

Of the 41 cases of new HIV infections during the study, 13 people were not receiving PrEP (IR 2.6 per 100 PY; 95%CI 1.5-4.5) and 28 were in the PrEP group (IR 1.8; 95%CI 1.3-2.6). In people receiving PrEP, incidence was 36% lower (95%CI: -24 to +67%) in unadjusted analysis and 49% lower (95%CI: -1 to +74%) after adjusting for high sexual risk. As both these ranges cross 1.0, it is important to note that neither of these reach statistical significance -- even though this is likely a factor of the limited number of infections and follow-up time.

Most importantly, as with iPrEX, drug level results were highly correlated with incidence of HIV during follow up, with risk reductions (95%CI) of 44% (-31 to 77%), 84% (21 to 99%) and 100% (86-100%) for the <2, 2-3 and >4 doses/week groups.


Table 1: Incident HIV Infections During iPrEX OLE by Dry Blood Spot Drug Exposure
Drug levels (fmol/punch) BLQ LLOQ -350 350-699 700-1249 >1250
Estimated weekly dose none <2 2-3 4-6 7
% of follow-up time 25% 26% 12% 21% 12%
Patient years 384 399 179 316 181
Number of new infections 18 9 1 0 0
HIV incidence (95% CI)

4·70

(2·99-7·76)

2·25

(1·19-4·79)

0·56

(0·00-2·50)

0·00

(0·00-0·61)

0·00

(0·00-1·06)

HR vs previous placebo (95% CI) *

1·55

(0·88-2·56)

0·69

(0·32-1·32)

0·19

(0·01-0·88)

0·00

(0·00-0·25)

0·00

(0·00-0·50)

HR vs concurrent off-PrEP (95% CI)

1·25

(0·60-2·64)

0·56

(0·23-1·31)

0·16

(0·01-0·79)

0·00

(0·00-0·21)

0·00

(0·00-0·43)

Key: BLQ: below limit of quantification; LLOQ: lower limit of quantification; HR: Hazard Ration.
* Adjusted for study site.
† Adjusted for study site, age, number of sexual partners, non-condom receptive anal intercourse, and syphilis. Drug measurements were not available for 5% of visits.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.


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