Another late breaker oral presentation provided results from the FEM-PrEP study in which daily TDF/FTC (Truvada) used as PrEP was not effective. The FEM-PrEP study, which had enrolled just over 2000 of the planned 3900 participants was closed in April 2011 due to lack of efficacy between daily TDF/FTC compared to placebo in over 2000 African heterosexual women.
The DSMB recommended stopping the study when the study was only half way through enrollment when 28 infections had been seen in each arm. More pregnancies occurred and side effects were also higher in the active arm.
The final results from the study were presented at CROI by Lut Van Damme and colleagues. 
Baseline characteristics included approximately 60% younger than 25 years, 50% condom use, 13% had transactional sex with other than primary partners. However, 70% of participants thought they were at low risk for HIV, but 15% had Chlamydia and 6% had gonorrhoea at screening. Women had sex on average four times a week (mean 3.7, range 0-28).
Of 68 infections occurring during the main study, 33 infections occurred in the active arm (incidence rate, 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), with an estimated hazard ratio (HR) for infection of 0.94 (95%CI 0.59 to 1.52, p = 0.81). Although seven infections were discounted due to lack of product at the study clinic, a sensitivity analysis censuring women at last date of product use did not change the main results (HR 0.82; 95%CI 0.49-1.36, p=0.44).
Tolerability generally good with no grade 3 events but included more nausea in the active group.
There were five cases of FTC-associated resistance (one in the placebo arm) but no cases of resistance to TDF.
As with other PrEP studies, adherence rates were very high by self-report (>95%) and pill count (~90%) but a pharmacokinetic analysis in a case-control sub study indicated that this was at best likely to be 20-30% in either arm, with detection lower in cases vs controls. Adherence levels below 50% in each arm also removed the power of this study to be able to detect a real impact of the active arm.
Of interest, an opinion piece by Anneke Grobler and colleagues in the 13 March edition of AIDS on the design challenges for future prevention studies includes a table that calculates projected effectiveness found with different levels of true efficacy of the comparator and new intervention in combination with different adherence levels. 
Although the lack of protection in this study was assigned to low adherence, this may be more complex as adherence was also low in iPrEX. This may also involve the baseline risk of participants and perception of risk, perhaps explaining the differences seen in other heterosexual studies such as TDF-2.
There may also be implications by gender related to pharmacokinetic and intermittent adherence highlighted in macaque studies, including the poster reported below.
Jessica Radzio and colleagues from the CDA in Atlanta presented results from a pharmacokinetic study in macaques. 
This study was important for studying both tenofovir and FTC in tissue site and intracellular levels. Both drugs peaked -- at two hours in plasma and five hours in vaginal secretions -- and then declined to low levels at 24 hours. In rectal secretions, levels increased more slowly and steadily, only peaking at 24 hours but then remaining high for at least 24 hours.
This aspect of the PK profile in macaques is comparable to that seen in women. The group then looked at active intracellular levels of the active metabolites of each drug, FTC-TP and TFV-DP.
FTC drug levels were very similar in vaginal, cervical, rectal and lymphoid tissue compared to cell biopsies with vaginal:rectal ratio of 1.04 in cells and 2.10 in tissue at 24 hours. This was similar for cervical:rectal ratios. However levels of tenofovir in vaginal, cervical and lyphoid tissue, both in tissue and cells was dramatically lower, while remaining high in rectal tissue and cells, with vaginal:rectal tissue concentrations ratios dropping to 0.04 for intracellular levels and 0.02 in tissue, with similar results for cervical:rectal ratios (0.04 and 0.03 respectively).
The group then looked at whether these levels would be sufficient for vaginal exposure in six macaques following oral dosing and repeat low dose exposure weekly for up to 18 weeks (through four menstrual cycles) to SIV to approximate to human sexual exposure, with six macaque controls. TDF/FTC or placebo was given 24 hours before or two hours after exposure. All control animals became infected quickly, mainly in the first menstrual cycle but none of the active macaques receiving intermittent TDF/FTC became infected over 18 weeks suggesting that the lower PK may be protective even with intermittent PrEP to prevent vaginal transmission.
This study reported a pattern of ratio (rather than absolute concentrations) suggesting this validates the macaque model for future studies. Although this study only looked at -24 plus +2 hour dosing for vaginal exposure, the rectal macaque studies emphasised the +2 hour dose to be essential and the protection from the pre-exposure dose extended from 1 to seven days. However dosing only 2 hours before exposure correlated with significantly reduced protection, though this was still higher than if no pre-exposure dose was given.
The potential for close to 100% protection against HIV infections with alternate or daily dosing should prompt pilot programmes that include access to this option in individuals who are at the highest risk for HIV.
For many people, higher risk behaviour and vulnerability to infection may be associated with a relatively short period of someone's life. Whether this is a period of weeks, months or several years, the option to use an oral prophylaxis when other prevention methods are unlikely to be used, can prevent the complications of life-long infection and treatment.
TDF/FTC (Truvada) has already been submitted to the FDA for an indication for use as PrEP with a decision expected later this year.
Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 58 March 2012, Seattle.
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