The TDF2 trial

The TDF2 or CDC 4940 trial was run by the US Centers for Disease Control in partnership with the Botswana Ministry of Health.¹ This study compared tenofovir/FTC (Truvada) against placebo in 1200 heterosexual men and women (600 per arm) in Francistown, Botswana, one of the world’s highest-prevalence locations. Originally designed as a phase III efficacy trial, incidence in the trial population turned out to be too low to demonstrate efficacy according to the trial’s preset protocol. It is important to note that this means that the study was not ‘powered’ to demonstrate efficacy.

This means that – due to there being fewer infections than expected – even a statistically significant positive result is based on too few cases for it to be regarded as a truly convincing efficacy result. Nonetheless, the headline finding of 63% efficacy against placebo was statistically significant.

In the primary analysis there were nine HIV infections amongst the 601 participants who received Truvada and 24 among the 599 who received placebo. This translates into a statistically significant 62.6% reduction in infections.

A secondary analysis, however, excluded infections that occurred amongst people who had run out of their pills and who had not taken one for at least 30 days. This found 77.9% fewer infections in people taking Truvada.

Unadjusted figures at first suggested that there might be some difference in efficacy between men and women.

The efficacy of Truvada in men was 80%, with two HIV infections in men on Truvada versus ten on placebo, and this was statistically significant. The efficacy in women was 49%, with seven infections on Truvada versus 14 on placebo, and was not statistically significant (in other words the reduction in infections seen might have been due to chance).

However when only participants who had refilled their pills at the clinic in the last 30 days were counted, there were three infections in women on Truvada versus 13 on placebo. This was an efficacy of 75.5%, which was statistically significant (p = 0.021). In men in this group there was one infection on Truvada versus six on placebo (82% efficacy), which was actually not statistically significant, due to the small numbers.

Adherence in the TDF2 study was somewhat lower than in the Partners PrEP trial. By pill count it was about 84%, which makes the efficacy reported more impressive.

It has been hypothesised that the lack of efficacy seen in the FemPrEP trial and the oral-tenofovir arm of VOICE might be caused by biological differences between men and women, such as lower drug concentrations in the vagina than in the rectum or urethra.² However the gender differences in adherence and efficacy in TDF2 suggest that differences in outcome might be due to structural and behavioural factors that affect women (such as difficulty in getting to clinics, or prioritising childcare over health), rather than biological difference in efficacy.   

There was no difference in reported adherence between seroconverters and others in the Truvada group, though it was slightly higher (93%) in the placebo group.

There were no differences observed in sexual behaviour: 14% in all arms reported having had more than one sexual partner in the previous month and 81% reported consistent condom use.

Truvada recipients were more likely to report nausea (19% compared to 7% on placebo), vomiting (11.5% compared to 7%) and dizziness (15% compared to 10.5%). However it was not specified at the presentation of the study results in Rome whether these were concentrated into the first month of dosing, as was found in iPrEx.

There was one case of a participant who started taking Truvada while having acute HIV infection, and developed multidrug-resistant HIV. This person tested positive for the K65R tenofovir resistance mutation and the M184V FTC (emtricitabine) mutation; and also had a broad-spectrum NNRTI mutation A62V, which suggests that the virus contracted was not wild-type. This individual currently has an undetectable viral load, taking AZT, 3TC and boosted lopinavir. One seroconverter in the placebo arm was also found to have HIV with low levels of the K65R mutation.

This is a reminder that PrEP does not protect against drug-resistant virus.