Designing second-generation trials

This first generation of trials will hopefully provide enough evidence to decide whether the regulatory approval for drugs like tenofovir and Truvada should be expanded to include use as pre-exposure prophylaxis, and perhaps to persuade public funders to roll out programmes, but may leave a range of questions partially unanswered.

Questions that remain include:

• Is daily dosing necessary or can episodic dosing provide equivalent protection?
• If episodic dosing is protective, are users able to anticipate when they will take a risk?
• Will other drugs with longer half-lives facilitate episodic dosing more effectively?
• How long does PrEP remain effective in a population? Is there a decline in adherence?
• What effect does taking PrEP have in individuals who acquire HIV infection? Do they develop resistance and do they transmit drug-resistant virus?
• What effect does PrEP have on risk taking – both among those who take it and in the wider community?
• Does FTC-containing PrEP protect against acquisition of drug-resistant virus in settings where the M184V mutation related to 3TC or FTC treatment is common and detectable viraemia frequent among sexually active individuals?

A further strategy may be to combine different types of drugs to prevent infection, such as the use of topical microbicides with oral drug treatment to prevent infection. A number of other antiretrovirals are currently in trials as various topical microbicide formulations. These include both licensed anti-HIV drugs such as maraviroc, ones never developed for use as treatments, like dapivirine, and ones with completely novel modes of action. As a result of concerns about systemic toxicity, no large efficacy trials are currently planned of antiretrovirals, other than tenofovir and FTC.

Boosted protease inhibitors have previously been dismissed as possible candidates for PrEP and microbicides because theoretically they do not prevent infection, as they act at a stage in HIV’s life-cycle subsequent to it integrating its genome into the human genome. There is, however, increasing evidence that they may be able to halt further viral replication and prevent infection of everything but the very first generation of mucosal cells. They are already used for PEP; they have a very high barrier to the development of resistance and primary (transmitted) resistance is uncommon; and they have been used successfully as a sole drug in treatment (monotherapy). Researchers are now proposing to study protease inhibitors/non-nucleoside reverse transcriptase inhibitors (PI/NNRTI) combinations as microbicides,¹ and maybe their time has come as candidates for PrEP.