The world needs to prepare for a resurgence of HIV drug resistance if pre-exposure prophylaxis is widely adopted, a veteran HIV researcher warned the Microbicides 2010 Conference last week.
Dr John Mellors of the University of Pittsburgh has studied the dynamics of viral suppression and how drug resistance arises since the beginning of HIV therapy.
He admitted that, so far, “there are highly divergent opinions on whether PrEP will spread resistance." There is only one person in a PrEP trial with documented seroconversion while taking PrEP whose drug resistance was measured and this person turned out to have non-resistant ‘wild type’ virus.
However four PrEP trials are due to produce results by the end of this year – of drug users in Thailand, gay men in the USA, heterosexuals in Botswana and the multi-country iPrEX trial in gay men - and if one produces a significant result there will be pressure to roll out national programmes. Adopting these without careful monitoring could spread resistance to tenofovir and emtricitabine (FTC), currently the only drugs under study as PrEP.
Tenofovir and FTC mutations happen fast if the drugs are given as monotherapy, even the multi-drug K65R mutation, which is slow to happen in failing triple combination therapy.
We have also learned from treatment roll-out to low-income countries that although viral suppression rates are at least as high as they are in high-income countries, 80% of people who are not virally suppressed acquire resistance.
Because of the patterns of drugs used most frequently, (AZT, d4T, 3TC and nevirapine) 75% fail with the M184V mutation, which confers complete resistance to FTC, and 5-10% with K65R; if tenofovir widely replaced AZT/d4T the proportion of K65R in resistant virus would increase. These would be enough to render PrEP ineffective though, because it reaches much higher local concentrations, a tenofovir microbicide might work with HIV with K65R.
Mellors said that individuals put on PrEP who were HIV-positive would probably develop K65R unless PrEP was given as triple-combination therapy which at present was probably impractical due to cost (and untested).
He was also concerned that the seeding of resistance into the viral population might not be detected if resistant virus existed at very low levels, only to reappear if treatment or PrEP regimens put HIV under selective drug pressure.
He instanced the OCTANE trial of triple-combination therapy for the prevention of mother-to-baby transmission of HIV. This used tenofovir/FTC in all participants and then randomised them to receive either lopinavir/ritonavir or nevirapine as their third drug. There were a lot more transmissions in the nevirapine arm, but these did not appear to be related to pre-existing nevirapine resistance in the mother. When mothers were re-tested using a hypersensitive resistance assay, it was found that proportions of nevirapine resistance as low as 0.8% of the viral population led to treatment failure and transmission. Could PrEP seed similarly low levels of, say, M184V into the viral population?
Mellors sketched out a ‘train wreck’ scenario in which PrEP might lead to a rapid rise in the prevalence of transmitted and acquired resistance to tenofovir and FTC, resulting in reduced efficacy of first-line regimens and PrEP containing these drugs, less public health benefit, and fiscal and political fallout.
To compute the possibility of avoiding this scenario, some key questions had to be answered: How transmissible was virus with M184V, K65R, or both? Would high-concentration gels still work against tenofovir-resistant virus? And how soon would resistant viruses decline and to what level?
Mellors finished by saying that in order to minimise resistance:
- pre-exposure prophylaxis should only be prescribed in the context of voluntary counselling and testing, in order to minimise the number of people who unwittingly take PrEP while HIV-positive;
- people taking PrEP should be closely monitored for seroconversion;
- people should be educated to the dangers of sharing their drugs;
- alternatives to tenofovir and FTC badly needed to be developed;
- whether topical microbicides still worked with resistant virus needed to be evaluated (one monkey study had shown that animals with M184V still responded to a tenofovir/FTC microbicide).
The best answer would be to use a combination of drugs that did not share resistance patterns with drugs used for treatment.
Anna Forbes, former director of the Global Campaign for Microbicides, commented that in a situation where antiretrovirals (ARVs) for treatment were not universally available, it was difficult to see how PrEP would not create a black market in ARVs.
Mellors agreed, saying an ideal country scenario would be a simultaneous rollout of the most effective measures. If care was taken, then although there might be a rise in resistance in the initial stages, the eventual development of more sophisticated and powerful prevention regimens would have a chance to overcome resistance in the end. When HAART had first started, huge levels of resistance had been feared, leading to HAART failing within years; the development of better drugs has stopped this happening.
However he said that the danger of resistance was not widely understood by public health policy bodies, even in the USA.
“I’ve explained the importance of resistance at major think-tanks and people just don’t get it,” he said. People did not make the connection between the misuse of drugs as prophylaxis and subsequent drug resistance: “Look at all the cows being bombed with antibiotics and the number of resistant enteropathogens like MRSA developing.”
He agreed with Lori Heise, former director of the Global Campaign for Microbicides, that the treatment benefits of ARVs should not be squandered by hasty or ill-designed PrEP rollout. “We need to protect our investment,” he said.
Not all experts agree that drug resistance is a likely consequence of PrEP. Robert Grant, Principal Investigator of the iPrEX Trials, said at the Adherence Conference in Miami last week that hie did not think PrEP would lead to much resistance - see this report.