Resistance concerns

There are concerns that the use of PrEP may lead to the spread of resistance. The data supporting this comes, at present, from animal studies.

In a study reported at the 13th CROI Conference in 2006, the potential of tenofovir to produce high-level anti-HIV drug resistance in already infected monkeys was measured.1 This found that four out of eleven monkeys dosed with high levels of tenofovir developed the K65R mutation within just one week, and another four within six weeks. At this point, the three non-resistant animals were taken off tenofovir for one week and then had it reinstated, in imitation of a treatment interruption; they too had all developed K65R by the ninth week. The initial proportion of resistant virus was below 10% of the whole viral population in five animals, and would not have been detected by conventional resistance tests, though it had increased to detectable levels within four weeks.

In a previously cited CDC study,7 some monkeys were infected, despite receiving high doses of FTC monotherapy. These animals continued to receive FTC after infection. Two out of six infected monkeys developed the M184V FTC resistance mutation, even though one of them was also taking tenofovir, and did not go on to achieve an undetectable viral load.

Veteran virologist and anti-HIV drug resistance expert John Mellors discussed resistance at the 2010 Microbicides Conference in Pittsburgh.2 He admitted that, so far, “there are highly divergent opinions on whether PrEP will spread resistance,” and added that there was 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, if one of the four PrEP due to produce results by the end of 2010 reports a significant efficacy there would be pressure to roll out national programmes, he said, and adopting programmes without careful monitoring could spread resistance to tenofovir and FTC. In treatment programmes, 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.

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 is 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 gave, as an example, 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.

At first these did not appear to be related to pre-existing nevirapine resistance in the mother, but when mothers were retested 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?

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 said 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 on 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 highly active antiretroviral therapy (or 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.

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 in 2010 that he did not think PrEP would lead to much resistance.3

He acknowledged that if a person started or restarted PrEP in the first weeks of infection, the selection of resistant mutations would be probable. But it was unclear that poor adherence to daily PrEP (or deliberate intermittent dosing) would lead to drug resistance. When treating a person with HIV, the virus population is huge and so there are many opportunities for mutations to generate. “The prevention setting is different: we’re not treating a multi-million population of virus, we’re treating about 15ml of genital secretion,” he said.

References

  1. Johnson J et al. Rapid emergence of drug-resistant SIV in tenofovir-treated macaques: implications for tenofovir chemoprophylaxis against HIV. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 609, 2006
  2. Mellors J Antiretrovirals for treatment and prevention – two trains on a collision course? Microbicides 2010 Conference, Pittsburgh. Symposium presentation 225, 2010
  3. Grant R Antiretroviral regimens as pre-exposure prophylaxis: adherence considerations. Fifth International Conference on HIV Treatment Adherence, Miami, 2010
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