CROI 2017: Treatment-as-Prevention Study Sees Substantial Drug Resistance, but No Impact on HIV Therapy
- Category: HIV Treatment
- Published on Tuesday, 28 February 2017 00:00
- Written by Gus Cairns
A study of the prevalence of transmitted drug resistance among participants in the ANRS 12249 trial of treatment as prevention, has found that a substantial minority of participants had HIV with drug resistance mutations. However, there was no evidence that pre-existing drug resistance had any impact on the success of treatment, according to a report at the Conference on Retroviruses and Opportunistic Infections this month in Seattle.
This is surprising, and contrary to previous findings; trial investigator Anne Derache said that longer follow-up was needed to find out whether people with drug resistance would maintain undetectable viral loads.
Drug resistance testing was done on samples from 1340 people in the study. Of these, 1069 were people in HIV care and attending clinics who tested HIV-positive when they first entered the study, and 77 were people who became infected with HIV during the course of the study.
However, one of the findings of the ANRS 12249 study, which reported its main results at the International AIDS Conference in Durban last year, was that while people willingly came forward for testing, a high proportion of those who tested HIV-positive did not present themselves for HIV medical care during the study. So drug resistance testing was also done on 195 dried blood samples taken from people who tested positive at study entry but did not present for care.
About 9% of people had resistance where more than 20% of the HIV strains in their body had resistance mutations (predominant resistance), and another 9% had resistance in 2% to 20% of viral strains (minority resistance). This applied both to participants who joined the trial already HIV-positive and those who acquired HIV during the trial.
There was very little multi-drug or multi-class resistance: most people with resistance (89%) only had 1 or 2 drug-resistance mutations and 73% of these only had resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs. In 61% of these cases, drug-resistant HIV formed more than 50% of HIV strains in people’s blood. The most common single drug mutation was K103N, which causes high-level resistance to efavirenz (Sustiva or Stocrin).
Only 11% had 3 or more resistance mutations, and Derache speculated that some of these might be people who had previously been exposed to antiretrovirals.
Among the 27% who had resistance to other classes, 13.5% had resistance to the nucleoside reverse transcriptase inhibitor (NRTI) class of drugs and 9% to protease inhibitors. The remaining 4.5% had resistance to more than 1 class of drugs. However, unlike NNRTI resistance, NRTI and protease inhibitor resistance was only seen as minority drug resistance, with less than 20% of viral strains in any individual containing these resistance mutations. This is probably because NRTI and protease inhibitor mutations tend to impair viral replicative capacity, whereas NNRTI resistance tends not to.
In phenotypic tests, about 7% of participants had high-level resistance to efavirenz and nevirapine (Viramune). In contrast, even with resistance mutations, lack of susceptibility to other antiretrovirals was rare. About 1% had reduced susceptibility to the second-generation NNRTIs rilpivirine (Edurant) and etravirine (Intelence), and not all of that was high-level resistance. Only 0.4% had loss of susceptibility to the NRTIs abacavir (Ziagen), emtricitabine (Emtriva) or lamivudine (3TC or Epivir), and almost none to tenofovir (Viread), zidovudine (AZT or Retrovir), or any protease inhibitor.
Of the 1146 people who were in care, nearly three-quarters (838) started antiretroviral therapy (ART). Viral suppression rates were very high, with 97% having a viral load below 400 copies/mL after a year on ART; on average people took 3 months to reach viral suppression.
There was, surprisingly, no association between having drug resistance mutations and virological failure. People with predominant drug resistance were only 4% less likely to achieve viral loads under 400 copies/mL, and those with minority resistance were actually 12% more likely, but these differences were not statistically significant and likely due to chance.
In contrast, people with a high initial viral load of over 100,000 copies/mL were 25% less likely to achieve undetectable viral load, and people with less than 95% adherence were 26.5% less likely to achieve it.
In ANRS 12249 the first-line therapy generally offered was Atripla, the pill that combines efavirenz with tenofovir and emtricitabine. Resistance surveillance was not done as pre-treatment screening, and individuals’ regimens were not modified if they had drug-resistance mutations. This means that the people with resistance to efavirenz were achieving viral suppression with tenofovir and emtricitabine (the drugs in Truvada) alone.
This contradicts the few studies that have previously studied the effects of drug resistance in lower-income settings. Derache quoted a study from Mexico which showed that drug resistance cut the likelihood of viral suppression by 75%. However, it is not inexplicable, given the susceptibility figures reported in this study.
The question is: How long will viral suppression last in people with drug resistance? The average length of follow-up for people taking ART in this study so far is 16 months. Will what is essentially tenofovir/emtricitabine dual therapy in people with resistance start to fail further down the line? Will adherence need to be much better in these people for them to stay suppressed? Or are the ANRS 12249 patients, once virologically suppressed, likely to remain so? Only time will tell.
A Derache, CC Iwuji, S Danaviah, et al. Prevalence and impact of pretreatment drug resistance in the ANRS 12249 TasP trial. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 43.