Treatment-as-prevention sees substantial transmitted drug resistance but no impact on Tx

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A study of the prevalence of transmitted drug resistance in participants in the ANRS 12249 trial of treatment as prevention, which reported its main results at the International AIDS Conference in Durban last year, has found that a substantial minority of participants in the trial had HIV with resistance mutations against the virus.

However there was no evidence that pre-existing drug resistance had any impact on the success of treatment. This is surprising, and contrary to previous findings; trial investigator Anne Derache, at the Africa Health Research Institute, Mtubatuba, South Africa, told the Conference on Retroviruses and Opportunistic Infections (CROI 2017) that longer follow-up was needed to find whether people with drug resistance would maintain undetectable viral loads.

Drug resistance testing was done on samples from 1,340 people in the study. Of these, 1,069 were people who were in HIV care and attending clinics who tested HIV-positive when they first entered the study, and 77 were in people who became infected with HIV during the course of the study.

However, one of the findings of the ANRS 12249 study 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 2-20% of viral strains (minority resistance). This applied both to participants who joined the trial already HIV-positive and to ones who acquired HIV during the trial.
There was very little multi-drug or multi-class resistance: most people with resistance (89%) only had one or two 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.

Only 11% had three or more resistance mutations, and Derache speculated that some of these might be people who had previously been exposed to antiretrovirals (ARVs). In 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 (PIs).

The remaining 4.5% had resistance to more than one class of drugs. However, unlike NNRTI resistance, NRTI and PI resistance was only seen as minority drug resistance, with less than 20% of viral strains in any patient containing resistance mutations. This is probably because NRTI and PI 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. In contrast, even with resistance mutations, lack of susceptibility to other ARVs was rare. About 1% had reduced susceptibility to the second-generation NNRTIs rilpivirine and etravirine, and not all of that was high-level resistance. Only 0.4% had loss of susceptibility to the NRTIs abacavir, emtricitabine or lamivudine, and almost none to tenofovir, zidovudine or any protease inhibitor.

Of the 1,146 people who were in care, nearly three-quarters (838) started antiretroviral therapy. Viral suppression rates were very high, with 97% of people having a viral load below 400 copies/ml after a year on ART: on average people took three months to reach viral suppression.

There was, surprisingly, no association between having drug resistance mutations and virologic failure. People with predominant drug resistance were only 4% less likely to achieve viral loads under 400 copies/ml, and ones with minority resistance actually 12% more likely, but these differences are statistically insignificant 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 viral undetectability, and people with less that 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. The resistance surveillance was not done as pre-treatment screening, and patients’ 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 (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 the study so far is 16 months. Will what is essentially tenofovir/emtricitabine dual therapy in the people with resistance start to fail further down the line? Will adherence need to be much better in these patients for them to stay suppressed? Or are the ANRS 12249 patients, once virologically suppressed, likely to remain so? Only time will tell.

Abstract
Increasing use of antiretroviral therapy (ART) in Test and Treat strategies may lead to higher levels of acquired and transmitted drug resistance (DR) and compromise ART efficacy for individual or population benefits. We assessed prevalence of pre-treatment DR (PDR) and impact on viral suppression (VS) [viral load (VL)
DR testing was done on samples from 1340 participants who were recently infected (RIn) during the trial or chronically infected (CIn) at entry (March 2012–June 2016). Pol gene Sanger sequencing was done on dried blood spots from 195 RIn participants who had not linked to HIV care. Full HIV genome sequencing using the MiSeq platform was done on plasma samples from 77 RIn and 1069 Cln participants who linked to care, of whom 838 initiated ART. Minority variants were called at a 2% level (Geneious and MiCall softwares). Cox regression was used to estimate hazard ratios (HR) for VS.
Overall PDR prevalence was 8,4% (95%CI=6,7-10%) and 17,8% (95%CI=15,1-20,5%) at 20% and 2% detection levels respectively; these proportions were similar between RIn and CIn participants. Among participants with PDR, 88% had only 1 or 2 DR mutations, associated with NNRTI resistance in 73% of the cases, and 61% were detected as a majority variant (>20%). 13,5% and 8,8% were associated with NRTI and PI resistance, respectively, with 90% of them being minority variants (100,000 vs
The prevalence of PDR approached 10% at >20% representation among RIn and CIn participants, while deep sequencing identified double the prevalence. Longer term follow up is needed to assess the lack of virological impact of PDR.

Authors
Anne Derache, Collins C Iwuji, Siva Danaviah, Anne-Geneviève Marcelin, Vincent Calvez, Tulio de Oliveira, François Dabis, Deenan Pillay

Aidsmap material
CROI 2017 abstract


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