When people contract HIV today, the virus is often already resistant to certain antiretrovirals (ARVs). However, in an ongoing study, having resistant virus when starting ARVs has not thus far been associated with differences in treatment success rates.

Researchers in the cluster-randomized ANRS 12249 trial conducted drug resistance testing on samples taken from 1,337 people with HIV in the province of KwaZulu-Natal, South Africa, who were recently infected or who were chronically infected upon entering the trial between March 2012 and June 2016. The samples were collected before the individuals began antiretrovirals (ARVs) for the first time and analyzed after they started treatment, all of them with Atripla (efavirenz/tenofovir/emtricitabine).

Anne Derache, PhD, of the Africa Health Research Institute in Mtubatuba, South Africa, presented findings from the study at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Anne Derache of the Africa Health Research Institute at CROI 2017 in SeattleCourtesy of Benjamin Ryan

The investigators conducted what is known as pol gene Sanger genetic sequencing on dried blood spots from 189 recently infected participants who had not yet been linked to HIV care. They conducted the more advanced full HIV genome sequencing using what is called the MiSeq platform on plasma samples from 88 recently infected participants and 1,060 chronically infected participants who were linked to care, of whom 920 started treatment. A total of 837 had the proper follow-up data to be included in the subsequent analysis.

The overall pretreatment drug resistance rate was 8.5 percent according to the lower threshold of drug resistance of a 20 percent level of mutation of the virus. The drug resistance rate was 17.1 percent according to the more sensitive threshold of a 2 percent level of mutation.

Among those with drug resistance, 88 percent had only one or two resistance mutations, which were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 73 percent of the cases (most of the resistance was associated with the ARV Sustiva (efavirenz), which is included in Atripla). Sixty-one percent of these drug resistance cases were detected as what is known as a majority variant, meaning that over 20 percent of the virus in an individual has at least one resistance mutation. A respective 13.5 percent and 8.8 percent of the cases were associated with nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs); 90 percent of them were minority variants (below the 20 percent threshold) for both classes of ARVs.

Among the recently infected people with pretreatment drug resistance, 92 had resistance associated with a single ARV class, mostly NNRTIs.

Among the 838 people who started HIV treatment during the study and were followed for a median 16 months while on ARVs, the median time until they reached full viral suppression was 3.6 months. Within a year, 97 percent of them had a fully suppressed viral load.

After adjusting the data for sex, age, viral load upon starting treatment and adherence to treatment, the researchers surprisingly found no evidence in either those with majority or minority variants that having pretreatment drug resistance was associated with viral suppression success compared with having no drug-resistance mutations.

“We need longer-term follow-up to actually confirm our findings,” Derache said at a CROI news conference. She added that she believed there is still a chance that “drug resistance may become a major issue in the coming years,” meaning that its prevalence would compromise the overall efficacy of HIV treatments.

If the finding that relatively widespread drug resistance does not lead to lower rates of HIV treatment success holds true, it will have particular significance for resource-poor settings where the kind of drug resistance tests that are standard in wealthy nations are not practical. If the overall chance of treatment failure remains low, clinicians can have more confidence in prescribing first-line HIV treatment regimens, which are considerably cheaper than second-line therapies.

Derache said she believed her findings would likely apply to any sub-Saharan African nation and to resource-limited countries elsewhere in the world.

After adjusting the data, Derache and her team did find that having an initial viral load greater than 100,000 was associated with a 25 percent decreased rate of viral suppression after 12 months of ARVs compared with having an initial viral load of below 10,000. Also, taking at least 95 percent of daily ARV doses compared with poorer adherence was associated with a 36 percent increased viral suppression rate at 12 months.

The study authors concluded that longer follow-up is needed to assess pretreatment drug resistance’s association with viral suppression.