Successful HIV drug resistance testing is possible when viral load is low

HIV drug resistance testing can perform well, even when viral load is as low as 250 copies/ml, results of two studies published in the online edition of Clinical Infectious Diseases show. In one study, genotyping was successfully performed on over 90% of samples when viral load was between 250 and 999 copies/ml. Moreover, resistance testing at low-level viraemia was shown to be of clinical benefit, with results accurately predicting the risk of an increase in viral load to above 1000 copies/ml and the virological failure of antiretroviral therapy.

“Each of these studies provides a robust practical experience with data from a large number of subjects and plasma samples,” writes Dr Douglas D Richman of the University of San Diego in an editorial. “They provide evidence for beneficial clinical outcomes as a result of…drug resistance testing at low levels of plasma HIV RNA.”

To help guide the choice of antiretroviral drugs, it is recommended that people with HIV should have a resistance test before starting or changing treatment. However, approved genotypic resistance tests require a viral load of at least 1000 copies/ml. Their performance at lower viral loads is uncertain.

Investigators in Canada and Italy designed separate studies examining the reliability and clinical utility of standard genotypic resistance tests in cases of low-level viraemia – a viral load between 50 and 999 copies/ml.

The investigators in Canada retrospectively studied 4915 samples collected from 2492 people who received care in British Columbia between 1996 and 2012.

Overall, 88% of resistance tests conducted when viral load was below 1000 copies/ml produced usable results. Successful results were obtained from three-quarters of samples with viral loads below 250 copies/ml and from 90% of samples where viral load was above 250 copies/ml.

The investigators also examined the use of resistance tests in a subset of 196 people taking their first antiretroviral combination who experienced low-level viraemia, and who did not have baseline resistance. At the time of resistance testing, the patients had a median CD4 count of 415 cells/mm³, and median viral load was 374 copies/ml. Approximately a fifth (19%) of the patients developed resistance during their time with low-level viraemia. Only 5% of patients with a viral load between 50 and 250 copies/ml developed resistance, compared to 30% of individuals with viral loads between 750 and 999 copies/ml.

After adjusting for confounders, people with resistance at low-level viraemia were shown to be twice as likely as people without resistance to experience an increase in viral load to above 1000 copies/ml (aHR = 2.1; 95% CI, 1.2-3.7, p = 0.007).

“We have shown that routine HIV genotyping of low-level viraemia samples can be performed with a reasonably high success rate,” comment the investigators. “Genotyping of low-level viraemia samples is predictive of future virologic outcomes in treatment-naive patients on their first antiretroviral therapy regimen.”

The Italian study was based on the retrospective analysis of 1535 viral load samples collected from people with low-level viraemia who received care in Rome between 1999 and 2012.

Overall, 96% of samples were successfully sequenced. Samples with viral loads between 50 and 200 copies/ml had a success rate of 67%, increasing to 93% when viral load was between 501 and 999 copies/ml.

Drug resistance was frequently detected at low-level viraemia, including 53% of samples with viral loads below 200 copies/ml and three-quarters of samples with viral loads between 501 and 999 copies/ml.

The presence of resistance mutations was associated with an increased risk of rebound in viral load to above 1000 copies/ml (p < 0.001).

“Our findings emphasize the importance of using the genotypic test at the first failures even at low viraemia, to guide the choice of an effective alternative regimen,” conclude the investigators.

The authors of both studies acknowledge that their research has limitations. For instance, both study teams were highly experienced and had specialised laboratories at their disposal. They used “in house” methods to genotype samples rather than the standard FDA-approved method used in most countries.

Despite this, Dr Richman believes the studies’ findings “provide robust data showing the practical feasibility” of resistance testing at low viral loads. “Implementing the conclusions of these two studies will expand the proportion of patients who will benefit from HIV drug resistance testing.”