When an HIV viral load rises despite treatment, the laboratory result does not immediately explain why. A person may have struggled to take medication consistently, or the virus may have developed resistance to the drugs intended to suppress it. Those possibilities can require very different responses.
A South African implementation study suggests that one relatively simple laboratory measurement can help separate those pathways earlier. By checking whether dolutegravir is detectable in the same blood sample used for viral-load monitoring, clinicians can identify people who are most likely to benefit from more expensive HIV drug-resistance testing.
The ITREMA-2 study, published in The Lancet HIV in September 2026, followed 288 people receiving HIV care at Hillbrow Community Health Centre and Helen Joseph Hospital in Johannesburg. The approach was designed around a practical problem created by the success of dolutegravir. The drug has a high barrier to resistance, which makes it an effective foundation for first-line antiretroviral treatment, but virological failure still needs to be investigated carefully when it occurs.
A drug level becomes a decision tool
The researchers used plasma dolutegravir exposure testing alongside viral-load assessment. The logic is straightforward. If dolutegravir cannot be detected, recent medication exposure is unlikely and inadequate adherence becomes a more plausible explanation for the raised viral load. If the drug is clearly present while HIV continues replicating, resistance becomes more concerning and genotypic resistance testing can be prioritised.
This distinction matters because resistance testing is more specialised and expensive than measuring drug exposure. Sending every person with viraemia directly for genotyping can consume laboratory resources even when the underlying problem is recent missed treatment rather than resistant virus. Waiting too long, however, creates the opposite risk for people whose virus really has acquired resistance.
ITREMA-2 therefore evaluated a targeted pathway rather than simply testing whether a laboratory assay works. The prospective two-centre implementation design examined how the strategy performed among patients in real public-sector HIV clinics, where turnaround times, costs and clinical decisions all matter.
An undetectable result was strongly reassuring
One of the clearest findings concerned the negative predictive value of the exposure test. When dolutegravir was not detectable, integrase inhibitor resistance could be ruled out with a negative predictive value of almost 98%.
That figure is clinically useful because it describes how informative a negative exposure result was in this study population. It does not mean that the drug-level test diagnoses every cause of treatment failure. Rather, it indicates that people without detectable dolutegravir were very unlikely to harbour the integrase resistance that would make immediate resistance testing most valuable.
The result changes the information available at a difficult point in care. A raised viral load on its own can trigger uncertainty. Adding recent drug exposure gives clinicians another piece of objective evidence when deciding whether to focus first on medication-taking barriers or escalate laboratory investigation for resistance.
The economics may matter almost as much as the diagnostics
The team also estimated what the pathway would mean for laboratory spending. When the targeted strategy was incorporated after confirmed virological failure, estimated monitoring costs were 23% lower than under the previous approach.
The saving comes from selectivity. Genotypic resistance testing is directed towards patients for whom the additional information is most likely to change management, rather than being used indiscriminately. In a health system managing HIV care at national scale, even a modest reduction in the number of unnecessary specialised tests can translate into meaningful laboratory capacity and budget effects.
The study is particularly notable because the findings have already moved beyond an academic proof of concept. An adapted reflex-testing strategy has been incorporated into South African public HIV care through the National Department of Health. That transition is important: implementation research is most useful when a technically sound idea can survive the realities of routine clinics and laboratory systems.
What the approach does not prove
The results should still be interpreted within the study’s boundaries. The 288 participants came from two large Johannesburg public clinics, so performance and cost estimates may differ in rural services, smaller laboratories or countries with different treatment pathways and resistance patterns.
A plasma drug concentration also provides information about recent exposure, not a complete history of adherence. Detectable dolutegravir cannot prove that every dose was taken correctly over preceding weeks, while an undetectable result does not explain why medication was missed. Social pressures, treatment fatigue, access problems, side effects and other barriers still require clinical attention rather than being reduced to a laboratory classification.
Cost estimates are similarly dependent on the prices, testing volumes and workflow assumptions of the health system in which the strategy is deployed. The reported 23% reduction should therefore be read as an estimate for the evaluated pathway, not a universal saving that every programme will automatically reproduce.
A more targeted response to treatment failure
The wider significance lies in making a common clinical decision more evidence-rich. Dolutegravir has strengthened HIV treatment because resistance is comparatively difficult to develop. That same strength means that a rising viral load should not automatically be interpreted as proof that the virus has defeated the drug.
ITREMA-2 offers a way to use that biology to organise testing more efficiently. People whose results point towards inadequate recent drug exposure can receive adherence support without immediately consuming a resistance test. Those with drug exposure despite ongoing viraemia can be prioritised for genotyping and, where necessary, a faster change in treatment.
For South Africa, the most consequential part of the research may be that the pathway has already reached routine public care. The study does not eliminate the complexity of HIV treatment failure, but it shows how one additional laboratory signal can help direct expensive diagnostic resources towards the patients most likely to need them.
Source Information
Study title: Plasma dolutegravir exposure testing to identify people with HIV at highest risk for dolutegravir resistance (ITREMA-2): a two-centre, prospective implementation study in South Africa
Authors: Kim Steegen et al.
Journal: The Lancet HIV
Year: 2026
DOI: 10.1016/S2352-3018(26)00144-X
