Lower Incidence of HIV-1 Blips Observed During Integrase Inhibitor–Based Combination Antiretroviral Therapy

Suzan Dijkstra, MD; L. Marije Hofstra, MD, PhD; Tania Mudrikova, MD, PhD; Annemarie M. J. Wensing, MD, PhD; Patrick G. A. Oomen, MD; Andy I. M. Hoepelman, MD, PhD; Berend J. van Welzen, MD, PhD


J Acquir Immune Defic Syndr. 2022;89(5):575-582. 

In This Article

Abstract and Introduction


Background: As the nature of viral blips remains unclear, their occurrence often leads to uncertainty. This study compares blip incidence rates during treatment with different combination antiretroviral therapy anchors.

Setting: Retrospective cohort study in a tertiary hospital.

Methods: All antiretroviral regimens between 2010 and 2020 containing 2 nucleos(-t)ide reverse transcriptase inhibitors and 1 anchor in virologically suppressed people living with HIV (PLWH) from our center were evaluated for the occurrence of blips [isolated viral loads (VLs) 50–499 copies/mL between measurements <50 copies/mL]. Factors associated with blips were identified using multivariable generalized estimating equation–based negative binomial models. The relationship between blips and either persistent low-level viremia (consecutive VLs ≥ 50 copies/mL not classified as failure) or virologic failure (consecutive VLs ≥ 200 or 1 VL ≥ 500 copies/mL) was also evaluated.

Results: In total, 308 blips occurred during 3405 treatment courses in 1661 PLWH. Compared with a non-nucleoside reverse transcriptase inhibitor anchor, blip incidence was higher for protease inhibitors (incidence rate ratio 1.37; 95% confidence interval 1.05 to 1.78) and lower for integrase inhibitors (INSTIs) (incidence rate ratio 0.64; 95% confidence interval: 0.43 to 0.96). In addition, blips were associated with higher zenith VL, higher VL test frequency, and shorter time since antiretroviral therapy initiation. PLWH experiencing blips were more likely to demonstrate persistent low-level viremia but not virologic failure. Blips led to extra consultations and measurements.

Conclusions: INSTI-based regimens display a low number of blips. Although we found no correlation with virologic failure, the occurrence of blips led to an increased clinical burden. Further research is needed to elucidate the implications and underlying mechanisms of these findings.


Although the past decades have brought tremendous progress in the reduction of HIV-related morbidity and mortality,[1] HIV infection still requires a lifelong treatment with antiretroviral agents.[2] First-line combination antiretroviral therapy (cART) regimens currently most often consist of 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) and 1 anchor drug: a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase strand transfer inhibitor (INSTI).[3] The primary goal of cART is to achieve and maintain virologic suppression below a specific threshold (50 copies/mL in our center) to avert the selection of drug-resistant HIV variants.[3] This target is reached in more than 90% of people living with HIV (PLWH) in multiple high-income countries.[4]

However, in a large number of otherwise well-suppressed PLWH, transient fluctuations of HIV RNA levels above the detection limit, the so-called viral blips, are observed.[5–8] The etiology of this phenomenon has not been completely elucidated. The various, mutually nonexclusive hypotheses include ongoing viral replication due to inadequate potency or concentrations of current cART,[7–13] intermittent bursts of virion production from both cellular and anatomical reservoirs,[13,14] and random assay variability.[15–17] Their clinical significance continues to be a matter of debate as well: previous, highly heterogeneous, studies have found conflicting evidence as to whether blips are associated with the emergence of drug resistance[15,18] and virologic failure.[8,19–22] Several studies have found an association with failure when high-level blips were encountered.[5,12] Nonetheless, the occurrence of blips often raises clinical concerns and may lead to spending of considerable time and resources for repeat viral load (VL) measurements, drug level testing, additional outpatient visits for adherence counseling, and uncertainty for both PLWH and physicians.[15]

Previous research has indicated that blips occur more frequently during PI-based cART than during NNRTI-based regimens,[5,20] which could be the result of a preference for PI-based treatment in nonadherent PLWH. However, to the best of our knowledge, no previous comparisons have been made for PLWH treated with the newer INSTI-based regimens despite the fact that these have become the preferred initial regimens in both American and European guidelines.[3,23] Similar to NNRTIs, INSTIs exert their effect before viral DNA integration and thereby limit new virion production, whereas PIs block the maturation of virus particles that have already been synthesized.[24] These different mechanisms of action may influence HIV-1 replication rate and thus blip occurrences. However, INSTIs have also been found to result in more rapid virologic suppression, less residual viremia (detectable HIV RNA < 50 copies/mL), and superior long-term virologic efficacy when compared with both NNRTIs and PIs.[25–28] Therefore, we hypothesized that the use of INSTI-based treatment courses would lead to a lower incidence of viral blips than NNRTI-based and PI-based courses, possibly due to more robust virologic suppression. This study aimed to evaluate the incidence of HIV blips among PLWH treated with different contemporary cART anchors.