Management of low-level HIV viremia during antiretroviral therapy: Delphi consensus statement and appraisal of the evidence

WHAT IS ALREADY KNOWN ON THIS TOPIC

It is well established that antiretroviral therapy (ART) effectively suppresses HIV-1 replication, leading to virological suppression in most individuals. However, low-level viremia (LLV), characterised by persistently or intermittently detectable low levels of HIV-1 RNA in plasma despite good adherence to ART, is a common clinical finding. The interpretation and management of LLV vary due to limited evidence supporting optimal strategies.

WHAT THIS STUDY ADDS

This project provides valuable insights into the management of LLV during ART. We conducted a consensus development study involving a panel of experts to address the lack of evidence-based guidelines. Through a systematic review and analysis of available data, this study identifies common clinical scenarios of LLV and proposes interventions tailored to each scenario. Key findings include recommendations on ART regimen modification, genotypic resistance testing, adherence assessment, therapeutic drug monitoring and follow-up strategies.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

The findings of this study offer practical guidance for clinicians in managing LLV during ART, addressing the uncertainties and variations in clinical practice. By providing evidence-based recommendations and suggestions, it helps standardise approaches to LLV management, potentially improving patient outcomes. Additionally, the study highlights the need for further higher quality studies to fill knowledge gaps and refine management strategies.

Introduction

Antiretroviral therapy (ART) is highly effective in suppressing HIV-1 replication and most individuals receiving currently recommended regimens achieve virological suppression.1 2 Despite this success, HIV cannot be eradicated due to the persistence of latently infected cells containing stably integrated HIV-1 DNA.3

In the course of effective ART, some individuals experience persistently or intermittently detection of low HIV-1 RNA levels in plasma despite reporting excellent adherence. Various definitions based on magnitude and persistence are used internationally to describe plasma HIV-1 RNA detection, including residual viremia (RV), low-level viremia (LLV) and viral blip (VB) (table 1).4–8 The interpretation and recommended management vary, reflecting the limited evidence base for this common clinical finding.9

Table 1

Definitions of plasma HIV-1 RNA detection during ART according to different guidelines and the Low-Level HIV Viremia Consensus Panel

In individuals with excellent adherence, the source of plasma HIV-1 RNA is probably multifactorial.2 HIV-1 RNA sequences in plasma typically do not evolve over time, with most evidence attributing the source of plasma HIV-1 RNA to bursts of viral production from memory CD4+ T cells harbouring integrated provirus, with ART immediately blocking further replication.10 One additional mechanism may involve ongoing virus replication due to suboptimal drug potency or exposure or within sanctuary sites characterised by reduced drug penetration and exclusion of immune response.11 Differentiating between these scenarios is important, as changing the ART regimen would only be effective in cases of ongoing virus replication.

Several interventions can be considered in the management of LLV, including investigations of adherence, drug resistance, HIV-1 DNA load (as a measure of the viral reservoir), chronic coinfections, plasma drug concentrations and inflammatory markers. Intensified monitoring with more frequent follow-up visits is common practice, and for some individuals, ART changes may be considered. As clinical practice varies, we conducted a consensus development project based on a modified Delphi procedure, with support from a systematic review (SR) employing a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE)-based approach.

Methods

The study was conducted over a 2-month period (figure 1). Initially, a SR employing a GRADE approach was conducted to identify clinical scenarios (CS) related to detection of plasma HIV-1 RNA at low copy numbers and its multiple definitions available in the literature and support panel’s recommendations. The identified CS were: (1) LLV during stable (≥ 6 months) first-line ART (≥2 consecutive HIV-1 RNA measurements 50–500 copies/mL); (2) a VB during otherwise suppressive ART (a HIV-1 RNA measurement 50–1000 copies/mL with adjacent measurements <50 copies/mL); (3) low-level viral rebound during previously suppressive ART (≥2 consecutive HIV-1 RNA measurements 50–500 copies/mL); (4) RV during suppressive ART (persistent HIV-1 RNA quantification below 50 copies/mL). Eight interventions for the management of each CS were assessed by the review, and respective statements were formulated, considering currently recommended oral ART regimes and excluding the use of long-acting injectable therapy. Statements concerning the proposed interventions included: (a) ART regimen modification; (b) genotypic resistance testing (GRT); (c) assessment of adherence; (d) performing therapeutic drug monitoring (TDM); (e) scheduling an earlier follow-up; (f) evaluating chronic coinfections; (g) assessing inflammatory markers; (h) quantification of HIV DNA in peripheral blood.

Figure 1

Flowchart of the development of the scenarios, statements and suggestions.

The search question and full-research protocol for the SR are available on PROSPERO (CRD CRD42024511492). The full methodology and results from the SR are reported in a separate publication.12

To determine recommendations for the management of the identified CS, we employed a modified Delphi procedure, where an expert panel of 17 HIV specialists was consulted and chosen based on expertise in Infectious Diseases, Virology and Immunology, current direct involvement in HIV care and engagement in the topic as indicated by field of research and scientific output. The procedure included two Delphi rounds separated by a group discussion moderated by MA and CFP.

The Delphi method,13 a consensus-building approach,14 involved collecting opinions through a procedure ensuring: (a) anonymity—the experts did not know the responses of the other specialists; (b) feedback—the experts could suggest additional information for research or justify their choices; (c) iterations—the number of rounds and (d) statistical analysis.15

Experts were invited to review the content of each scenario and the statements linked to it and to rate each one in terms of its validity and relevance by indicating a value from 1 to 5 on a Likert scale, where 1=strongly disagree (I do not agree with this statement in the context of this scenario) and 5=strongly agree (This statement is relevant and I agree in the context of this scenario). At the end of the first round, the mean and SD, as well as the content validity index (CVI), were calculated for each statement.16 Furthermore, Cronbach’s alpha was calculated for each scenario.17 18 Content validity determines the ability of the selected items to reflect the variables of the construct in the measure, addressing the degree to which the items of an instrument sufficiently represented the content domain. This could be quantified through the CVI, deriving from the ratio between number of experts that rate a singular item with 4 and 5 (maximum rates) and the total number of experts involved. CVI ranges from 0 to 1 or from 0 to 100%. A CVI greater than 70% is deemed to be suggestive of the item’s consensus, a rate above 75% is considered indicative for strong consensus, while a rate lower than 70% is deemed to be suggestive of non-consensus.16 Experts were also asked to rank each statement based on the clinical priority in order to manage every CS.

Subsequently, the panel of experts gathered to discuss the scenarios and statements during a 2-day meeting. Facilitators went through all the scenarios and statements, presenting the results of the first round of Delphi, and receiving comments and suggestions from the panel with the aim of modifying the statements with poor agreement. After collecting and incorporating all the suggestions, the modified version of the document was sent to the panel of experts for a second round of Delphi, resulting in the final version of the document with the recommendations.

The full expert panel and their role of expertise are available in online supplemental file 1.

Results

The outcome of the final Delphi round, level of agreement, consensus results and CVI are provided in table 2. After the second round, 18/32 (56.2%) statements achieved strong consensus, 3/32 (9.4%) reached moderate consensus and 11/32 (34.4%) statements did not achieve consensus. The level of priority assigned to each proposed intervention is reported in figure 2.

Table 2

Statements and panel consensus

Figure 2

. Opinion on the priority of interventions in the management of people with low-level viremia during ART. (A) Scenario 1. Low-level viremia during stable (≥6 months) first-line ART (≥2 consecutive HIV-1 RNA measurements 50–500 copies/mL); (B) Scenario 2. A viral blip during otherwise suppressive ART (a HIV-1 RNA measurement 50–1000 copies/mL with adjacent measurements <50 copies/mL) (C) Scenario 3. Low-level viral rebound during previously suppressive ART (≥2 consecutive HIV-1 RNA measurements 50–500 copies/ml); (D) Scenario 4: Residual viremia during suppressive ART (persistent HIV-1 RNA quantification below 50 copies/mL). ART, antiretroviral therapy; GRT, genotypic resistance testing; TDM, therapeutic drug monitoring; FU, follow-up.

Statement 1: immediate need to modify the ART regimenData identified from SR

The systematic search identified 14 studies evaluating the topic, including three randomised controlled trials (RCTs).19–21

The meta-analysis of four cohort studies,22–25 reporting virologic suppression (defined as <20 cp/mL) among a total of 435 people with HIV (PWH) with LLV who switched therapy and 532 PWH with LLV who belonged to the non-intervention group, reported no significant association between therapeutic switch and virologic suppression. The meta-analysis of three studies (one RCT, one cohort and one case–control) reporting virologic suppression (defined as <50 cp/mL) in a total of 121 PWH with LLV who switched therapy and 192 PWH with LLV who continued therapy, also reported no significant association between therapeutic switch and virologic suppression.21 26 27

Among the studies that could not be meta-analysed a non-randomised study and an RCT report that treatment intensification of ART with raltegravir did not decrease the rate of RV in subjects on ART.20 28 A French study investigating a switch to a dual therapy based on maraviroc and raltegravir did not find a correlation with reducing RV.29 Another non-randomised study found that RV was not reduced by ART intensification.30 Conversely, a beneficial effect of an ART switch in PWH with RV was reported in two studies.19 31 A cohort study conducted on PWH with LLV found a virologic suppression in 20/27 cases after ART modification.32