Persistent Low-level Viremia Research Articles

Virological History Predicts Non-sustained Viral Suppression With Long-Acting Cabotegravir and Rilpivirine Therapy, Independent of Pharmacokinetic Parameters

Abstract Background This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). Methods A prospective cohort study was conducted on people with human immunodeficiency virus (HIV, PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB + RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma human immunodeficiency virus type 1 (HIV-1) viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. Results Among 173 patients with a median (interquartile range [IQR]) follow-up of 11.1(7.1–13.2) months and 789 pre-dose measurements, 38.7% experienced VL ≥ 20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in 2 cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis (adjusted hazard ratio [AHR]: 1.49 per log10 VL, 95% confidence interval [CI]: 1.04–2.12, P = .027), detectable viremia on oral ART (AHR: 2.45, 95% CI: 1.29–4.65, P = .006), and the level of viral suppression at transition (AHR: 0.38, 95% CI: .19–.75, P = .004). We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. Conclusions Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB + RPV LA was linked to preexisting factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

Consequences of low-level viremia among women with HIV in the United States.

Investigate the outcomes of women with HIV (WWH) with low-level viremia (LLV). The prevalence of LLV and potential clinical sequelae, such as virologic failure and non-AIDS comorbidity (NACM) development, are poorly characterized among WWH. We analyzed data from the Women's Interagency HIV Study among WWH enrolled from 2003 to 2020 who reported antiretroviral therapy use at least 1 year followed by an HIV-1 viral load less than 200 copies/ml. Consecutive viral load measurements from four semi-annual visits were used to categorize women at baseline as having: virologic suppression (all viral load undetectable), intermittent LLV (iLLV; nonconsecutive detectable viral load up to 199 copies/ml), persistent LLV (pLLV; at least two consecutive detectable viral load up to 199 copies/ml), or virologic failure (any viral load ≥200 copies/ml). Adjusted hazard ratios quantified the association of virologic category with time to incident virologic failure and multimorbidity (≥2 of 5 NACM) over 5-year follow-up. Of 1598 WWH, baseline median age was 47 years, 64% were Black, 21% Hispanic, and median CD4 + cell count was 621 cells/μl. After excluding 275 women (17%) who had virologic failure at baseline, 58, 19, and 6% were categorized as having virologic suppression, iLLV, and pLLV, respectively. Compared with WWH with virologic suppression, the adjusted hazard ratio [aHR; 95% confidence interval (CI)] for incident virologic failure was 1.88 (1.44-2.46) and 2.51 (1.66-3.79) for iLLV and pLLV, respectively; and the aHR for incident multimorbidity was 0.81 (0.54-1.21) and 1.54 (0.88-2.71) for iLLV and pLLV, respectively. Women with iLLV and pLLV had an increased risk of virologic failure. Women with pLLV had a trend towards increased multimorbidity risk.

Persistent low-level viraemia is associated with non-infectious comorbidities in an observational cohort in four African countries.

People living with HIV (PLWH) have higher rates of non-infectious comorbid diseases (NCDs) than individuals without HIV. We characterized the risk of NCDs among PLWH with undetectable viral load and persistent low-level viraemia (pLLV) in the African Cohort Study (AFRICOS). We secondarily quantified the role of immune activation in the association between LLV and NCDs. AFRICOS enrols participants in 12 clinics in Uganda, Kenya, Tanzania and Nigeria. Participants on antiretroviral therapy ≥ 6 months without an NCD at enrolment were included. PLLV was defined as at least two consecutive visits with a detectable viral load <1000 copies/ml. We examined elevated blood pressure, hypercholesterolemia, hyperglycaemia, renal insufficiency and a composite variable of any NCD. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard modelling. Among a subset of participants with biomarker data, we assessed the interaction between viral load and 13 biomarkers in the association with any NCD. From 23 January 2013 to 1 December 2022, 1755 participants met the inclusion criteria for these analyses. At the first eligible visit, the majority of participants had an undetectable viral load (n = 1375, 78.35%). Participants with pLLV had an increased rate of developing any NCD (aHR: 1.22, 95% CI: 1.02-1.47) compared to participants with an undetectable viral load. There was a statistically significant interaction between LLV and TNF-α, CCL2/MCP-1 and TNF-RII in the association with any NCD. PLLV was significantly associated with NCDs and immune inflammation in this population. Aggressive management of LLV may positively impact NCDs in PLWH.

Periodontal inflammation as a potential driver of HIV low level viremia.

HIV can be successfully suppressed to undetectable levels by antiretroviral therapy (ART) in most people with HIV (PWH). However, a small proportion continues to have persistent low-level viremia (LLV) during ART. A presumed source of LLV is production or replication from viral reservoirs, which are maintained in the presence of ART. It is unknown whether the oral cavity can be considered an HIV reservoir. As periodontal inflammation is a common problem in PWH, we hypothesize that periodontal inflammation in the oral cavity activates (latently) infected cells and thus might be associated with LLV. We included 11 individuals with HIV LLV, and compared HIV-RNA levels in saliva and plasma at baseline and at week 24 after switch of ART. We compared the LLV-group at baseline with 11 age-matched controls with suppressed viremia. To investigate the severity of periodontitis we used Periodontal Inflamed Surface Areas (PISA) by measuring probing depth, gingival recession, bleeding on probing and clinical attachment level. Severity of periodontitis was classified according to the CDC-AAP case definition. Additional insights in periodontal inflammation were obtained by comparing immune activation markers and the presence of periodontal pathogens. In four individuals of the LLV group, residual levels of HIV-RNA were detected in saliva at baseline (N = 1) or at week 24 (N = 2) or both (N = 1). Of the four individuals with LLV, three had residual levels of HIV-RNA in saliva. All 22 individuals had moderate to severe periodontitis. PISA was not significantly different between cases with LLV and controls. Similarly, periodontal pathogens were frequently observed in both groups. Total activated HLA-DR+CD38+ CD4+ cells and CD8+ cells were significantly higher in the LLV group than in the control group (p = <0.01). No immune markers were associated with LLV. In conclusion, periodontal inflammation is an unlikely driver of HIV LLV compared to HIV suppressed individuals.

Real-World Effectiveness of Dolutegravir/Lamivudine in People With HIV-1 in Test-and-Treat Settings or With High Baseline Viral Loads: TANDEM Study Subgroup Analyses.

Dolutegravir/lamivudine (DTG/3TC) was first approved by the US Food and Drug Administration in 2019 for the treatment of antiretroviral therapy (ART)-naive people with HIV-1 based on results from the pivotal GEMINI-1/GEMINI-2 trials. Around that time, immediate initiation of treatment upon diagnosis was recommended in the US Department of Health and Human Services guidelines. Here we report results from 126 treatment-naive people with HIV-1 who initiated DTG/3TC as part of a test-and-treat strategy (n = 61) or with high baseline viral loads (HIV-1 RNA ≥ 100,000 copies/ml; n = 16) from the TANDEM study. TANDEM was a US-based, retrospective chart review study that included a cohort of 126 individuals aged ≥ 18years with no prior history of ART who initiated DTG/3TC before September 30, 2020, and had ≥ 6months of follow-up. Test-and-treat was defined as ART initiation shortly after diagnosis without available viral load, CD4 + cell count, or HIV-1 resistance data. Outcomes included virologic suppression (HIV-1 RNA < 50 copies/ml; overall and by baseline viral load) and discontinuations. Analyses were descriptive. Among 61 individuals who initiated DTG/3TC in a test-and-treat setting (median [interquartile range (IQR)] treatment duration, 1.3 [0.9-1.7] years), 57 (93%) achieved virologic suppression, and 51 (84%) remained suppressed; 1 (< 1%) individual discontinued DTG/3TC due to persistent low-level viremia. The most common healthcare provider (HCP)-reported reason for initiating DTG/3TC was avoidance of long-term toxicities among individuals in the test-and-treat subgroup. Of 16 treatment-naive individuals with high baseline viral loads (median [IQR] treatment duration, 100,000-250,000 copies/ml: 1.2 [0.8-1.8] years; > 250,000 copies/ml: 1.0 [0.7-1.1] years), 14 (88%) achieved virologic suppression, 13 (81%) remained suppressed, and none discontinued DTG/3TC. Patient preference was the most common HCP-reported reason for initiating DTG/3TC in this subgroup. Results demonstrate real-world effectiveness of DTG/3TC, with few discontinuations, in people with HIV-1 in test-and-treat settings or with high baseline viral loads.

Prevalence and predictors of persistent low-level HIV viraemia: a retrospective cohort study among people receiving dolutegravir-based antiretroviral therapy in Southern Nigeria.

Persistent low-level viraemia (PLLV) is a risk factor for virologic failure among people receiving antiretroviral therapy (ART). We assessed the prevalence and predictors of PLLV among individuals receiving Dolutegravir-based ART in southern Nigeria. This retrospective cohort study used routine program data from electronic medical records of persons receiving Dolutegravir-based first-line ART in 154 PEPFAR/USAID-supported health facilities in Akwa Ibom and Cross Rivers states, Nigeria. Clients on first-line Dolutegravir-based ART ⩾6 months, who had a viral load result in the 12 months preceding October 2021 (baseline), and a second viral load result by September 2022 were included. Persons with low-level viraemia (LLV) (viral load 51-999 copies/ml) received additional adherence support. The outcome analysed was PLLV (two consecutive LLV results). Indices were summarized using descriptive statistics, and predictors of PLLV were determined using multivariate logistic regression. In total, 141,208 persons on ART were included, of which 63.3% (n = 89,944) were females. The median age was 36 [29-44] years, median ART duration was 19 [11-42] months. At the end of the study, 10.5% (14,759/141,208) had initial LLV, 90.1% (13,304/14,759) of which attained undetectable viral load (⩽50 copies/ml), and 1.1% (163/14,759) transitioned to virologic failure (⩾1000 copies/ml) by the end of the study. PLLV prevalence was 0.9% (1292/141,208). Increasing ART duration [adjusted odds ratio (aOR) = 1.0; 95% confidence interval (CI): 1.005-1.008; p < 0.001] and viral suppression (<1000 copies/ml) before initial LLV (aOR = 1.7; 95% CI: 1.50-2.00; p < 0.001) were positively associated with PLLV, while receipt of tuberculosis preventive therapy reduced the likelihood of PLLV (aOR = 0.3; 95% CI: 0.10-0.94; p = 0.039). PLLV was uncommon among individuals receiving dolutegravir-based ART and was associated with longer ART duration, prior viral suppression, and non-receipt of tuberculosis preventive therapy. This strengthens recommendations for continuous adherence support and comprehensive health services with ART, to prevent treatment failure.

Predictors of Post-switch Viremia in People With HIV on Injectable Cabotegravir/Rilpivirine.

Predictors of virologic failure in those receiving long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) have been evaluated; however, factors associated with low-level viremia, including blips and persistent low-level viremia (pLLV), are not well-described. A retrospective cohort study was performed using data from April 2021 through December 2022. Inclusion criteria included treatment with CAB/RPV for at least 3 months, availability of pre- and postswitch HIV RNA values, HIV RNA value of <200 copies/mL (cpm) at the time of switch to CAB/RPV, and at least 1 postswitch HIV RNA collected >21 days after the start of CAB/RPV. Outcomes included incidence of HIV RNA ≥20, ≥50, and ≥200 cpm after switch and factors associated with detectable HIV RNA after switch. The median duration of follow-up among 144 participants was 287 days. After switching to CAB/RPV, occurrences of at least 1 HIV RNA ≥20, ≥50, and ≥200 cpm after switch were 34.7%, 15.3%, and 2.8%, respectively. Those with pLLV before switch were significantly more likely to have detectable HIV RNA after switch [hazard ratio 24.39 (8.71-68.34)], and 44.4% of those with pLLV before switch continued with pLLV after switch to LAI CAB/RPV. Body mass index, late injection, and monthly versus every two-month dosing were not associated with detectable viremia after switch. Despite virologic suppression at the time of switch and the perceived adherence benefits, participants still experienced blips or pLLV after switch to LAI CAB/RPV. Having detectable HIV RNA on oral therapy before switch was associated with detectable HIV RNA after switching.

Decreased Efficacy of Sofosbuvir/Velpatasvir in HIV Patients Coinfected with HCV Genotype 3b

Aim: To retrospectively assess the efficacy and safety of sofosbuvir/velpatasvir for hepatitis C virus (HCV) genotype 3b in HIV-infected patients receiving antiretroviral therapy (ART) treatment of lamivudine/tenofovir disoproxil fumarate/efavirenz. Methods: The primary end point of HCV treatment was estimated by sustained virologic response 12 weeks after treatment (SVR12). Results: Sixteen subjects who were followed up for 48 weeks after treatment were included. The SVR12 and SVR48 were 87.5% (95% CI: 60.4–97.8%) and 81.3% (95% CI: 53.7–95.0%), respectively. One patient experienced persistent low-level viremia of HIV after 12 weeks of treatment. Conclusion: 12 weeks of sofosbuvir/velpatasvir is safe but has limited efficacy for HCV GT3b in HIV-infected patients receiving ART regimen including efavirenz, especially among patients with baseline HCV RNA≥6.0 log10 IU/ml.

Pro-and Anti-Inflammatory Cytokines in Persistent Low-Level Viremia HIV-1 Patients on Combination Antiretroviral Therapy in Western Kenya

Pro-and Anti-Inflammatory Cytokines in Persistent Low-Level Viremia HIV-1 Patients on Combination Antiretroviral Therapy in Western Kenya

Viral and host mediators of non-suppressible HIV-1 viremia

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

Low-level HIV viraemia during antiretroviral therapy: Longitudinal patterns and predictors of viral suppression.

Our objective was to characterize longitudinal patterns of viraemia and factors associated with viral suppression in people with HIV and low-level viraemia (LLV) during antiretroviral therapy (ART). We included people with HIV in the EuResist Integrated Database with LLV following ART initiation after 2005. LLV was defined as two or more consecutive viral load (VL) measurements of 51-199 copies/mL 30-365 days apart after >12 months of ART. Viraemia patterns were analyzed over 24 months. Factors associated with viral suppression at 12 months after LLV episodes were identified using univariable and multivariable logistic regression. Of 25 113 people with HIV, 2474 (9.9%) had LLV. Among 1387 participants with 24 months of follow-up after LLV, 406 (29%) had persistent suppression, 669 (48%) had transient viraemic episodes, 29 (2%) had persistent LLV, and 283 (20%) had virological failure. Following LLV episodes, the proportion with detectable viraemia declined (p for trend <0.001 and 0.034, in the first and second year, respectively). At 12 months, 68% had undetectable VL, which was associated with suppression before LLV (adjusted odds ratio [aOR] 1.7; 95% confidence interval [CI] 1.2-2.4) and ART modification after LLV (aOR 1.6; 95% CI 1.0-2.4). The following factors were negatively associated with undetectable VL at 12 months: higher VL during LLV (aOR 0.57 per log10 copies/mL; 95% CI 0.37-0.89), injecting drug use (aOR 0.67; 95% CI 0.47-0.96), and regimens with protease inhibitors (aOR 0.65; 95% CI 0.49-0.87) or combined anchor drugs (aOR 0.52; 95% CI 0.32-0.85). Most people with LLV did not experience sustained viral suppression during 24-month follow-up, supporting the association between LLV and inferior treatment outcome.

Transcriptome analysis of CD4+ T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity

Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50–1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4+ T cell pool is a source of LLV. However, the intrinsic characteristics of CD4+ T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4+ T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4+ T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1β factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4+ T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.

Real world use of dolutegravir two drug regimens.

Since 2015, we prescribed dolutegravir (DTG)-based two drug regimens (DTG-2DR) for 620 people [total cohort 3133 (19.8%)]. Clinic database search 1 January 15 to 31 October 21. Demographic, tolerability and HIV related data analysed. In total, 620 people identified; 561 had complete data. 446 male (79.5%); median age 54 years (interquartile range 46, 59). 343 (61.1%) MSM. Nine people who initiated naïvely achieved viral suppression (100%). 546/552 (99.0%) switched or continued and were suppressed at data censor. 460/552 (83.3%) received DTG-lamivudine (DTG/3TC), 74/552 (13.4%) received DTG-rilpivirine (DTG/RPV) and 18/552 (3.3%) received DTG-emtricitabine (DTG/FTC). 70 (12.5%) switched off DTG-2DR (55 DTG/3TC, 13 DTG/RPV, two DTG/FTC) due to side-effects. 41 episodes of blip (1 off >50 copies/ml) occurred in 30 people (5.3%). 11/41 on DTG-RPV [ n = 7 multi-tablet regimen (MTR), n = 4 single tablet regimen (STR)]. 27/41 DTG-3TC, 3/41 DTG/FTC ( n = 26 MTR, n = 4 STR). Six people (1.1%) failed (confirmed viral load >200 copies/ml or persistent low level viraemia) ( n = 4 DTG-3TC STR, n = 1 DTG-3TC MTR, n = 1 DTG-RPV MTR). Four failures due to low level viraemia, one due to non-adherence and one due to high viral load. Resistance tests performed for 5/6 - mutations detected only in latter person with high viral load failure (on DTG-3TC MTR) who developed triple class resistance. Majority of experience is in DTG/3TC stable switch. Minority of patients developed side-effects. Low number of virological failures, one developed integrase inhibitor resistance. Viral failure associated with MTR, commensurate with trial data showing no failure with resistance if DTG/3TC STR used. Overall DTG-2DR demonstrates high efficacy in real-world setting.

HIV Virologic Failure among Patients with Persistent Low-Level Viremia in Nairobi, Kenya: It Is Time to Review the >1000 Virologic Failure Threshold.

Persistent low-level viremia (PLLV) of 200-999 copies/ml has been reported as a risk factor for HIV virologic failure (VF). This retrospective study was aimed at characterizing patients with PLLV, determining factors associated with VF, and determining the effect of regimen change. Data were extracted from electronic medical records for HIV care and treatment. Patients' characteristics (N = 705) were as follows: a mean age of 42 years, majority female (55%), and 51% married. A majority (78.7%) had a history of opportunistic infections in their ART lifetime. To determine factors associated with VF, 187 records on patients who maintained PLLV and 12 on deceased patients at the time of data review were eliminated from the analysis, leaving 506 patient records. Out of the 506, 89% (451/506) suppressed VL to nondetectable levels while 11% (55/506) had VF, and the difference was significant (P = 0.0001). Virologic failure was significantly associated with ages 10-30 years (P < 0.05). Baseline VL ≥ 1000 (OR 3.929; P = 0.002) and 200-999 copies/ml (OR 4.062; P = 0.004) were associated with VF. During PLLV, factors associated with VF included the following: PLLV of 200-999 copies/ml (P < 0.05), viral blips (OR 4.545; P = 0.0001), mean maximum VL (P < 0.05), and age (P = 0.043). Married marital status was inversely associated with VF (OR 0.318; P = 0.026). Regimen change was not significantly associated with virologic outcomes. However, patients who switched regimens to the second line had a high risk of VF (P = 0.028; OR 3.203). Regimen change was significantly high (P < 0.05) among adolescents and patients with a start regimen of 2NRTI+1NNRTI. Most of the PLLV patients (89%) achieved nondetectable VL after their continued ART monitoring for at least 12 months. Therefore, PLLV was not an indicator of VF. However, a consistent VL of ≥200-999 copies/ml at baseline and more than 12 months of ART care and treatment were significantly associated with VF. Patients with VL 200-999 copies/ml, adolescents, and young adults require intensive ART monitoring and support.

Inflammatory Cytokines in Persistent Low-Level Viremia in Human Immunodeficiency Virus-1 Patients on Combination Antiretroviral Therapy in Western Kenya

Inflammatory Cytokines in Persistent Low-Level Viremia in Human Immunodeficiency Virus-1 Patients on Combination Antiretroviral Therapy in Western Kenya

The virological consequences of low-level viraemia

With highly active antiretroviral therapy (ART), people living with HIV can achieve and maintain viral suppression below a detectable level, preventing transmission of HIV and AIDS-related mortality.1,2 However, persistent low-level viraemia (usually defined as plasma HIV-RNA between 50 copies per mL to below the threshold for virological failure) occurs among some people living with HIV receiving ART.3–5 Despite its occurrence, the clinical significance and management of low-level viraemia remains unclear,3,5,6 particularly with dolutegravir-based ART regimen.

HIV-1 Genotypic Resistance Testing Using Sanger and Next-Generation Sequencing in Adults with Low-Level Viremia in China

In this study, we aimed to determine drug-resistance mutations (DRMs) in HIV-1 patients with low-level viremia (LLV) and explored the performance of next-generation sequencing (NGS) in detecting HIV DRMs by using LLV samples. Overall, 80 samples with LLV were amplified and sequenced using a commercial Sanger sequencing (SS) genotyping kit. Furthermore, 51 samples successfully sequenced using SS were simultaneously subjected to NGS. Genotyping success rates of various viremia categories by two sequencing methods were calculated. Stanford HIV-1 drug-resistance database (HIVdb version 8.9) was used to analyze the DRMs.In the NGS assay, a threshold of 5% was considered for reporting low-frequency variants, and the DRMs detected using SS and NGS were compared. The overall success rate of PR/RT regions was 88.1% (67/80) using SS and 86.3% (44/51) using NGS. Furthermore, a significant linear trend was noted between viral load and the genotyping success rate. A total of 38.8% (26/67) participants harbored at least onemutation, as revealed through SS. Moreover, the prevalence of DRMs in persistent LLV was significantly higher than that in intermittent LLV (62.1% vs. 21.1%; P < 0.05). A total of 69 DRMs were detected using the two sequencing methods at the threshold of 5%. Moreover, 10 DRMs missed by SS were detected using NGS, whereas 8 DRMs missed by NGS were detected by SS. Our data suggested that the genotyping resistance testing is necessary to guide antiretroviral therapy optimization in LLV patients.

The Impact of Low-Level Viraemia on Virological Failure-Results From a Multicenter HIV Antiretroviral Therapy Cohort Study in Yunnan, China.

BackgroundHIV viral load (VL) is an important indicator to monitor treatment response in antiretroviral therapy (ART). Patients on ART may experience viral blips, with low-level elevations of VL between 50 and 999 copies/mL known as low-level viraemia (LLV), but not reaching the threshold for virological failure (≥1,000 copies/mL) defined by WHO guidelines. The objective was to investigate the long-term impact of LLV on virological failure.MethodsWe analyzed adults who were ART naïve at baseline. LLV was defined as having an VL of 51–999 copies/mL at least once. The subjects with LLV were grouped into three categories: 51–199, 200–399, and 400–999 copies/mL. Patients with multiple episodes of LLV were classified based on the highest VL result. The subjects with LLV were also grouped by the frequency of LLV, i.e., a single episode, two consecutive episodes, two intermittent episodes, more than two consecutive episodes, and more than two intermittent episodes. Multivariable Cox models were used to predict the association of LLV with virological failure.ResultsA total of 93,944 subjects were included. The median number of VL tests performed was 3. There were 21,203 LLV cases, with an overall incidence of 22.6%. Most of the LLV cases were found in subjects with LVs of 50–199 copies/mL, followed by 400–999 and 200–399 copies/mL. Most of the LLV cases experienced single episodes, and the numbers of LLV with two consecutive episodes, two intermittent episodes, more than two consecutive episodes and more than two intermittent episodes were decreased successively. The risk factors associated with virological failure include: intermediate-level (200–399 copies/mL) and high-level (400–999 copies/mL) LLV, single episodes of LLV and two or more than two consecutive episodes of LLV, which may put the subjects at a 1.28–2.26-fold higher risk for virological failure.ConclusionStrengthened immediate medical attention should be placed on patients with VL of 200–999 copies/mL. The patients having experienced LLV once should be targeted for case management and repeat VL testing within 24 weeks to determine persistent LLV and monitor virological failure.

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

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. Retrospective cohort study in a tertiary hospital. 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. 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. 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.

Research status and challenges of low-level viremia in chronic hepatitis B

Persistent low-level viremia during chronic hepatitis B therapy can promote drug-resistant mutations, liver fibrosis progression and even hepatocellular carcinoma occurrence, which further seriously affect the prognosis of patients. Herein, we hope to clarify and analyze the possible occurrence mechanisms and clinical outcomes of low-level viremia by sorting out the key points, so as to assist in the adjustment of individualized treatment plans and provide references for the diagnosis and treatment.