Table 5.
| Study authors | Study design | Location/time frame | Pertinent inclusion/exclusion criteria | Pertinent definitions | Results | Conclusions |
|---|---|---|---|---|---|---|
| Amstutz, A, 202034 | Multicentre, parallel-group, open-label superiority randomized controlled trial with 80 PLWH | Southern Africa, 2017–2019 | Inclusion: HIV-positive patients taking NNRTI-based first-line ART for at least 6 months Patients presented 2 VL measurements ≥100 copies/mL and one being between 100 and 999 copies/mL Exclusion: Poor adherence defined as missing at least 1 dose per month WHO stage 3 or 4 clinical conditions at enrolment On a PI at enrolment |
VS defined as VL <50 copies/mL at 36 weeks after randomization was the primary endpoint | Enrolled participants had a median age of 42 years, median baseline VL of 347 copies/mL and a median ART duration of 5.9 years; there were 40 patients randomized to both the control and switch group; participants were followed up for 36 weeks Patients who were in the switch group were switched from an NNRTI to a PI and one of the two NRTIs was also switched to one that the patient had not been on previously; lamivudine was kept for all patients; all patients had only been exposed to NRTIs and NNRTIs, the most common ART regimen was tenofovir disoproxil fumarate/lamivudine/efavirenz Patients who were in the control group stayed on standard of care, first-line NNRTI-based ART 56 (70%) patients had VLs between 100 and 599 copies/mL whilst 24 (30%) patients had VLs between 600 and 999 copies/mL; 22/40 (55%) in the switch group and 10/40 (25%) in the control group achieved VS (p=0.009); post hoc analysis concluded that, of the 55 patients that had VL 200–999 copies/mL, 54% in the switch group and 17% in the control group achieved VS No deaths, hospitalizations, or grade 3 or 4 WHO events were reported; however, adverse events were more commonly reported in patients in the switch group (p=0.002); self-reported good adherence was lower at 51% in the switch group versus 72% in the control group |
After 36 weeks, more patients in the switch group compared to the control group were able to achieve VL <20 (p=0.002), VL <100 (p=0.05), VL <200 (p=0.003), VL <400 (p=0.02) and VL <600 (p=0.04) but not VL <1000 copies/mL Sustained VF was seen in 30% and 70% in the switch and placebo groups, respectively (p=0.001) The study concluded that switching from first-line NNRTI-based ART to second-line ART regimens in patients with persistent LLV (100–999 copies/mL) resulted in increased VS and these patients were also more likely to achieve VS by week 24 instead of 36 |
| Elvstam, O, 20205 | Nationwide observational cohort study with 6956 PLWH | Sweden, 1996–2017 | Inclusion: Started cART in January 1996 or later At least 15 years old at cART initiation Had a personal identity number. Had at least 2 VL measurements 6 months after starting cART Exclusion: Those not meeting the inclusion criteria |
Cardiovascular diseases, venous thromboembolic disease, pulmonary arterial hypertension, chronic kidney disease, decompensated liver disease and non–AIDS-defining malignancies were all considered to be serious non-AIDS events Participants were categorized by their 6-month VL measurements to either 1) VS (<50 copies/mL) 2) LLV (50–999 copies/mL × 2 consecutively at least 1 month apart) 3) non-suppressed viraemia (>1000 copies/mL at least once) |
Enrolled participants had a median follow-up time of 5.7 years and a median baseline VL of 73,000 copies/mL before ART initiation 58% of enrolled participants were on a cART regimen that included a PI, 36% included NNRTI, 20% included abacavir and only 8% included an INSTI At the end of the follow-up period, 60% of patients were VS, 5% LLV 50–199 copies/mL, 4% LLV 200–999 copies/mL and 31% non-suppressed viraemia Of the 5169 individuals who achieved VS, 35% had at least one isolated VL between 50 and 999 copies/mL Patients with LLV had statistically significant higher mortality, so long as >25% of the VL measurements were >50 copies/mL Older age, male sex, injection drug use and treatment interruptions were all also associated with higher all-cause mortality |
Patients with VS were less likely to be started on a PI-based ART regimen, had lower rates of prior cART use and were more likely to be included in a later date of the study Adjusting the ART did not change the increased all-cause mortality risk in patients with LLV Neither PI, NNRTI, INSTI or abacavir were associated with any increased risk of all-cause mortality In conclusion, LLV 50–999 copies/mL was associated with increased all-cause mortality, and patients with LLV 200–999 copies/mL were also at higher risk for SNAEs |
| Taramasso, L, 202023 | Retrospective cohort study with 1607 PLWH | Italy, 2015–2017 | Inclusion: HIV-positive patients, 18 years and older with at least one HIV-RNA measurement Exclusion: Those not meeting the inclusion criteria |
LLV was defined as VL of 50–500 copies/mL for 4 consecutive months after achieving VS on ART VF was defined as VL >1000 copies/mL and suppression as undetectable values for 6 consecutive months after LLV event |
Out of all enrolled patients throughout the study period, 21 presented with persistent LLV 7/21 (33%) of patients presented with at least one prior episode of LLV and 15/21 (71%) presented with at least one episode of VF 12 patients reported non-adherence’ of those, 3 patients had suboptimal ART and changes were made resulting in 3/3 (100%) VS; 9/12 patients had an optimal ART regimen; of those, 3 ART regimens were changed which resulted in 3/3 (100%) VS; 6/9 patients that did not change their ART regimens resulted in the first VF with only 4/6 achieving VF and 2/6 VF |
7 patients with no evidence of suboptimal ART intensified their regimen, 6 patients achieved VS by adding an INSTI-based or PI-based therapy, 1 patient had persistent LLV even after switch 6 patients with reported good adherence had adequate, fully effective ART regimens; 4 patients’ regimens were changed and 2 were left unchanged; no VF were reported; however, in patients whose regimens were changed, 75% achieved VS compared to only 50% in the unchanged arm |
| Puertas, MC, 201835 | Proof-of-concept, single-arm, pilot clinical trial with 33 PLWH | Spain, 2018 | Inclusion: HIV-positive patients that had VS (<50 copies/mL) on PI/r ART (400/100 mg lopinavir/ritonavir BID or 800/100 mg darunavir/ritonavir daily) for at least 1 year and had switched from triple ART to PI/r whilst in VS CD4+ T cell count ≥500 cells/mm3 No history of VF on PI-based therapy Exclusion: Those not meeting the inclusion criteria |
De novo infection markers include long terminal repeats (2-LTR); 2-LTR circles in CD4+ T cells are a surrogate marker of recent infection | Participants enrolled had a mean age of 47 years, median baseline VL of 5.2 log10 HIV-RNA copies/mL and had a median ART duration of 7.4 years All 33 patients (18 on darunavir/ritonavir and 15 on lopinavir/ritonavir) underwent the raltegravir intensification regimen that consisted of raltegravir 400 mg twice daily 97% of patients self-reported adherence levels >96% Isolated viral blips were seen in 4 patients with only 1 being noted in the intensification period but no VF was observed Higher amounts of residual viraemia samples between 10 and 60 copies/mL were seen in the preintensification phase (21%) and decreased in the intensification phase (7%), and increased again in the withdrawal phase (15%) 2-LTR circles were found in 18 patients, the number detected transiently increased during the first 2 months of intensification but no significant changes were noted from overall beginning to end of intensification period |
PI/r intensification with raltegravir resulted in increased low-level viral replication but decreased the frequency of detectable intermediate residual viraemia (10–60 copies/mL) suggesting that dual therapy may result in improved VS |
| Chen, GJ, 202116 | Single-centre retrospective observational cohort with 492 PLWH | NTUH, September 1, 2016 to April 20, 2017 | Inclusion: PLWH 20 years and older and received HIV care at NTUH Previous VF or intolerance to first-line NNRTI-based therapy who received boosted or unboosted PI regimens with VL <200 copies/mL for more than 6 months Exclusion: Previous treatment failure to INSTIs PLWH with emergent genotypic resistance to dolutegravir |
LLV was defined as VL between 50 and 999 copies/mL and events between 20 and 50 copies/mL were defined as VLLV The WHO definition of VF was used (>1000 copies/mL) |
Enrolled participants had a median age of 40.2 years in the dolutegravir group and 44.7 years in the PI group and had a median baseline VL of 1.3 log10 HIV-RNA copies/mL; median observation was 49 weeks Treatment arm 1: PLWH were switched to 2 NRTIs and dolutegravir regimen (DTG group); treatment arm 2: PLWH continued their PI + 2 NRTIs regimen (PI group) Of the 492 patients, 183 switched to the DTG group whilst 309 patients continued in the PI group Patients in the DTG group were younger, virologically suppressed prior to inclusion for 5 years versus 6 years, and had higher rates of previous VF (53.3% versus 19.8% in the PI group) Of all VL tests in the observation period, 96 (7.1%) qualified for VLLV with 42 in the DTG group and 54 in the PI group; of all VL tests in the observation period, 43 (3.2%) qualified for LLV with 21 in the DTG group and 22 in the PI group |
Univariate analysis concluded that the choice of the third agent in the ART regimen (dolutegravir or PI), as well as LLV or VLLV events, was significantly associated with VF Patients who were virologically suppressed for shorter amounts of time were at higher risk of LLV and VLLV even after switching regimens |
| Qin, S, 202114 | Retrospective follow-up on 1860 PLWH | Guangxi, China, 2003–2019 | Inclusion: Available baseline VL data before ART initiation ART for at least 6 months Two or more VL records during follow-up Interval between VL test not more than 12 months Exclusion: Not matching inclusion criteria |
VF defined as VL >400 copies/mL High LLV defined as 201–400 copies/mL Low LLV defined as 20–200 copies/mL |
Participants enrolled had a mean age of 40 years and a median baseline VL of 4.89 log10 HIV-RNA copies/mL Cumulative incidence rates for VF were found to be insignificant for low LLV but significant for high LLV |
Lopinavir and other PIs lead to higher rates of ART modification when compared to efavirenz ART modification is a VL high-risk factor for VF (p<0.01) |
| Joya, C, 201917 | NHS Prospective, multicentre, open cohort with PLWH, 2006 PLWH were included, this analysis was a retrospective analysis | United States, 1996–2017 | Inclusion: ART initiation during the study period who had at least 2 documented VL 6 months after initiation whilst on ART Exclusion: Those not meeting the inclusion criteria |
LLV was defined as 50–199 copies/mL, high LLV was a VL of 200–1000 copies/mL LLV was subcategorized into iLLV and persistent LLV Continuous suppression was defined as VL <50 copies/mL VF was defined as >2 consecutive VL measurements of 200 copies/mL or more or any VL of >1000 copies/mL 6 months after initiation of ART |
Participants enrolled had a median baseline VL of 4.5 log10 HIV-RNA copies/mL Definition of ART used was 2 NRTIs plus a third agent of either an INSTI, PI, NNRTI or third NRTI NNRTI-based regimens were most commonly initiated (49%) compared to unboosted PI (24%), INSTIs (11%) and boosted-PI (10%) 20% of included patients received mono or dual ARV prior to initiation of a triple regimen |
Per this study, risk factors for VF included prior mono or dual ARV use (p<0.0001) and unboosted-PI regimens (p<0.0001) Per this study, risk factors for iLLV included initiating ART with an NNRTI or INSTI, and lower rates of mono or dual ARV use prior to initiation; iLLV was found to be protective against developing VF; therefore, the above are protective factors for VF but risk factors for iLLV |
ART, antiretroviral therapy; ARV, antiretroviral; cART, combined antiretroviral therapy; DTG, dolutegravir; iLLV, intermittent low-level viraemia; INSTI, integrase strand transfer inhibitor; LLV, low-level viraemia; LTR, long terminal repeats; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NTUH, National Taiwan University Hospital; PI, protease inhibitor; PI/r, protease inhibitor boosted with ritonavir; PLWH, people living with HIV; SNAE, serious non-AIDS events; VF, virological failure; VL, viral load; VLLV, very-low-level viraemia; VS, virological suppression; WHO, World Health Organization.