Background: In acute HIV infection in humans, HIV-specific CD8+ T cells are critical for the initial control of HIV infection. CD3+CD8low T cells are recognized as a subset of CD8+ T cells with down-regulated CD8 expression, whose increase is observed in patients infected with chronic HIV infection, but little is known about whether HIV-1 suppression benefits from low CD8 expression on CD8 T subpopulation during acute infection stage in the absence of antiretroviral therapy (ART).

Materials & Methods: A total of nineteen acute HIV-1-infected individuals in 1st, 3rd month, and 1st year after infection were enrolled from the Beijing Primo Cohort in this study to evaluate HIV-1-specific effector functions of CD3+CD8low T cells. Samples of 20 individuals in chronic HIV infection were also analyzed, and without ART. Immunophenotypic and functional characterization of CD3+CD8low and CD3+CD8hi T cells were analyzed by the multicolor flow cytometry. HIV-specific CD8 T-cell responses were measured by quantifying interferon gamma (IFN-γ) release with an intracellular cytokine staining assay, and the degranulation (CD107a) of CD8 subpopulations were also measured in untreated individuals with acute/chronic HIV-1 infection.

Results: We found for the first time that CD3+CD8low cells quickly expanded after HIV-1 infection and lasted for a short time, and then decreased until to the chronic phase of infection, while CD3+CD8hi T cells were significantly increased from the 1st year of HIV infection to chronic infection over 2 years. Interestingly, the immune activation of CD3+CD8low cells was significantly higher than that in CD3+CD8hi T cells at different stage of HIV infection (all p<0.05). In addition, we observed that a comparable proportion of CD3+CD8hi and CD3+CD8low T cells produced HIV-1-specific IFN-γ on the 1st, 3rd month and 1st year of infection, while the levels of CD3+CD8low T cell expressing CD107a degranulation were lower in untreated individuals after 3rd month of HIV-1 infection than those induced in CD3+CD8hi T cells.

Conclusions: Our findings suggest that a better understanding of the involvement of CD3+CD8low T subpopulation at the earliest stage of HIV infection would significantly improve our knowledge of the impaired T-cell responses in HIV-1-infected patients, which has important implications for HIV vaccine development.

Background
The Torque Teno Virus (TTV) is a single-stranded DNA anellovirus and part of the human virome. Clinical manifestations associated with the virus are unknown, but the TTV-DNA plasma concentration has been identified as predictive marker for risk assessment in immunosuppressed patients after transplantation.
In the context of HIV-1 infections, a prediction of the course of immune reconstitution (IR) upon initiation of combined antiretroviral therapy (cART) may contribute to guide individualized treatment. Thus, this work aimed to measure if the extent of TTV plasma concentration correlates with the amount of IR in these patients.

Methods
301 plasma samples of therapy-naïve HIV-1-infected patients of the RESINA cohort were retrospectively analyzed. TTV-DNA was quantified according to Maggi F et al., J Virol 2003. TTV plasma level were correlated to CD4 cell count, HIV load, age and sex. Patients were subdivided, according to their initial CD4 cell count (<100, 100-200, 200-350, >300 CD4 cells/μl) and the extent of CD4 cell count increase within the first year with cART (<50, 50-200, >200 CD4 cells/μl).

Results
TTV plasma DNA was detectable in 96% of the samples. The median TTV plasma concentration was 235,844 copies/ml. Baseline CD4 cell count correlated significantly negative to TTV plasma concentration (p=0.037).
Analyzing IR, patients with a CD4 cell recovery <50 cells/µl within the first year on cART presented TTV viremia in 100%. Notably, compared to patients with CD4 cell count increase of >200 CD4 cell/µl, patients lacking a robust increase showed significantly higher TTV plasma concentrations (median 481,963 cop/ml versus 97,471 cop/ml; p=0.011).
Overall, CD4 cell recovery within the first year of cART correlated negatively to TTV plasma concentration and baseline CD4 cell count (p=0.001).

Conclusion
There is a high prevalence of TTV viremia within the RESINA cohort. Significantly higher TTV plasma concentrations in patients with low CD4 cell counts prior cART initiation compared to those with higher CD4 cell counts were confirmed. Remarkably, higher TTV plasma concentrations correlated with reduced CD4 cell recovery within the first year on cART, indicating a more severe immune defect. In summary, this study shows that TTV plasma concentration before initiation of cART is predictive for the amount of IR in HIV-infected patients with severe immunodeficiency.

Background: During antiretroviral therapy (ART), HIV-1-infected patients may present with ultrasensitive (US) HIV-RNA viral loads (VL) below quantification levels of current assays. Reasons for US-VL detection and its relation to virological rebound (VR) are unclear. The purpose of this study was to determine the virological, immunological and therapeutic correlates of US -VL detection in a large group of ART-naïve patients from outpatient clinics initiating more recent ART combinations. Furthermore, we aimed to use long-term repeated sampling of US-VLs during treatment in order to more concretely establish the effect of persistent residual viremia on VR.
Methods: HIV-1-infected, ART-naïve patients followed at two university hospitals were included. HIV-RNA had to be >200 copies/mL at ART-initiation and VL<50 copies/mL achieved during ART. US-VL was defined as an undetectable PCR signal from a commercially-available assay (COBAS® TaqMan, Roche). Random-effect Poisson regression was used for assessing determinants of US-VL<1 copy/mL over time and conditional risk-set analysis for VR (one VL>200 copies/mL or two VL>50 copies/mL), while accounting for frequency of VL measurements.
Results: Between 2009-2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTI) plus a non-NRTI (29.4%), protease inhibitor (58.4%) or integrase-strand transfer inhibitor (INSTI) (12.1%). During a median 3.4 years (IQR=2.3-4.6), 676 (94.3%) patients achieved US-VL<1 copy/mL. In multivariable analysis, US-VL<1 copy/mL over time was associated with decreased age (p<0.001), female gender (p=0.04), lower baseline VL (p<0.001), baseline CD4+ >500 versus <350/mm3 (p<0.001), and INSTI-containing ART (p=0.009). 131 (18.3%) patients had VR during follow-up, which was independently associated with CD4/CD8 ratio <0.8 during follow-up (p=0.01) and time spent <1 copy/mL (p<0.001). When US-VL<1 copy/mL occurred ≥50% of follow-up duration (n=290), faster time to US-VL<1 copy/mL (p<0.001), faster CD4+ T-cell count increase (p=0.03), and faster CD4/CD8 ratio increase (p=0.001) were observed.
VR occurred 237 times during follow-up and was defined by two consecutive HIV-RNA VL >50 copies/mL for 102 (43.0%) VRs, one HIV-RNA VL >200 copies/mL for 124 (52.3%) VRs, or both criteria for 11 (4.6%) VRs. In multivariable analysis accounting for conditional risk-sets (Model 1), VR was associated with having a CD4/CD8 <0.8 during follow-up (p=0.01) and higher number of HIV-RNA VL tests/year (p=0.001). When replacing cumulative duration under <1 copy/mL with ART regimen in the final multivariable model (given the collinearity between these two variables), longer periods of US-VL suppression were significantly and inversely associated with VR (Model 2). Patients with VR during follow-up had a significantly longer time until achieving HIV-RNA <1 copy/mL (p<0.001), slower increase in CD4+ T-cell count (p=0.04), and slower increase in CD4/CD8 ratio (p<0.001) than those without VR.
Conclusion: This study demonstrated the effect of ART regimen and immune status not only on residual viremia but also subsequent VR during a median follow-up of more than 3 years. Indeed VL-suppression at ultrasensitive level is associated with INSTI-class ART initiation. Moreover, given the association between residual viremia and immune activation, INSTI class antiretrovirals, a preferred third agent for first-line ART according to current recommendations, could also lead to improvement in immunological parameters and possibly reduced inflammation.

Background

Since the introduction of effective combination ART, combining at least three antiretroviral agents to reduce the risk of treatment failure has been standard of care. The higher barrier to resistance of newer drugs has led to increased interest in simplified treatment strategies. Recent studies show that certain dual regimens are effective in maintaining virologic suppression in treatment-experienced patients. Consequently, both European and US guidelines currently recommend dual therapy to selected virologically suppressed persons. This is still a new treatment strategy, however, and more studies with longer follow-up are warranted to guarantee long-term safety of dual therapy.
Here, we assess the efficacy of dual regimen as switch in patients with undetectable VL as a retrospective study on the EuResist data set. The potential benefits of two-drugs regimens include reduced toxicity, lower cost, fewer drug-to-drug interactions, improved tolerability and possibly increased adherence to treatment. Several clinical trials have shown non-inferiority for dual regimens as maintenance therapy, and the strategy with dual regimen as switch has been tried at several European sites. EuResist Integrated Data Base thus contains real-world data on dual regimen after switch.

Materials & Methods

This retrospective study uses the EuResist Integrated Database. EuResist is a meta database of HIV related data. At present, the central database contains data from >81.000 patients, including >100,000 genotypes, >170,000 treatments, >1 million viral load and >1 million CD4 data.
Patients were selected into either the dual therapy or triple therapy treatment group. Older treatment combinations were disregarded. Both groups need to have a VL (viral load) measurement shorty before switch with VL under 50 cp/mL and multiple viral load measurements while on therapy. Viral failure was defined as two consecutive VL measurements with VL over 200.
The triple therapy cases were then selected via propensity score matching to contain similar covariates gender, age, route of transmission and cd4 at start resulting in 994 cases in either group.
Those data were used to generate Kaplan Meier curves for the dual and triple therapy groups. Afterwards, a TOST (two-one-sided-t-test) was performed comparing the Kaplan Meier estimator at 48 weeks, the endpoint for most prospective studies in this area.

Results

We found no significant difference between the two treatment groups in the Kaplan Meier curve p=0.99. We found a 98% likelihood of success (no virological failure) 48 weeks after switch, regardless of regimen. The two-one-sided-t-test at week 48 showed that Dual-therapy was significantly non-inferior compared to triple-therapy (95% confidence interval for the difference -0.002–0.000; equivalence defined as ±0.005).

Conclusions

Our results showed that in a real-life clinical setting, dual therapy has a similar success rate compared to triple therapy. Therefore, we consider dual therapy as a valuable addition in HIV management.

*Presenting on behalf of the authors.

Background: The overall goal of HIV therapy is to maintain virologic suppression over the entire course of a patient’s treatment. Despite that the clinical significance and subject management of transient “blips” remains controversial, their appearance may lead to concerns about the durability of an antiretroviral therapy regimen. Within the SWORD trial, we assessed elevated viral load (VL), including blips during 2 years of study conduct, with the 2-drug regimen (2DR) of dolutegravir (DTG) + rilpivirine (RPV).

Materials & Methods: SWORD-1 and SWORD-2 are identical open-label, multicenter, global, phase III, non-inferiority studies evaluating the efficacy and safety of switching from current antiretroviral regimen (CAR) to DTG+RPV once daily in HIV-1-infected adults with HIV-1 RNA <50 c/mL (VL<50 c/mL) and no history of virologic failure. Participants switched to either DTG+RPV on Day 1 (Early Switch [ES] DTG+RPV group) or remained on CAR (CAR group) and switched to DTG+RPV at Week 52 (Late Switch [LS] DTG+RPV group) if still on the study and experienced viral suppression. US FDA Snapshot algorithm uses HIV-1 RNA 50 c/mL as the viral suppression cut-off. Patients with ≥1 on-treatment VL ≥50 c/mL were categorized as either: (1) participants with VL between 50 and 200 c/mL and no VL ≥200 c/mL or (2) participants with ≥1 VL ≥200 c/mL. Blips were defined as any VL between 50 and 200 c/mL preceded and followed by VL <50 c/mL.

Results: 1024 participants were randomized and exposed (DTG+RPV, 513; CAR, 511) across both studies. At Week 100 in the ES DTG+RPV group, 456 (89%) participants had Snapshot VL <50 c/mL and 6 (1.2%) met confirmed virologic withdrawal (CVW) criterion. In the LS DTG+RPV group, 444 (93%) had Snapshot VL <50 c/mL and 2 (<1%) met CVW criterion. During the first year of exposure to DTG+RPV, 34 (6.6%) and 20 (4.2%) participants had blips in the ES and LS groups, respectively. During the second year of follow-up, there were only an additional 3% of participants in the ES DTG+RPV group with blips.

Conclusions: The incidence of blips in the first year after switching to DTG+RPV 2DR was low in both the ES and LS DTG+RPV groups, and it was comparable with the 3-drug regimen (3DR) comparator and remained low in the second year. All other categories of VL>50 c/mL occurred infrequently in all groups. These results suggest no difference exists in blip rates or in any clinical consequences from VL elevations ≥200 c/mL, because efficacy rates were high and equal between arms (95% each) and CVW numbers were low DTG+RPV and traditional 3DRs of therapy.

Data included in this abstract have been previously presented at HIV Drug Therapy Glasgow; October 28-31, 2018; Glasgow, UK.