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The focus of this review is to examine the importance of quantifying total HIV DNA to target the HIV reservoir and the clinical implications and challenges involved in its future application in clinical practice. Despite intrinsic limitations, the quantification of total HIV DNA is currently the most widely used marker for exploring the HIV reservoir. As it allows estimating all forms of HIV DNA in the infected cells, total HIV DNA load is the biomarker of the HIV reservoir that provides most of the insights into HIV pathogenesis. The clinical role of total HIV-DNA in both untreated and treated patients is extensively supported by important lines of evidence. Thus, predictive models that include total HIV DNA load together with other variables could constitute a prognostic tool for use in clinical practice. To date, however, this marker has been primarily used in experimental evaluations. The main challenge is technical. Although the implementation of droplet digital PCR could improve analytical performance over real-time PCR, the lack of standardization has made cross-comparisons of the data difficult. An effort by investigators to compare protocols is needed. Furthermore, the main effort now should be to involve the biomedical industry in the development of certified assays for in vitro diagnostics use.

Background: this study aimed to determine the proportion of people living with HIV (PLWH) with anti-SARS-CoV-2 IgG antibodies in a large sample from a single HIV referral center in Rome, Italy, the time-frame included both the first and the second wave of the Italian COVID-19 pandemic, Methods: we conducted a cross-sectional study on stored cryopreserved samples from 1 March 2020 to 30 November 2020. Total antibodies against SARS-CoV-2 were preliminarily tested using a chemiluminescent immunoassay. Positive results were re-tested with an ELISA assay as an IgG confirmatory test, Results: overall, 1389 samples were analyzed from 1106 PLWH: 69% males, median age 53 years, 94% on antiretroviral treatment, 93% with HIV-RNA &lt, 50 copies/mL, median CD4 cell count 610 cell/µL. Our analysis revealed a total of n = 8 patients who tested IgG positive during the study period. Seroprevalence was equal to 0% in the first months (March–June), this started to increase in July and reached a maximum rate of 1.59% in October 2020. The overall seroprevalence was 0.72% (8/1106, 95% CI 0.37–1.42). Conclusion: our findings from this setting show a low IgG SARS-CoV-2 prevalence among PLWH as compared to data available from the general population.

Introduction Long-term comparative immunologic response to 13-valent pneumococcal conjugate vaccine (PCV13) versus 23-valent polysaccharide vaccine (PPV23) among HIV-infected adults has not yet been investigated. Methods In this prospective pilot study, we quantified in HIV-positive adults serotype-specific IgG concentrations of the 12 pneumococcal serotypes shared by both vaccines 5 years after vaccination with two doses of PCV13 8 weeks apart (group 1) or one dose of PPV23 (group 2) and compared them with those assessed prior to vaccination (BL) and after 1 year (T1). Comparison of immunogenicity was based on geometric mean concentration (GMC), proportion of individuals with ≥ twofold increase from BL in specific antibody concentration against ≥ 2 serotypes and percentage of individuals with serotype-specific IgG ≥ 0.35 μg/ml, ≥ 1 μg/ml and ≥ individual serotype-specific correlates of protection. Results We included 91 subjects (median CD4+ 650 cells/µl, > 90% with HIV-RNA

OBJECTIVES Two-drug antiretroviral regimens based on lamivudine (3TC) plus either a protease inhibitor (PI) or dolutegravir (DTG) are becoming increasingly popular in switch strategies. Our goal was to derive a predictive score for virological failure (VF). METHODS We retrospectively analysed data for a cohort of 587 virologically suppressed (HIV RNA

Background Direct comparisons between lamivudine plus bPIs and lamivudine plus dolutegravir as maintenance strategies in virologically-suppressed HIV positive patients are lacking. Methods Time to treatment discontinuation (TD) and virological failure (VF) were compared in a cohort of HIV+ patients on a virologically-effective ART starting lamivudine with either darunavir/r, atazanavir/r or dolutegravir. Changes in laboratory parameters were also evaluated. Results Four-hundred-ninety-four patients were analyzed (170 switching to darunavir/r, 141 to atazanavir/r, 183 to dolutegravir): median age was 49 years, with 8 years since ART start. Groups differed for age, HIV-risk factor, time since HIV-diagnosis and on ART, previous therapy and reasons for switching. Estimated proportions free from TD at week 48 and 96 were 79.8 and 48.3% of patients with darunavir/r, 87.0 and 70.9% with atazanavir/r, and 88.2 and 82.6% with dolutegravir, respectively (p

Currently approved 2-drug therapies are as effective as 3-drug regimens but could potentially lead to increased cancer risk due to less efficient immune recovery. We conducted a longitudinal cohort study in a tertiary Italian hospital to investigate HIV+ patients starting a triple therapy (TT) (2 NRTIs +3rd agent) or a dual therapy (DT) (3TC/FTC+boosted-PI, boosted-DRV+RAL, and 3TC/FTC or RPV+DTG) regimen between 2009 and 2018. The effect of DT (vs. TT) on tumor onset was evaluated by the multivariable Cox regression and the marginal structural Cox model, after estimating the inverse probability of treatment weights (IPTW). One thousand one hundred and seven patients who had a median follow-up of 4.2 person-years (py) were evaluated; 69.2% were males, with a median age of 43 years. Overall 2,513 treatments were started during the study period (479 DT, 2,034 TT). Eight tumors occurred over 965 py with DT and 35 over 3,817 py during TT (

Objectives Nucleoside reverse transcriptase inhibitor (NRTI) transmitted drug resistance mutations (TDRMs) could increase the risk of virological failure (VF) of first-line integrase strand transfer inhibitor (InSTI)-based regimens. Methods Patients starting two NRTIs (lamivudine/emtricitabine plus abacavir/tenofovir) plus raltegravir or dolutegravir were selected from the EuResist cohort. The role of NRTI genotypic susceptibility score and of specific TDRMs in VF (i.e. two consecutive viral loads > 50 HIV-1 RNA copies/mL or a single viral load ≥ 200 copies/mL after 3 months from antiretroviral therapy start) was evaluated in the overall population and according to the InSTI employed. Results From 2008 to 2017, 1095 patients were eligible for the analysis (55.5% men, median age 39 years). In all, 207 VFs occurred over 1023 patient-years of follow-up. The genotypic susceptibility score (GSS) had no effect on the risk of VF in the overall population. However, the presence of M184V/I independently predicted VF of raltegravir- but not dolutegravir-based therapy when compared with a fully-active backbone [adjusted hazard ratio (aHR) = 3.09, P = 0.035], particularly when associated with other non-thymidine analogue mutations (aHR = 27.62, P = 0.004). Higher-zenith HIV-RNA and lower nadir CD4 counts independently predicted VF. Conclusions NRTI backbone TDRMs increased the risk of VF with raltegravir-based but not dolutegravir-based regimens.

Objectives To assess the impact of switching to dolutegravir plus lamivudine maintenance therapy on the HIV cellular reservoir size. Patients and methods This was a prospective, longitudinal, matched, controlled study. We enrolled virologically suppressed patients on stable three-drug ART who switched at baseline (BL) to dolutegravir/lamivudine (DT group) or maintained triple therapy (TT group); subjects in the TT group were matched 1:1 with those in the DT group according to age, gender, years since HIV diagnosis, years on ART and anchor drug. Total blood-associated HIV DNA levels were assessed by droplet digital PCR at BL and after 48 weeks (T48). Results were expressed as log10 HIV DNA copies/106 leucocytes. Results We enrolled 40 patients in the DT group and 40 in the TT group; the two groups were homogeneous for all main characteristics except nadir CD4 cell count. At BL, HIV DNA levels were comparable between the DT and TT groups: 2.27 (IQR 1.97–2.47) and 2.26 (IQR 2.05–2.61) log10 HIV DNA copies/106 leucocytes, respectively. Change in HIV DNA load from BL to T48 was −0.105 (IQR −0.384 to 0.121, P = 0.041) in the DT group and −0.132 (IQR −0.362 to 0.046, P = 0.005) in the TT group, with a comparable decline observed between the two groups (P = 0.821). A higher HIV DNA decline was associated with higher BL CD4/CD8 ratio. Conclusions Maintenance therapy with dolutegravir/lamivudine had the same impact as the triple regimen on HIV DNA levels after 48 weeks of treatment. These data seem to support the effectiveness of a dolutegravir/lamivudine dual regimen in controlling the magnitude of the cellular reservoir (www.clinicaltrials.gov, number NCT02836782).

Here we evaluated hospitalisation rates and associated risk factors of human immunodeficiency virus (HIV)-infected individuals who were followed up in an Italian reference hospital from 1998 to 2016. Incidence rates (IR) of hospitalisations were calculated for five study periods from 1998 to 2016. The random-effects Poisson regression model was used to assess risk factors for hospitalisation including demographic and clinical characteristics. To consider that more events may occur for the same subject, multiple failure-time data analysis was also performed for selected causes using the Cox proportional hazards model. We evaluated 2031 patients. During 13 173 person-years (py) of follow-up, 3356 hospital admissions were carried out for 756 patients (IR: 255 per 1000 py). IR decreased significantly over the study period, from 634 in 1998–2000 to 126 per 1000 py in 2013–2016. Major declines were detected for AIDS-defining events, non-HIV/AIDS-related infections and neurological diseases. Older age, female sex, longer HIV duration and HCV coinfection were associated with a higher hospitalisation risk, whereas higher CD4 nadir and antiretroviral therapy were associated with a reduced risk. Influence of advanced HIV disease markers declined over time. Hospitalisation rates decreased during the study period in most causes. The relative weight of hospitalisations for non-AIDS-related tumours, cardiovascular, respiratory and kidney diseases increased during the study period, whereas those for AIDS-defining events declined.

Background Neuropsychiatric symptoms (NPs) have been reported with dolutegravir use. We hypothesized that increasing dolutegravir trough concentrations (Ctrough) and/or polymorphism in the SLC22A2 gene, encoding the organic cation transporter-2 (OCT2), which is involved in monoamine clearance in the CNS and is inhibited by dolutegravir, might be associated with NPs. Methods A cross-sectional cohort of HIV-positive patients treated with a dolutegravir-containing regimen underwent determination of allelic discrimination for SLC22A2 808 C → A polymorphism and dolutegravir Ctrough. The Symptom Checklist-90-R [investigating 10 psychiatric dimensions and reporting a general severity index (GSI)], a self-reported questionnaire and the Mini-International Neuropsychiatric Interview were offered to investigate current NPs. The effects of dolutegravir Ctrough and the SLC22A2 gene variant on NPs were explored by multivariable logistic regression. Results A cohort of 203 patients was analysed: 71.4% were male, with median age 51 years and 11 years of ART exposure. Median time on dolutegravir was 18 months. Dolutegravir was associated with different antiretroviral combinations (mainly lamivudine, 38.9%, and abacavir/lamivudine, 35.5%). SLC22A2 CA genotype was independently associated with an abnormal GSI [adjusted OR (aOR) 2.43; P = 0.072], anxiety (aOR 2.61; P = 0.044), hostility (aOR 3.76; P = 0.012) and with moderate to severe headache (aOR 5.55; P = 0.037), and dolutegravir Ctrough was associated with hostility (fourth versus first quartile aOR 6.70; P = 0.007) and psychoticism (fourth versus first quartile aOR 19.01; P = 0.008). Other NPs were not associated with SLC22A2 polymorphism or dolutegravir Ctrough. Conclusions A variant of the OCT2-encoding gene, in addition to or in synergy with higher dolutegravir Ctrough, is associated with a set of NPs observed during dolutegravir therapy.

Background The influence of HIV-1 co-receptor usage on the course of therapy in subjects fully responding to ART has been poorly investigated. Objectives To explore the relationship between co-receptor tropism and cellular reservoir size, residual viremia and subsequent virological outcome in ART-treated patients with HIV-1 RNA stable Study design Viral co-receptor usage was predicted by viral env DNA sequencing with geno2pheno interpretation (FPR20%) and classified as R5 and non-R5. Total blood-associated HIV-1 DNA levels (log10 copies/106 leukocytes) were measured by qRT-PCR (5′LTR). Residual plasma viremia was categorized as detectable (1–49 cps/mL) or undetectable ( 50 copies/mL) were evaluated over 96 weeks. Results The study included 116 subjects. Patients with R5 virus (n = 59) and non-R5 virus (n = 57) were homogeneous for the main characteristics except for the lower nadir CD4 cell count in the non-R5 group. Patients with non-R5 variants showed higher levels of HIV-1 DNA as compared to patients with R5 virus: mean 2.47 (95% CI 2.37–2.56) vs 2.17 (2.08–2.26) (p Conclusion The presence of non-R5 viral DNA variants is related to a higher probability of residual viremia and to a larger size of the cellular viral reservoir in this setting. These data highlight a potential role of viral tropism in the monitoring of HIV-1 infection in virologically controlled subject.

Background The integrase inhibitor raltegravir has been used to intensify antiretroviral therapy in patients with undetectable plasma HIV-1RNA, resulting in variable perturbation of HIV-1 nucleic acids levels in peripheral blood. Objectives We aimed at monitoring residual plasma HIV-1RNA and total cellular HIV-1DNA in virologically suppressed patients switching to raltegravir-based regimens. Study design Fifty-eight subjects on protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, with plasma HIV-1RNA levels 200 cells/μl for ≥12 months were enrolled. Thirty-four patients were from the treatment simplification RASTA randomized study switching standard therapy to a raltegravir-based regimen (RASTA group), while 24 continued a PI or NNRTI based-regimen (controls). Residual plasma HIV-1RNA (5-40 copies/mL) and HIV-1DNA were assessed at 0, 24 and 48 weeks. Results At week 0 (W0), HIV-1DNA was detected in all patients while at W48 it was detectable in 82.4% of the RASTA group vs 100% of controls (p = 0.03). There was a significant decline of HIV-1DNA at W48 in the RASTA group (mean change from baseline −0.21 [95% CI −0.41; −0.01] log 10 copies/10 6 CD4; p = 0.03) but not in controls. Ultrasensitive HIV-1RNA was detectable at baseline in 50% of RASTA group vs 67% of controls and at W48 in 32.4% vs 42%, respectively. No differences were found between HIV-1RNA levels at baseline and W48 within and between groups. Conclusions Switching successful therapy to raltegravir-based regimens may be associated with a decrease of the HIV-1 reservoir, as measured by peripheral blood cellular HIV-1DNA levels.

Objectives Definition of the optimal pneumococcal vaccine strategy in HIV-infected adults is still under evaluation. We aimed to compare immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) versus the 23-valent polysaccharide vaccine (PPSV23) in HIV-infected adults. Methods We performed a pilot, prospective controlled study enrolling HIV-infected pneumococcal vaccine-naïve outpatients, aged 18–65 years with CD4 counts ≥200 cells/μL. Eligible subjects were recruited into two parallel groups: group 1 (n = 50) received two doses of PCV13 eight weeks apart, and group 2 (n = 50) received one dose of PPSV23, as part of their standard of care. Anti-pneumococcal capsular polysaccharide immunoglobulin G concentrations were quantified by ELISA at baseline, 8, 24 and 48 weeks. Clinical and viro-immunological follow-up was performed at the same time points. Unvaccinated, age-matched HIV-negative adults (n = 100) were also enrolled as baseline controls. Results Pre-vaccination specific IgG titers for each pneumococcal antigen did not differ between study groups but they were constantly lower than those from the HIV-negative controls. After immunization, significant increases in IgG titers were observed in both study groups at each time point compared to baseline, but response to serotype 3 was blunted in group 1. Antibody titers for each antigen did not differ between study groups at week 48. Overall, the proportion of subjects achieving seroprotection and seroconversion to all serotypes was comparable between groups. A marked decrease in IgG levels over time was observed with both vaccines. No relevant adverse reactions were reported in either group. Conclusions In this population with favorable immune profile, no relevant differences were observed in immunogenicity between PCV13 and PPSV23. Both vaccines were safe and well tolerated. Trial Registration ClinicalTrials.gov NCT02123433

Introduction : Raltegravir intensification is associated with an increase in 2-LTR episomal HIV DNA= circles, indicating a persistent low-level replication, in some individuals in ART with suppressed HIV RNA. We aimed at monitoring residual plasma HIV RNA and cellular HIV DNA in virologically suppressed patients switching to a raltegravir-based regimen. Materials and Methods : Forty-six HIV-infected subjects on PI or NNRTI based-regimens, with plasma HIV RNA level 200 cells/µL for ≥12 months were enrolled. Thirty-four patients switched to raltegravir-based regimen (RASTA study group) and 12 continued a PI or NNRTI based-regimen (control group). Ultrasensitive HIV residual viremia and total PBMC HIV DNA were assessed at baseline (W0), 24 (W24) and 48 (W48) weeks. HIV RNA levels were determined by an ultrasensitive test derived from a commercial real time PCR (limit of detection 5 copies/ml). A real time PCR was used to quantify HIV DNA copy numbers in PBMCs. Results : At W0, HIV DNA was detected in all patients while at W48 it was detectable in 82.3% of RASTA group vs 100% of controls (p=0.01). The difference between the average values of HIV DNA log 10 copies/10°6 CD4 at W0 (median 3.11, IQR 2.70–3.45) and W48 (median 2.87, IQR 2.24–3.38) was statistically significant for RASTA group (p=0.035). Male gender (mean difference −0.37 log 10 copies/10°6 PBMC, p=0.023) and previous PI based-ART (mean difference +0.39 log 10 copies/10°6 PBMC, p=0.036) were predictive of HIV DNA level at W0. After adjusting for previous PI based-ART, male gender was the only variable independently associated with HIV DNA size at W0 (mean difference −0.326 log 10 copies/10°6 PBMC, 95% CI −0.641, −0.011 p=0.043). Ultrasensitive HIV-1 RNA was detectable at W0 in 50% of RASTA group versus 66.7% of controls and at W48 in 32.4% versus 45.5%, respectively. No differences were found between HIV RNA levels at W0 and W48 within and between the two groups. Conclusions : Switching to raltegravir-based regimens may be associated with a decrease of HIV reservoir, as measured by total PBMC HIV DNA. A larger sample size is required to confirm this finding. (Published: 2 November 2014) Citation: Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Bianco C et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19791 http://www.jiasociety.org/index.php/jias/article/view/19791 | http://dx.doi.org/10.7448/IAS.17.4.19791