Plasma HIV-1 RNA Research Articles

Is this atherosclerosis in patients with HIV? Data received by OCT

Abstract Background Chronic infection by HIV evolves with a vascular inflammatory action causing endothelial dysfunction. The action of the virus as well as the side effects of antiretroviral drugs contributes to the progression of cardiovascular diseases. The study aimed to characterise the changes of the structure of the coronary wall and the thickening of the intima by Optical Coherence Tomography in HIV-infected patients with or without symptoms of coronary heart disease. Methods Fifty-two HIV-infected individuals had a mean age of 49.8±11.4 years. There were 75% men, diabetes 30,8%, hypertension 30,8%, smokers 34,62% and 7,7% with cholesterol levels ≥99 mg/dl. Control group included 120 non-HIV-infected controls with coronary heart disease. All the participants from HIV-group receive ART, 100% of participants had plasma HIV RNA <20 copies/mL and 78,85% of them have symptoms of coronary artery disease. Results The average diffuse homogeneous thickening of the intima in patients with HIV was 0.67±0.24 mm, and 0.34±0.18 mm in control group, with normal values not exceeding 0.05 mm. There was impaired three-layer structure of coronary wall in 90,4% (47 of 52) HIV-infected participants and in 60% of control group, atherosclerotic plaque had only 34,62% of HIV group. All HIV-infected patients receive ART more than 5 years. Conclusion The coronary angiography and OCT demonstratedthat the inflammatory process resulting from HIV-infection or HAART may be relevant in the changes of coronary arteries in HIV-positive patients. The changes are predominantly represented by thickening of the intima, impaired three-layer structure of arterial wall and accelerating atherosclerosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Russian National Research Medical University named after N.I. PirogovCentral Clinical Hospital of Russian Academy of Science, Moscow, Russia

Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal.

The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal. Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal. Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram. The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.

Dental implants in individuals living with HIV-1: Results from a prospective study in patients undergoing highly active antiretroviral therapy.

To assess survival and success rates of dental implants and the occurrence of peri-implant diseases (mucositis/peri-implantitis) in HIV-1-infected individuals. In this prospective study, 13 HIV-1-infected individuals undergoing highly active antiretroviral therapy (with undetectable plasma HIV RNA levels, and CD4+ T cells>350/mm3 ) were followed after implant placement, as well as 13 non-HIV-1-infected matched controls. Patients enrolled in this study were followed up to 120 months (mean=40.6 months; standard deviation=22.2; range 18 -120 months). Twenty-five implants were placed in pristine healed sites for each group and bone augmentation procedures, when needed, were done only for contour augmentation. Patients were enrolled in a strict periodontal/peri-implant supportive therapy protocol with three recalls per year. The two groups were compared regarding subject-level characteristics (age, gender, smoking, diabetes) and implant-level characteristics (marginal bone level, peri-implant health status). All the implants healed uneventfully and reached 100% survival rates (after at least 18 months) in both groups. There were no significant differences between groups for peri-implant diseases (mucositis/peri-implantitis) and for all subject-level co-variables (p>.05). Only the variables dental implant prosthesis type (DIPT) (p=.021, d=.86) and follow up (p=.011, d=.77) showed statistically significant differences between groups. The findings suggest that well-controlled HIV-1-infected individuals are eligible to undergo implant therapy, achieving survival and success rates comparable to non-HIV-1-infected controls.

Natural Occurring Polymorphisms in HIV-1 Integrase and RNase H Regulate Viral Release and Autoprocessing.

Recently, a genome-wide association study using plasma HIV RNA from antiretroviral therapy-naive patients reported that 14 naturally occurring nonsynonymous single-nucleotide polymorphisms (SNPs) in HIV derived from antiretrovirus drug-naive patients were associated with virus load (VL). Those SNPs were detected in reverse transcriptase, RNase H, integrase, envelope, and Nef. However, the impact of each mutation on viral fitness was not investigated. Here, we constructed a series of HIV variants encoding each SNP and examined their replicative abilities. An HIV variant containing a Met-to-Ile change at codon 50 in integrase [HIV(IN:M50I)] was found as an impaired virus. Despite the mutation being in integrase, the virus release was significantly suppressed (P < 0.001). Transmission electron microscopy analysis revealed that abnormal bud accumulation on the plasma membrane and the released virus particles retained immature forms. Western blot analysis demonstrated a defect in autoprocessing of GagPol and Gag polyproteins' autoprocessing in the HIV(IN:M50I) particles, although Förster resonance energy transfer (FRET) assay displayed that GagPol containing IN:M50I forms a homodimer with a similar efficiency with GagPol (wild type). The impaired maturation and replication were rescued by two other VL-associated SNPs, Ser-to-Asn change at codon 17 of integrase and Asn-to-Ser change at codon 79 of RNase H. These data demonstrate that Gag and GagPol assembly, virus release, and autoprocessing are regulated by not only integrase but also RNase H. IMPORTANCE Nascent HIV-1 is a noninfectious viral particle. Cleaving Gag and GagPol polyproteins in the particle by mature HIV protease (PR), the nascent virus becomes an infectious virus. PR is initially translated as an inactive embedded enzyme in a GagPol polyprotein. The embedded PR in homodimerized GagPol polyproteins catalyzes a proteolytic reaction to release the mature PR. This excision step by self-cleavage is called autoprocessing. Here, during the evaluation of the roles of naturally emerging nonsynonymous SNPs in HIV RNA, we found that autoprocessing is inhibited by Met-to-Ile change at codon 50 in integrase GagPol. Other coexisting SNPs, Ser-to-Asn change at codon 17 in integrase or Asn-to-Ser mutation at codon 79 in RNase H, recovered this defect, suggesting that autoprocessing is regulated by not only integrase but also RNase H in GagPol polyprotein.

Prevalence of undetectable and suppressed viral load in HIV-infected pregnant women initiating Option B+\u2009in Uganda: an observational study nested within a randomized controlled trial

BackgroundViral load (VL) testing is key in monitoring adherence to antiretroviral therapy (ART) and documenting HIV treatment response. As per HIV treatment guidelines in Uganda, the first VL test is recommended 6 months after initiation of ART. Undetectable VL (uVL) at ART initiation may be helpful in detecting elite controllers in the absence of previous ART use. We investigated viral suppression at ART initiation among a cohort of HIV-positive pregnant women enrolled in the Friends for Life Circles (FLC) for Option B+ randomized controlled trial (RCT).MethodsPregnant women ≥ 18 years of age testing positive for HIV at their first antenatal care visit and starting on ART Option B+ as per the National PMTCT Program guidelines were enrolled into the FLC for Option B+ RCT in urban Kampala and rural Mityana districts of Uganda. Each participant had whole blood samples collected at enrolment to assess baseline VL. Plasma HIV-1 RNA was quantified using COBAS Ampliprep /COBAS Taqman. Baseline VL below 400 RNA copies/ml was considered as viral suppression while baseline VL below 20 RNA copies/ml was considered uVL.ResultsThe mean duration from the date of ART initiation to time of sample collection for baseline VL assessment was 4.4 days (SD 3.6). Of the 532 HIV-positive pregnant women enrolled in the FLC for Option B+ study and newly starting Option B+ without a self-reported history of prior ART use, 29 (5.5%) had uVL and 113 (21.4%) had suppressed VL at baseline. There was no association between participants’ age, gravidity, marital status, mean monthly income, educational level, disclosure of HIV status to partner, and uVL or viral suppression at baseline. However, non-disclosure of HIV status to any other person was associated with decreased odds of viral suppression at baseline (OR 0.640; 0.416–0.982).ConclusionTwenty-one percent of HIV-positive Ugandan pregnant women initiating ART (Option B+) showed virological suppression at baseline and were presumed to be “elite controllers” or to have misreported being ART-naive. Further studies are needed to better understand the biologic mechanisms of elite controllers among pregnant women as well as to differentiate elite controllers from concealed ART use.Trial Registration The trial was registered as NCT02515370 (04/08/2015) on Clinicaltrials.gov.

Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study.

In order to design effective strategies to eradicate the HIV, an understanding of persistent viral reservoirs is needed. Many studies have demonstrated HIV residual viremia prevalence in high income countries, data from low- and middle-income countries (LMIC) are limited. We assessed the prevalence, and factors associated with residual viremia in people with HIV (PWH), who were virally-suppressed on antiretroviral therapy (ART) in LMIC. We also compared residual viremia prevalence between the LMIC and US.This is a cross-sectional, retrospective study that utilized stored specimen samples from the AIDS clinical trials group (ACTG) studies A5175 and A5208. The last available sample among participants with plasma HIV RNA < 400 copies/mL for ≥3 years were tested by the HIV molecular and monitoring core gag (HMMCgag) single copy assay (SCA). Residual viremia was defined as detectable if ≥1 copy/mL. Spearman's correlation and multivariable stepwise logistic regression were used to assess associations of various factors with SCA.A total of 320 participants, 246 (77%) from LMIC and 74 (23%) from US, were analyzed. Median (IQR) age was 33 (2840) years; baseline CD4 166 (88,230) cells/mm3; HIV RNA 5.0 (4.5, 5.3) log10 copies/mL; duration of viral suppression 3.4 (3.1, 4.0) years and 48% were male. In 85 participants with information available, 53% were subtype C, 42% subtype B and 5% other subtypes. Overall prevalence of residual viremia was 57% [95% CI, 52–63] with 51% [40–63] in US and 59% [53–65] in LMIC. Among participants with detectable SCA, the median (IQR) HIV RNA was 3.8 (2.2, 8.1) copies/mL. The multivariable model conducted in LMIC participants showed that higher baseline HIV RNA was associated with detectable residual RNA (OR 2.9, 95% CI 1.8, 4.6 for every log10 increase, P < .001). After including both US and LMIC in the final model, baseline HIV RNA remained significant. No difference in SCA detestability was found between US and LMIC sites (OR 1.1 [0.6, 2.0], P = .72) after adjusting for baseline RNA and parent study.The prevalence of residual viremia between both groups were not different and more than half of the participants had detectable viremia. Higher baseline HIV RNA was independently associated with residual viremia.

No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach

ObjectiveHIV-remission strategies including kick-and-kill could induce viral transcription and immune-activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)). DesignSub-study measuring serial plasma NfL concentrations. MethodsPlasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4+ T-cells) were measured at randomisation (following ≥22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post-randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics. ResultsAt randomisation, 58 male participants had median age 32 years and CD4+ count 696 cells/μL. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4+ T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8+ count and lower body mass index. ConclusionsDespite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only.

Performance of Xpert MTB/RIF Ultra for the Diagnosis of Pulmonary Tuberculosis Using Bronchoalveolar Lavage Samples in People Living with HIV/AIDS (PLWHA) in China: A Prospective Study.

BackgroundSputum is commonly used for the diagnostic testing of pulmonary tuberculosis (PTB), but people living with HIV/AIDS (PLWHA) usually have little sputum. Moreover, the automated molecular test, Xpert MTB/RIF assay (Xpert), has a low sensitivity in PLWHA. We aimed to estimate the performance of Xpert Ultra on the detection of Mycobacterium tuberculosis (MTB) using bronchoalveolar lavage (BAL).MethodsFrom February 5, 2018 to March 30, 2019, a total of 99 PLWHA with suspected PTB at the Third People’s Hospital of Shenzhen, China, were recruited. The information on demographics and medical history, blood MTB antigen-specific interferon gamma enzyme-linked immunospot assay (T-SPOT.TB), T lymphocyte subsets, and plasma HIV RNA load were collected. Computed tomography (CT) and flexible bronchoscopy were performed, and BAL and blood samples were collected. Testing of acid-fast bacilli (AFB), tuberculosis real-time fluorescence quantitative PCR (TBDNA), Ultra, Xpert, and MTB culture were conducted.ResultsCompared to BAL MTB culture for tuberculosis diagnosis, Ultra, Xpert, T-SPOT.TB, TBDNA and AFB smear had the sensitivity of 0.96 (24/25), 0.80 (20/25), 0.84 (21/25), 0.44 (11/25), and 0.12 (3/25), respectively; and the specificity of 0.92 (68/74), 0.96 (71/74), 0.93 (69/74), 0.96 (71/74), and 0.99 (73/74), respectively. Our study found that the sensitivity of Ultra was higher than that of culture and Xpert (AUC 0.92, 0.86 and 0.84, respectively). The results also indicated that PLWHA with CD4 <200 cells/mm3 had reduced both sensitivity (from 1.00 and 0.86 to 0.94 and 0.78, respectively) and specificity (from 0.96 and 1.00 to 0.90 and 0.41, respectively) of Ultra and Xpert for the diagnosis of PTB.DiscussionOur data supported an increased sensitivity of Ultra compared to that of Xpert on BAL samples of PLWHA, regardless of the CD4 counts and reference diagnosis standards.

Neurocognitive course at 2-year follow-up in a Swiss cohort of people with well-treated HIV

Objective:The aim of this study was to examine neurocognitive course over time among people with well treated HIV.Design:The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is an ongoing, prospective, longitudinal, multicenter and multilingual study within the Swiss HIV Cohort Study (SHCS). Participants undergo neuropsychological assessment at baseline and two-yearly follow-up.Setting:Seven SHCS centres.Participants:Patients aged at least 45 years enrolled in the SHCS with fluency in the local language (French, German or Italian) and agreeing to participate in the NAMACO study: 981 participants at baseline, 720 at 2-year follow-up of whom 644 had complete data sets.Intervention:Standardized neuropsychological assessment at baseline and 2-year follow-up.Main outcome measure:Neurocognitive performance using Frascati criteria and mean z-scores.Results:Four participants (of 644, 0.6%) had plasma HIV-1 RNA more than 50 copies/ml; median CD4+ cell count was 660 cells/μl. According to Frascati criteria, 204 participants (31.7%) had neurocognitive impairment (NCI) at baseline. NCI severity in these participants changed little over 2 years and comprehensive models based on Frascati criteria were not feasible. Examining mean z-scores, however, we observed neurocognitive stability or improvement over two years in five of seven neurocognitive domains assessed. Age at least 65 years (P = 0.02) and cognitive complaints (P = 0.004) were associated with neurocognitive decline, while black race (P = 0.01) and dolutegravir treatment (P = 0.002) were associated with improvement.Conclusion:Frascati criteria were less sensitive in measuring NCI change and therefore unsuitable for following neurocognitive course in our cohort of people with well treated HIV. Examining neurocognitive course by mean z-score change, we observed stability or improvement.

Impact of HIV-1 CRF55_01B infection on the evolution of CD4 count and plasma HIV RNA load in men who have sex with men prior to antiretroviral therapy

BackgroundCRF55_01B is a newly identified HIV-1 circulating recombinant form originated from MSM in China. However, its impact on the disease progression and transmission risk has not been investigated. This study aimed to determine the impact of CRF55_01B infection on viral dynamics and immunological status so as to provide scientific evidence for further control and prevention effort on CRF55_01B. Linear mixed effect models were applied to evaluate CD4 cell count decline and viral load increase by subtype.ResultsOf the 3418 blood samples, 1446 (42.3%) were CRF07_BC, 1169 (34.2%) CRF01_AE, 467 (13.7%) CRF55_01B, 249 (7.3%) type B, and 87 (2.5%) other subtypes (CRF_08BC, CRF_01B, C). CRF55_01B had become the third predominant strain since 2012 in Shenzhen, China. CRF55_01B-infected MSM showed lower median of CD4 count than CRF07_BC-infected MSM (349.5 [IQR, 250.2–474.8] vs. 370.0 [IQR, 278.0–501.0], P < 0.05). CRF55_01B infection was associated with slower loss of CD4 count than CRF01_AE (13.6 vs. 23.3 [cells/µl]¹/²/year, P < 0.05)among MSM with initial CD4 count of 200–350 cells/µl. On the other hand, those infected with CRF55_01B showed higher median plasma HIV RNA load (5.4 [IQR, 5.0–5.9]) than both CRF01_AE (5.3 [IQR, 4.8–5.7], P < 0.05) and CRF07_BC (5.0 log10 [IQR, 4.5–5.5], P < 0.001) at the initiation of antiretroviral therapy. Furthermore, the annual increasing rate of viral load for CRF55_01B infection was significantly higher than that of CRF07_BC (2.0 vs. 0.7 log10 copies/ml/year, P < 0.01).ConclusionsThe relatively lower CD4 count and faster increase of plasma HIV RNA load of CRF55_01B-infected MSM without antiretroviral therapy suggest that CRF55_01B may lead to longer asymptomatic phase and higher risk of HIV transmission. Strengthened surveillance, tailored prevention strategies and interventions, and in-depth research focusing on CRF55_01B are urgently needed to forestall potential epidemic.

Low-Level HIV RNA in Cerebrospinal Fluid and Neurocognitive Performance: A Longitudinal Cohort Study.

Cognitive complications persist in persons with HIV during suppressive antiretroviral therapy (ART). Low levels of HIV during ART could contribute to these complications. In this study, we measured cerebrospinal fluid (CSF) HIV using a single-copy assay (SCA) to investigate a possible relationship between low-level HIV and cognition. SCA data were analyzed from 3 consecutively paired CSF-plasma specimens collected over a mean of 456 days from 96 participants on suppressive ART. Using mixed models, the presence of CSF HIV by SCA as a risk factor for worse neurocognitive performance was examined. At baseline on the SCA, 45.8% of participants had detectable plasma HIV RNA (median 8 copies/mL and interquartile range = 3-17 among detectable values) and 17.7% had detectable CSF HIV RNA (median CSF concentration= 3 copies/mL and interquartile range= 2-13 among detectable values). The frequency of CSF HIV RNA detection declined over time in CSF (P = 0.018) with a trend toward decline in plasma (P = 0.064). Detectable CSF HIV RNA during the study was associated with worse performance in the domains of recall (P = 0.014) and motor (P = 0.040) and a trend with worse overall global performance (P = 0.078). Integrase inhibitor use, although very infrequent in this cohort, was associated with better performance in 2 domains. Low-level CSF HIV RNA declines with time but is associated with worse cognitive performance in 2 domains. Additional research is needed to better understand the relationship between HIV RNA persistence during long-term ART and central nervous system complications in persons with HIV.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Association between frailty phenotype, quantification of plasma HIV-1 RNA, CD4 cell count and HAART in HIV-positive subjects: a systematic review and meta-analysis of observational studies

ABSTRACT HIV infection causes a constant activation of the immune system and contributes to an enhanced systemic pro-inflammatory cytokine milieu, which has been associated with premature aging and frailty. We performed a systematic review and meta-analysis to analyze whether the HIV-1 RNA load, CD4+ T-lymphocyte counts and exposure to HAART in HIV-positive subjects are associated with frailty phenotype. Searches were performed in PubMed, SCOPUS, Lilacs, Web of Science, Google Scholar, and OpenThesis databases. We used the odds ratio as a measure of the association. We used either a fixed or random-effects model to pool the results of individual studies depending on the presence of heterogeneity. Eleven studies were included in the review. Data from 8035 HIV-positive subjects were analyzed; 2413 of the subjects had viral load detectable, 981 had a CD4T-cell count <350 cells/μL, and 1342 had HAART exposure information. We found an association between frailty and CD4T-cell count <350 cells/μL (OR 2.68, CI 95% 1.68–4.26, I2 = 46%), HIV-1 RNA load detectable (OR 1.71, CI 95% 1.38–2.12, I2 = 0%), and protease inhibitor-containing HAART regimen (OR 2.21, CI 95% 1.26–3.89, I2 = 0%). Further studies are necessary to evaluate the effects of other factors on the development of clinical features related to frailty.

Safety and Effectiveness Analysis of Dolutegravir in Patients with HIV-1: Interim Report of Post-Marketing Surveillance in Japan.

IntroductionDolutegravir (DTG), a novel HIV-integrase strand transfer inhibitor (INSTI), is usually used with multiple antiretrovirals (ARVs) for treatment of HIV. DTG is now approved as Tivicay tablets in over 120 countries and Triumeq combination tablets (DTG/abacavir [ABC]/lamivudine [3TC]) in over 90 countries. In Japan, these formulations have been marketed since 2014 and 2015. The post-marketing prospective surveillance has been conducted as part of the HIV-Related Drug (HRD) cooperative survey aimed to collect actual drug use information in all of these DTG-treated patients in accordance with conditions for initial approvals.MethodsThe survey has been conducted to evaluate long-term safety and effectiveness of DTG since 2014, for approximately 6 years. The safety was evaluated by incidence of adverse drug reactions (ADRs) and change in body weight. The effectiveness was evaluated by plasma HIV RNA copies/mL and peripheral CD4+ cell counts.ResultsOf 2292 patients in 30 Japanese sites, 565 (24.65%) reported ADRs. The most common ADR was blood creatinine increased (4.28%). Incidence of ADRs was statistically significantly higher in patients with severe symptoms (Centers for Disease Control and Prevention [CDC] categories B and C) than those with category A, and in patients with comorbidities than those without comorbidities. Whereas incidence of ADRs was statistically significantly lower in antiretroviral therapy (ART)-experienced patients than that in ART-naïve patients. Incidence of ADRs related to suicide or self-injurious behavior was statistically significantly higher in patients with comorbidities of psychiatric disorders than those without comorbidities. The body weight tended to increase over time and those changes and percentage changes from baseline were greater in ART-naïve patients compared with ART-experienced patients. HIV RNA copies/mL and CD4+ cell counts showed favorable shifts from baseline in both ART-naïve and ART-experienced patients.ConclusionThe results of the survey identified no new safety and effectiveness risks in Japanese patients with HIV/AIDS treated with DTG.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01842-3.

Dual therapy with dolutegravir plus boosted protease inhibitor as maintenance or salvage therapy in highly experienced people living with HIV

Real-world experience with dolutegravir (DTG) plus boosted protease inhibitor (bPI) as a two-drug regimen is limited for highly experienced HIV-positive patients with virological failure or intolerance to antiretroviral therapy. Patients receiving DTG plus bPI between September 2016 and June 2019 at 15 designated hospitals for HIV care in Taiwan were retrospectively included in this study. A standardised case record form was used to collect clinical data. The primary endpoint was virological response, defined as achieving or maintaining plasma HIV-RNA <50 copies/mL at Week 48. A total of 77 patients were included; 58 (75.3%) had documented genotypic resistance to 1-4 antiretroviral classes. The most commonly used PI was darunavir (87.0%; 67/77). Seven patients (9.1%) had no virological data at Week 48, including three with loss to follow-up, one severe hyperlipidaemia, one renal failure and cardiovascular disease, one superimposed HBV infection and one death from anal cancer. The virological response rate increased from 59.7% at baseline to 90.9% at Week 24 and 85.7% at Week 48. The only patient (1.3%) with virological failure at Week 48 had poor adherence and baseline low-level resistance to darunavir with resistance-associated mutations at M46L, I50V and V82A. Compared with baseline, mean total cholesterol increased by 20.1 mg/dL and weight by 2.8 kg at Week 48, while the estimated glomerular filtration rate decreased by 14.4 mL/min/1.73m2 (both P < 0.05). We conclude that a two-drug regimen containing DTG plus bPI was effective in highly-experienced HIV-positive patients, but metabolic impact and weight gain should be closely monitored.

HIV-1 viral blips are associated with repeated and increasingly high levels of cell-associated HIV-1 RNA transcriptional activity.

Objective:Some HIV+ patients, virally suppressed on ART, show occasional ‘blips’ of detectable HIV-1 plasma RNA. We used a new highly sensitive assay of cell-associated HIV-1 RNA to measure transcriptional activity in PBMCs and production of infectious virus from the viral reservoir, in patients with and without ‘blips’.Design/methods:RNA and DNA extracted from cells in 6 ml of peripheral blood, from suppressed patients with one to two ‘blip’ episodes over the past 2 years of ART (n = 55), or no ‘blips’ (n = 52), were assayed for HIV-1 RNA transcripts and proviral DNA targeting the highly conserved ‘R’ region of the LTR. Follow-up samples were also collected. Purified CD4+ T cells were cultured with anti-CD3/CD28/CD2 T-cell activator to amplify transcription and measure replication competent virus.Results:HIV-1 RNA transcripts ranged from 1.3 to 5415 copies/106 white blood cells. ‘Blip’ patients had significantly higher levels vs. without blips (median 192 vs. 49; P = 0.0007), which correlated with: higher levels of inducible transcripts after activation in vitro, sustained higher HIV-1 transcription levels in follow-up samples along with increasing HIV-1 DNA in some, and production of replication-competent HIV-1.Conclusion:Viral ‘blips’ are significant reflecting higher transcriptional activity from the reservoir and contribute to the reservoir over time. This sensitive assay can be used in monitoring the size and activity of the HIV-1 reservoir and will be useful in HIV-1 cure strategies.

HIV-1 RNA Kinetics in Blood Plasma and in Seminal Plasma of Men Starting a Dolutegravir-Based Triple-Combination Regimen at the Time of Primary HIV-1 Infection.

We compared the proportion of participants achieving first undetectable HIV-1 RNA (VL) in seminal plasma (SP) and blood plasma (BP) in 19 men starting dolutegravir-based regimen at primary HIV infection. At baseline, median VL was 6.5 (interquartile range [IQR], 5.6-7.9) and 4.5 (IQR, 3.5-5.0) log10 copies/mL in BP and SP, respectively. Between baseline and week 48, significantly higher proportion of participants achieved first VL below limit of quantification in SP (93.0%) than in BP (84.2%; P = .008). Time to first undetectable VL was 8 weeks in SP (95% confidence interval [CI], 5.6-10.4) and 24 weeks in BP (95% CI, 14.1-33.9).

Therapeutic prediction of HIV-1 DNA decay: a multicenter longitudinal cohort study

BackgroundFactors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions.MethodsTwo sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART.ResultsThe total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (< 100 copies/106 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P < 0.001] and higher baseline CD4+ T cell count (RR = 1.72, per 100 cells/μL, P < 0.001) were significantly associated with a low total HIV-1 DNA count at week 96. In an independent cohort of 117 patients, this model achieved a sensitivity of 75.00% and specificity of 69.52%.ConclusionsBaseline total HIV-1 DNA and CD4+ T cell count are two independent predictors of total HIV-1 DNA after treatment. The derived model based on these two baseline factors provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

The symptomatology of cerebrospinal fluid HIV RNA escape: a large case-series.

To characterize the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape. Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in the United Kingdom and Italy. PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (<2 weeks-6 months), or chronic (>6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/ml determined. We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54; 50.9%), confusion (n = 20; 18.9%) and headache (n = 28; 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs. 35.3%, P = 0.0002). Sixty PWH had CSF HIV RNA at least 1000 copies/ml and presented more frequently with confusion (n = 15/60; 25.0%) compared with PWH with CSF HIV RNA less than 1000 copies/ml at presentation (n = 5/46; 10.9%; P = 0.03). Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration.

Relationship of polypharmacy to HIV RNA suppression in people aged ≥ 50 years living with HIV.

People living with HIV (PLWH) aged ≥ 50years face unique challenges regarding their medication therapies, especially antiretroviral therapy (ART). Use of ARTs, along with medications for comorbidities, may lead to adverse events, drug-drug interactions (DDIs) and poor adherence. The objective of this study was to identify the number of medications above which PLWH aged ≥ 50 years are less likely to be virally suppressed and to describe other associated patient-specific risk factors. This was a cross-sectional study of PLWH aged ≥ 50years, prescribed ART, and seen at least once in the Northwestern Infectious Disease Center between 1 June 2013 and 31 May 2015. Variables concerning medication use and comorbidities were collected. The primary outcome was the presence of an undetectable plasma HIV RNA level (viral load). Among the 621 included patients, there was a higher percentage taking ≤15 medications with an undetectable plasma HIV RNA (n=453; 80.6%) vs. patients taking >15 medications (n=40; 67.8%; P=0.03). Taking >15 medications [odds ratio (OR) 0.49; 95% confidence interval (CI) 0.26-0.96], pulmonary disease (OR 0.54; 95% CI 0.3-0.97) and CD4 T-lymphocyte count <200 cells/μL (OR 0.39; 95% CI 0.22-0.68) decreased the odds of having an undetectable plasma HIV RNA. PLWH taking >15 medications were less likely to have an undetectable HIV RNA. Further studies are needed to evaluate the impact of overall medication economic burden on clinical outcomes among PLWH ≥50years of age.