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Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART-treated HIV-1-infected patients with immune recovery. All subjects participated in EraMune 02, an open-label randomized clinical trial of ART intensification followed by a six plasmid DNA prime (envA, envB, envC, gagB, polB, nefB) and rAd5 boost HIV vaccine with matching inserts. Antibody binding levels were determined with a recently developed microarray approach. We also analyzed neutralization efficiency and antibody-dependent cellular cytotoxicity (ADCC). We found that the DNA prime-rAd5 boost vaccine induced a significant cross-clade HIV-specific antibody response, which correlated with antibody neutralization efficiency. However, despite the increase in antibody binding levels, the vaccine did not significantly stimulate neutralization or ADCC responses. This finding was also reflected by a lack of change in total CD4+ cell associated HIV DNA in those who received the vaccine. Our results have important implications for further therapeutic vaccine design and administration, especially in HIV-1 infected patients, as boosting of preexisting antibody responses are unlikely to lead to clearance of latent proviruses in the HIV reservoir.

BackgroundSpecific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation.MethodsWe compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss.ResultsAt week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss.ConclusionsBMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

ObjectiveThis article compares the effects of initiating three contemporary antiretroviral therapy (ART) regimens on progression of carotid artery intima-media thickness (IMT) over 3 years.DesignRandomized clinical trial.SettingMulticenter (26 institutions).PatientsART-naive HIV-infected individuals (n = 328) without known cardiovascular disease or diabetes mellitus.InterventionRandom assignment to tenofovir/emtricitabine along with atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL).Main outcome measuresRight-sided carotid IMT was evaluated by B-mode ultrasonography before ART initiation, and then after 48, 96, and 144 weeks. Comparisons of yearly rates of change in carotid IMT used mixed-effects linear regression models that permitted not only evaluation of the effects of ART on carotid IMT progression but also how ART-associated changes in traditional risk factors, bilirubin, and markers of HIV infection were associated carotid IMT progression.ResultsHIV-1 RNA suppression rates were high in all arms (>85%) over 144 weeks. Modest increases in triglycerides and non-high-density lipoprotein cholesterol levels were observed in the protease inhibitor-containing arms compared with decreases with RAL. In contrast, carotid IMT progressed more slowly on ATV/r [8.2, 95% confidence interval (5.6, 10.8) μm/year] than DRV/r [12.9 (10.3, 15.5) μm/year, P = 0.013]; changes with RAL were intermediate [10.7 (9.2, 12.2) μm/year, P = 0.15 vs. ATV/r; P = 0.31 vs. DRV/r]. Bilirubin and non-high-density lipoprotein cholesterol levels appeared to influence carotid IMT progression rates.ConclusionIn ART-naive HIV-infected individuals at low cardiovascular disease risk, carotid IMT progressed more slowly in participants initiating ATV/r than those initiating DRV/r, with intermediate changes associated with RAL. This effect may be due, in part, to hyperbilirubinemia.

BackgroundAchievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine.MethodsIn this multicentre, randomised, open-label, non-comparative, phase 2 clinical trial, we enrolled eligible adults 18-70 years of age with chronic HIV-1 infection on suppressive antiretroviral therapy with current CD4 count of at least 350 cells per μL and HIV DNA between 10 and 1000 copies per 10(6) peripheral blood mononuclear cells. After an 8 week lead-in of antiretroviral intensification therapy (standard dose raltegravir and dose-adjusted maraviroc based on baseline antiretroviral therapy), patients were randomly assigned (1:1) to receive antiretroviral therapy intensification alone or intensification plus injections of HIV DNA prime vaccine (4 mg VRC-HIVDNA016-00-VP) at weeks 8, 12, and 16, followed by HIV rAd5 boost vaccine (10(10) particle units of VRC-HIVADV014-00-VP) at week 32. Randomisation was computer generated in permuted blocks of six and was stratified by study site. The primary endpoint was a 0·5 log10 or greater decrease in HIV DNA in peripheral blood mononuclear cells at week 56. This study is registered with ClinicalTrials.gov, number NCT00976404.FindingsBetween Nov 29, 2010, and Oct 28, 2011, we enrolled 28 eligible patients from three academic HIV clinics in the USA. After the 8 week lead-in of antiretroviral intensification therapy, 14 patients were randomly assigned to continue antiretroviral therapy intensification alone and 14 to intensification plus vaccine. Enrolled participants had median CD4 count of 636 cells per μL, median HIV DNA 170 copies per 10(6) peripheral blood mononuclear cells, and duration of antiretroviral therapy of 13 years. The median amount of HIV DNA did not change significantly between baseline and week 56 in the antiretroviral therapy intensification plus vaccine group. One participant in the antiretroviral therapy intensification alone group reached the primary endpoint, with 0·55 log10 decrease in HIV DNA in peripheral blood mononuclear cells. Both treatments were well tolerated. No severe or systemic reactions to vaccination occurred, and five serious adverse events were recorded during the study, most of which resolved spontaneously or were judged unrelated to study treatments.InterpretationAntiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir. A multifaceted approach that includes stronger activators of HIV expression and novel immune modulators will probably be needed to reduce the latent HIV reservoir and allow for long-term control in patients off antiretroviral therapy.FundingObjectif Recherche Vaccin SIDA (ORVACS).

ObjectivesArtesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ).MethodsThis was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods.ResultsExposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC₀₋₂₄ 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC₀₋₉₆ 14,571 versus 21,648 ng·h/mL, P < 0.01). The AUCDEAQ/AUC(amodiaquine) ratio was not different between groups (ART group 116 versus control group 102, P = 0.67).ConclusionsSubjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.

BackgroundThe COVID-19 pandemic has severely impacted Europe, resulting in a high caseload and deaths that varied by country. The second wave of the COVID-19 pandemic has breached the borders of Europe. Public health surveillance is necessary to inform policy and guide leaders. ObjectiveThis study aimed to provide advanced surveillance metrics for COVID-19 transmission that account for weekly shifts in the pandemic, speed, acceleration, jerk, and persistence, to better understand countries at risk for explosive growth and those that are managing the pandemic effectively. MethodsWe performed a longitudinal trend analysis and extracted 62 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in Europe as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. ResultsNew COVID-19 cases slightly decreased from 158,741 (week 1, January 4-10, 2021) to 152,064 (week 2, January 11-17, 2021), and cumulative cases increased from 22,507,271 (week 1) to 23,890,761 (week 2), with a weekly increase of 1,383,490 between January 10 and January 17. France, Germany, Italy, Spain, and the United Kingdom had the largest 7-day moving averages for new cases during week 1. During week 2, the 7-day moving average for France and Spain increased. From week 1 to week 2, the speed decreased (37.72 to 33.02 per 100,000), acceleration decreased (0.39 to –0.16 per 100,000), and jerk increased (–1.30 to 1.37 per 100,000). ConclusionsThe United Kingdom, Spain, and Portugal, in particular, are at risk for a rapid expansion in COVID-19 transmission. An examination of the European region suggests that there was a decrease in the COVID-19 caseload between January 4 and January 17, 2021. Unfortunately, the rates of jerk, which were negative for Europe at the beginning of the month, reversed course and became positive, despite decreases in speed and acceleration. Finally, the 7-day persistence rate was higher during week 2 than during week 1. These measures indicate that the second wave of the pandemic may be subsiding, but some countries remain at risk for new outbreaks and increased transmission in the absence of rapid policy responses.

BackgroundThe emergence of SARS-CoV-2, the virus that causes COVID-19, has led to a global pandemic. The United States has been severely affected, accounting for the most COVID-19 cases and deaths worldwide. Without a coordinated national public health plan informed by surveillance with actionable metrics, the United States has been ineffective at preventing and mitigating the escalating COVID-19 pandemic. Existing surveillance has incomplete ascertainment and is limited by the use of standard surveillance metrics. Although many COVID-19 data sources track infection rates, informing prevention requires capturing the relevant dynamics of the pandemic. ObjectiveThe aim of this study is to develop dynamic metrics for public health surveillance that can inform worldwide COVID-19 prevention efforts. Advanced surveillance techniques are essential to inform public health decision making and to identify where and when corrective action is required to prevent outbreaks. MethodsUsing a longitudinal trend analysis study design, we extracted COVID-19 data from global public health registries. We used an empirical difference equation to measure daily case numbers for our use case in 50 US states and the District of Colombia as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. ResultsExamination of the United States and state data demonstrated that most US states are experiencing outbreaks as measured by these new metrics of speed, acceleration, jerk, and persistence. Larger US states have high COVID-19 caseloads as a function of population size, density, and deficits in adherence to public health guidelines early in the epidemic, and other states have alarming rates of speed, acceleration, jerk, and 7-day persistence in novel infections. North and South Dakota have had the highest rates of COVID-19 transmission combined with positive acceleration, jerk, and 7-day persistence. Wisconsin and Illinois also have alarming indicators and already lead the nation in daily new COVID-19 infections. As the United States enters its third wave of COVID-19, all 50 states and the District of Colombia have positive rates of speed between 7.58 (Hawaii) and 175.01 (North Dakota), and persistence, ranging from 4.44 (Vermont) to 195.35 (North Dakota) new infections per 100,000 people. ConclusionsStandard surveillance techniques such as daily and cumulative infections and deaths are helpful but only provide a static view of what has already occurred in the pandemic and are less helpful in prevention. Public health policy that is informed by dynamic surveillance can shift the country from reacting to COVID-19 transmissions to being proactive and taking corrective action when indicators of speed, acceleration, jerk, and persistence remain positive week over week. Implicit within our dynamic surveillance is an early warning system that indicates when there is problematic growth in COVID-19 transmissions as well as signals when growth will become explosive without action. A public health approach that focuses on prevention can prevent major outbreaks in addition to endorsing effective public health policies. Moreover, subnational analyses on the dynamics of the pandemic allow us to zero in on where transmissions are increasing, meaning corrective action can be applied with precision in problematic areas. Dynamic public health surveillance can inform specific geographies where quarantines are necessary while preserving the economy in other US areas.

Background An enhanced understanding of renal outcomes in persons with chronic HBV, HIV, and HBV/HIV coinfection is needed to mitigate chronic kidney disease in regions where HBV and HIV are endemic. Objectives To investigate changes in estimated glomerular filtration rate (eGFR) in adults with HBV, HIV or HBV/HIV enrolled in a 3 year prospective cohort study of liver outcomes in Dar es Salaam, Tanzania and initiated on antiviral therapy. Methods We compared eGFR between and within groups over time using mixed-effects models. Results Four hundred and ninety-nine participants were included in the analysis (HBV: 164; HIV: 271; HBV/HIV: 64). Mean baseline eGFRs were 106.88, 106.03 and 107.18 mL/min/1.73 m2, respectively. From baseline to Year 3, mean eGFR declined by 4.3 mL/min/1.73 m2 (95% CI −9.3 to 0.7) and 3.7 (−7.8 to 0.5) in participants with HBV and HIV, respectively, and increased by 5.1 (−4.7 to 14.9) in those with HBV/HIV. In multivariable models, participants with HBV had lower eGFRs compared with those with HIV or HBV/HIV and, after adjusting for HBV DNA level and hepatitis B e antigen (HBeAg) status, significantly lower eGFRs than those with HBV/HIV at all follow-up visits. Conclusions In this Tanzanian cohort, coinfection with HBV/HIV did not appear to exacerbate renal dysfunction compared with those with either infection alone. Although overall changes in eGFR were small, persons with HBV experienced lower eGFRs throughout follow-up despite their younger age and similar baseline values. Longer-term studies are needed to evaluate continuing changes in eGFR and contributions from infection duration and other comorbidities. [ABSTRACT FROM AUTHOR]