Intersections between HIV and obesity in emerging economies.

PURPOSE OF REVIEW: HIV epidemics are increasing in many emerging economy countries, whilst the very process of 'economic emergence' is obesogenic. Annual deaths related to obesity and overweight are now four times more than for HIV globally. We describe the intersections between HIV and obesity in emerging economies, and highlight potential mitigation options, including antiobesity medications (AOMs), which are safe and effective, but inaccessibly priced. RECENT FINDINGS: We summarize what is known about weight-change in HIV and review strategies including public health policies and clinical interventions for emerging economy countries to fight obesity. We also illustrate the landscape from a selection of 'emerging economy' countries with available data from UNAIDS, World Bank and World Obesity Federation to visualize the developing challenges faced. AOM course prices are high in many countries, but could be manufactured and sold profitably for much less. We present lessons from the early HIV/AIDS movements on how to improve access and pricing for AOMs for people with HIV with obesity in emerging economy countries. SUMMARY: We illustrate the complex intersectional issues that 'emerging economy countries' may experience, with a 'double burden' of increasing HIV and obesity epidemics, and explore potential mitigation options, focussing on AOM access and pricing.

Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment.

OBJECTIVE: Novel antiobesity treatments are highly effective in recent clinical trials. Access to these medications is needed to supplement lifestyle and surgical interventions for millions living with obesity worldwide, but high prices are limiting. This study aimed to review current treatment costs and calculate potential estimated minimum prices (EMPs). METHODS: The authors searched national drug price databases across various countries for orlistat, naltrexone-bupropion, topiramate-phentermine, liraglutide, semaglutide, and tirzepatide. EMPs for antiobesity medications were calculated using established methodology, using active pharmaceutical ingredients (API) from the Panjiva database. EMPs were calculated per 30-day course and include costs of active pharmaceutical ingredients, excipients, formulation, taxation, and 10% profit margin. RESULTS: National prices of antiobesity medications were significantly higher than calculated EMPs. Semaglutide 30-day course prices ranged from $804 (United States) to $95 (Turkey) while the EMP was $40. Liraglutide prices ranged from $1418 (United States) to $252 (Norway) while the EMP was $50. Some oral treatments could be generically manufactured at very low costs per course ($7 for orlistat; $5 for phentermine/topiramate combination tablets), while naltrexone/bupropion was more expensive ($54). CONCLUSIONS: This study shows that certain weight loss treatments can be manufactured and sold profitably at low costs, but prices currently range widely between countries, limiting access for those in need.

Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Efficacy of Approved Versus Unapproved Vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Randomized Blinded Clinical Trials.

Background: Five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca, and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Zifivax, Medicago, Clover, and Cansino, but they are not approved in high-income countries. This meta-analysis compared the efficacy of US Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved and -unapproved vaccines in randomized clinical trials (RCTs). Methods: A systematic review of trial registries identified RCTs of SARS-CoV-2 vaccines. Risk of bias was assessed using the Cochrane tool (RoB 2). In the meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method). Results: Twenty-two RCTs were identified and 1 was excluded for high-risk of bias. Ten RCTs evaluated 5 approved vaccines and 11 RCTs evaluated 9 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% confidence interval [CI], 68%-92%) for approved vaccines versus 72% (95% CI, 66%-77%) for unapproved vaccines, with no significant difference between vaccine types (P = .12). Prevention of severe SARS-CoV-2 infection was 94% (95% CI, 75%-98%) for approved vaccines versus 86% (95% CI, 76%-92%) for unapproved vaccines (P = .33). The risk of serious adverse events was similar between vaccine types (P = .12). Conclusions: This meta-analysis of 21 RCTs in 390 459 participants showed no significant difference in efficacy between the FDA/EMA-approved and -unapproved vaccines for symptomatic or severe infection. Differences in study design, endpoint definitions, variants, and infection prevalence may have influenced results. New patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly.

Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

[This retracts the article DOI: 10.1093/ofid/ofab358.]

Minimum Manufacturing Costs, National Prices, and Estimated Global Availability of New Repurposed Therapies for Coronavirus Disease 2019.

BACKGROUND: Currently, only dexamethasone, tocilizumab, and sarilumab have conclusively been shown to reduce mortality of coronavirus disease 2019 (COVID-19). Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programs. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices. METHODS: We searched for repurposed drugs that have been approved by at least one of the World Health Organization, US Food and Drug Administration, or the United Kingdom National Institute of Health and Care Excellence organizations or at least given emergency use authorization or recommended for off-label prescription. Drug prices were searched for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab, and imdevimab, and sarilumab, using active pharmaceutical ingredients (APIs) data extracted from global shipping records. This was compared with national pricing data from a range of low-, medium-, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. RESULTS: Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from US $2.58 for intravenous (IV) dexamethasone (or US $0.19 orally) and US $4.34 for inhaled budesonide. No export price data were available for baricitinib, tocilizumab, casirivimab, and imdevimab, or sarilumab, but courses of these treatments have higher prices, ranging from US $6.67 for baricitinib to US $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries. CONCLUSIONS: Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whereas monoclonal antibodies and IV treatment courses are more expensive.

Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

Ivermectin is an antiparasitic drug being investigated for repurposing against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ivermectin showed in vitro activity against SARS-COV-2, but only at high concentrations. This meta-analysis investigated ivermectin in 23 randomized clinical trials (3349 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv, and trial registries. The primary meta-analysis was carried out by excluding studies at a high risk of bias. Ivermectin did not show a statistically significant effect on survival (risk ratio [RR], 0.90; 95% CI, 0.57 to 1.42; P = .66) or hospitalizations (RR, 0.63; 95% CI, 0.36 to 1.11; P = .11). Ivermectin displayed a borderline significant effect on duration of hospitalization in comparison with standard of care (mean difference, -1.14 days; 95% CI, -2.27 to -0.00; P = .05). There was no significant effect of ivermectin on time to clinical recovery (mean difference, -0.57 days; 95% CI, -1.31 to 0.17; P = .13) or binary clinical recovery (RR, 1.19; 95% CI, 0.94 to 1.50; P = .15). Currently, the World Health Organization recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.

The Joint United Nations Programme on HIV/AIDS 95-95-95 targets: worldwide clinical and cost benefits of generic manufacture.

BACKGROUND: The Joint United Nations Programme on HIV/AIDS aims for HIV testing, treatment and viral suppression rates to be 95%--95%--95% by 2025. Patented drug prices remain a barrier to HIV treatment. Generic alternatives are being produced and exported from countries without patent barriers at a fraction of the cost. METHODS: We collated export records of active pharmaceutical ingredient for HIV drugs to estimate the minimum costs of production. Using epidemiological data describing national HIV epidemics, we calculated the cost to treat 164 countries at 95%--95%-95%. Using weighted log-linear regression models, we estimated the mother-to-child transmissions (MTCTs), HIV-related deaths and new HIV infections preventable every year by increased treatment. FINDINGS: We estimated that TDF/3TC/DTG could be produced for $59 per person per year. At this price, the 164 countries in our analysis could be treated at 95%--95%--95% for $2 billion a year, preventing 66 308 MTCTs, 241 811 HIV-related deaths and 631 398 new HIV infections every year. In comparison, global expenditure on HIV pharmaceuticals in 2019 was $28 billion. INTERPRETATION: At $2 billion/year, the 164 countries in our analysis could be treated for the price of 4 weeks of current global sales. Global access to generic alternatives could reduce expenditure and improve clinical outcomes.

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial.

INTRODUCTION: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. METHODS: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. RESULTS: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. CONCLUSIONS: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.

Comparison of automated beam hardening correction (ABHC) algorithms for myocardial perfusion imaging using computed tomography.

PURPOSE: Myocardial perfusion imaging using computed tomography (MPI-CT) and coronary CT angiography (CTA) have the potential to make CT an ideal noninvasive imaging gatekeeper exam for invasive coronary angiography. However, beam hardening can prevent accurate blood flow estimation in dynamic MPI-CT and can create artifacts that resemble flow deficits in single-shot MPI-CT. In this work, we compare four automatic beam hardening correction algorithms (ABHCs) applied to CT images, for their ability to produce accurate single images of contrast and accurate MPI flow maps using images from conventional CT systems, without energy sensitivity. METHODS: Previously, we reported a method, herein called ABHC-1, where we iteratively optimized a cost function sensitive to beam hardening artifacts in MPI-CT images and used a low order polynomial correction on projections of segmentation-processed CT images. Here, we report results from two new algorithms with higher order polynomial corrections, ABHC-2 and ABHC-3 (with three and seven free parameters, respectively), having potentially better correction but likely reduced estimability. Additionally, we compared results to an algorithm reported by others in the literature (ABHC-NH). Comparisons were made on a digital static phantom with simulated water, bone, and iodine regions; on a digital dynamic anthropomorphic phantom, with simulated blood flow; and on preclinical porcine experiments. We obtained CT images on a prototype spectral detector CT (Philips Healthcare) scanner that provided both conventional and virtual keV images, allowing us to quantitatively compare corrected CT images to virtual keV images. To test these methods' parameter optimization sensitivity to noise, we evaluated results on images obtained using different mAs. RESULTS: In images of the static phantom, ABHC-2 reduced beam hardening artifacts better than our previous ABHC-1 algorithm, giving artifacts smaller than 1.8 HU, even in the presence of high noise which should affect parameter optimization. Taken together, the quality of static phantom results ordered ABHC-2> ABHC-3> ABHC-1>> ABHC-NH. In an anthropomorphic MPI-CT simulator with homogeneous myocardial blood flow of 100 ml⋅min-1 ⋅100 g-1 , blood flow estimation results were 122 ± 24 (FBP), 135 ± 24 (ABHC-NH), 104 ± 14 (ABHC-1), 100 ± 12 (ABHC-2), and 108 ± 18 (ABHC-3) ml⋅min-1 ⋅100 g-1 , showing ABHC-2 as a clear winner. Visual and quantitative evaluations showed much improved homogeneity of myocardial flow with ABHC-2, nearly eliminating substantial artifacts in uncorrected flow maps which could be misconstrued as flow deficits. ABHC-2 performed universally better than ABHC-1, ABHC-3, and ABHC-NH in simulations with different acquisitions (varying noise and kVp values). In the presence of a simulated flow deficit, all ABHC methods retained the flow deficit, and ABHC-2 gave the most accurate flow ratio and homogeneity. ABHC-3 corrected phantom flow values were slightly better than ABHC-2, in noiseless images, suggesting that reduced quality in noisy images was due to reduced estimability. In an experiment with a pig expected to have uniform flow, ABHC-2 applied to conventional images improved flow maps to compare favorably to those from 70keV images. CONCLUSION: The automated algorithm can be used with different parametric BH correction models. ABHC-2 improved MPI-CT blood flow estimation as compared to other approaches and was robust to noisy images. In simulation and preclinical experiments, ABHC-2 gave results approaching gold standard 70 keV measurements.

Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial.

BACKGROUND: New therapeutic options are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). Repurposing existing pharmaceuticals provides an immediate treatment opportunity. We assessed the efficacy of sofosbuvir and daclatasvir with ribavirin for treating patients with COVID-19. METHODS: This was a single-centre, randomized controlled trial in adults with moderate COVID-19 admitted to the Ghaem Shahr Razi Hospital in Mazandaran Province, Iran. Patients were randomly assigned to 400 mg sofosbuvir, 60 mg daclatasvir and 1200 mg ribavirin (intervention group) or to standard care (control group). The primary endpoint of this study was length of hospital stay. This study is registered by IRCT.ir under the ID: IRCT20200328046886N1. RESULTS: Between 20 March 2020 and 8 April 2020, 48 patients were recruited; 24 patients were randomly assigned to the intervention group and 24 to the control group. The median duration of hospital stay was 6 days in both groups (P = 0.398). The number of ICU admissions in the sofosbuvir/daclatasvir/ribavirin group was not significantly lower than the control group (0 versus 4, P = 0.109). There was no difference in the number of deaths between the groups (0 versus 3, P = 0.234). The cumulative incidence of recovery was higher in the sofosbuvir/daclatasvir/ribavirin arm (Gray's P = 0.033). CONCLUSIONS: This randomized trial was too small to make definitive conclusions. There were trends in favour of the sofosbuvir/daclatasvir/ribavirin arm for recovery and lower death rates. However, there was an imbalance in the baseline characteristics between the arms. Larger randomized trials should be conducted to investigate this treatment further.

Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial.

BACKGROUND: Currently no effective antiviral therapy has been found to treat COVID-19. The aim of this trial was to assess if the addition of sofosbuvir and daclatasvir improved clinical outcomes in patients with moderate or severe COVID-19. METHODS: This was an open-label, multicentre, randomized controlled clinical trial in adults with moderate or severe COVID-19 admitted to four university hospitals in Iran. Patients were randomized into a treatment arm receiving sofosbuvir and daclatasvir plus standard care, or a control arm receiving standard care alone. The primary endpoint was clinical recovery within 14 days of treatment. The study is registered with IRCT.ir under registration number IRCT20200128046294N2. RESULTS: Between 26 March and 26 April 2020, 66 patients were recruited and allocated to either the treatment arm (n = 33) or the control arm (n = 33). Clinical recovery within 14 days was achieved by 29/33 (88%) in the treatment arm and 22/33 (67%) in the control arm (P = 0.076). The treatment arm had a significantly shorter median duration of hospitalization [6 days (IQR 4-8)] than the control group [8 days (IQR 5-13)]; P = 0.029. Cumulative incidence of hospital discharge was significantly higher in the treatment arm versus the control (Gray's P = 0.041). Three patients died in the treatment arm and five in the control arm. No serious adverse events were reported. CONCLUSIONS: The addition of sofosbuvir and daclatasvir to standard care significantly reduced the duration of hospital stay compared with standard care alone. Although fewer deaths were observed in the treatment arm, this was not statistically significant. Conducting larger scale trials seems prudent.

Minimum costs to manufacture new treatments for COVID-19.

INTRODUCTION: 'Repurposing' existing drugs to treat COVID-19 is vital to reducing mortality and controlling the pandemic. Several promising drugs have been identified and are in various stages of clinical trials globally. If efficacy of these drugs is demonstrated, rapid, mass availability at an affordable cost would be essential to ensuring equity and access especially amongst low- and middle-income economies. METHODS: Minimum costs of production were estimated from the costs of active pharmaceutical ingredients using established methodology, which had good predictive accuracy for medicines for hepatitis C and HIV amongst others. Data were extracted from global export shipment records or analysis of the route of chemical synthesis. The estimated costs were compared with list prices from a range of countries where pricing data were available. RESULTS: Minimum estimated costs of production were US $0.93/day for remdesivir, $1.45/day for favipiravir, $0.08/day for hydroxychloroquine, $0.02/day for chloroquine, $0.10/day for azithromycin, $0.28/day for lopinavir/ritonavir, $0.39/day for sofosbuvir/daclatasvir and $1.09/day for pirfenidone. Costs of production ranged between $0.30 and $31 per treatment course (10-28 days). Current prices of these drugs were far higher than the costs of production, particularly in the US. CONCLUSIONS: Should repurposed drugs demonstrate efficacy against COVID-19, they could be manufactured profitably at very low costs, for much less than current list prices. Estimations for the minimum production costs can strengthen price negotiations and help ensure affordable access to vital treatment for COVID-19 at low prices globally.

Rare giant inguinal hernia causing end-stage dialysis-dependent renal failure.

A 72-year-old man presented with urinary retention, weight loss, haematuria and severe acute kidney injury. He had never before been admitted to hospital and his past medical history included only an inguinal hernia. On examination, he appeared uraemic and had a right-sided painful hernia. A three-way catheter was inserted, bladder washouts performed and irrigation started. An ultrasound showed severe bilateral hydronephrosis and a 'thickened bladder' and this was thought to be obstructive uropathy secondary to bladder cancer. Twenty-four hours later his hernia doubled in diameter, became incarcerated and a CT of the abdomen and pelvis showed an inguinal hernia of both bladder and bowel, with the catheter tip inside the bladder hernia. He was taken to theatres and an open mesh repair was performed with a rigid cystoscopy to assist in locating and reducing the bladder. He required intensive care and dialysis postoperatively and remains on regular dialysis following discharge.

Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy.

BACKGROUND: The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs. METHODS: Four pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class "congenital or familial disorders" were searched for NTDs. RESULTS: NTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators. CONCLUSIONS: Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

SLICR super-voxel algorithm for fast, robust quantification of myocardial blood flow by dynamic computed tomography myocardial perfusion imaging.

We created and evaluated a processing method for dynamic computed tomography myocardial perfusion imaging (CT-MPI) of myocardial blood flow (MBF), which combines a modified simple linear iterative clustering algorithm (SLIC) with robust perfusion quantification, hence the name SLICR. SLICR adaptively segments the myocardium into nonuniform super-voxels with similar perfusion time attenuation curves (TACs). Within each super-voxel, an α-trimmed-median TAC was computed to robustly represent the super-voxel and a robust physiological model (RPM) was implemented to semi-analytically estimate MBF. SLICR processing was compared with another voxel-wise MBF preprocessing approach, which included a spatiotemporal bilateral filter (STBF) for noise reduction prior to perfusion quantification. Image data from a digital CT-MPI phantom and a porcine ischemia model were evaluated. SLICR was ∼ 50 -fold faster than voxel-wise RPM and other model-based methods while retaining sufficient resolution to show clinically relevant features, such as a transmural perfusion gradient. SLICR showed markedly improved accuracy and precision, as compared with other methods. At a simulated MBF of 100 mL/min-100 g and a tube current-time product of 100 mAs (50% of nominal), the MBF estimates were 101 ± 12 , 94 ± 56 , and 54 ± 24 mL / min - 100 g for SLICR, the voxel-wise Johnson-Wilson model, and a singular value decomposition-model independent method with STBF, respectively. SLICR estimated MBF precisely and accurately ( 103 ± 23 mL / min - 100 g ) at 25% nominal dose, while other methods resulted in larger errors. With the porcine model, the SLICR results were consistent with the induced ischemia. SLICR simultaneously accelerated and improved the quality of quantitative perfusion processing without compromising clinically relevant distributions of perfusion characteristics.

Most new HIV infections, vertical transmissions and AIDS-related deaths occur in lower-prevalence countries.

OBJECTIVES: The Joint United Nations Programme on HIV/AIDS (UNAIDS) targets aim to reduce new HIV infections below 500,000 per year by 2020. Despite targeted prevention programmes, total new infections remained in 2016 and 2017 at 1,800,000 cases. We have aimed to analyse data from 2017 and to compare HIV incidence, AIDS-related deaths and provision of antiretroviral therapy (ART) to adults, pregnant women and children living with HIV in lower- and higher-prevalence countries. Vertical or mother-to-child transmission (MTCT) and early infant diagnosis (EID) rates were also investigated. METHODS: UNAIDSinfo data use the Spectrum model to represent country-level HIV data. Countries with epidemics over 40,000 HIV cases were separated into higher prevalence (≥4.5%) and lower prevalence (<4.5%). Least squares linear regression, weighted by epidemic size and controlled for gross domestic product/capita, was used to compare HIV prevalence with estimated ART coverage in adults (≥15 years), children (0-14 years), pregnant women, and EID rates and MTCT rates. Data were then compared between higher- and lower-prevalence groups, including numbers of new HIV infections and AIDS-related deaths. RESULTS: Data were available for 56 countries. Twelve higher-prevalence countries accounted for 16.7 million and 44 lower-prevalence ones for 15.1 million people living with HIV, altogether making up 87.5% of the global estimate. Lower-prevalence countries had less ART coverage for adults, pregnant women and children, lower EID rates and higher AIDS-related death levels. There were more new HIV infections in adults and children in lower- than higher-prevalence countries. CONCLUSIONS: Most new HIV infections, MTCTs and AIDS-related deaths occurred in countries with an HIV prevalence rate below 4.5%. Many of these countries are not targeted by access programmes, such as the President' Emergency Plan for AIDS Relief. More intensive programmes of diagnosis and treatment are needed in these countries in the effort to reduce global new HIV infections below 500,000 per year by 2020.

Calibration-free beam hardening correction for myocardial perfusion imaging using CT.

PURPOSE: Computed tomography myocardial perfusion imaging (CT-MPI) and coronary CTA have the potential to make CT an ideal noninvasive imaging gatekeeper exam for invasive coronary angiography. However, beam hardening (BH) artifacts prevent accurate blood flow calculation in CT-MPI. BH correction methods require either energy-sensitive CT, not widely available, or typically, a calibration-based method in conventional CT. We propose a calibration-free, automatic BH correction (ABHC) method suitable for CT-MPI and evaluate its ability to reduce BH artifacts in single "static-perfusion" images and to create accurate myocardial blood flow (MBF) in dynamic CT-MPI. METHODS: In the algorithm, we used input CT DICOM images and iteratively optimized parameters in a polynomial BH correction until a BH-sensitive cost function was minimized on output images. An input image was segmented into a soft tissue image and a highly attenuating material (HAM) image containing bones and regions of high iodine concentrations, using mean HU and temporal enhancement properties. We forward projected HAM, corrected projection values according to a polynomial correction, and reconstructed a correction image to obtain the current iteration's BH corrected image. The cost function was sensitive to BH streak artifacts and cupping. We evaluated the algorithm on simulated CT and physical phantom images, and on preclinical porcine with optional coronary obstruction and clinical CT-MPI data. Assessments included measures of BH artifact in single images as well as MBF estimates. We obtained CT images on a prototype spectral detector CT (SDCT, Philips Healthcare) scanner that provided both conventional and virtual keV images, allowing us to quantitatively compare corrected CT images to virtual keV images. To stress test the method, we evaluated results on images from a different scanner (iCT, Philips Healthcare) and different kVp values. RESULTS: In a CT-simulated digital phantom consisting of water with iodine cylinder insets, BH streak artifacts between simulated iodine inserts were reduced from 13 ± 2 to 0 ± 1 HU. In a similar physical phantom having higher iodine concentrations, BH streak artifacts were reduced from 48 ± 6 to 1 ± 5 HU and cupping was reduced by 86%, from 248 to 23 HU. In preclinical CT-MPI images without coronary obstruction, BH artifact was reduced from 24 ± 6 HU to less than 5 ± 4 HU at peak enhancement. Standard deviation across different regions of interest (ROI) along the myocardium was reduced from 13.26 to 6.86 HU for ABHC, comparing favorably to measurements in the corresponding virtual keV image. Corrections greatly reduced variations in preclinical MBF maps as obtained in normal animals without obstruction (FFR = 1). Coefficients of variations were 22% (conventional CT), 9% (ABHC), and 5% (virtual keV). Moreover, variations in flow tended to be localized after ABHC, giving result which would not be confused with a flow deficit in a coronary vessel territory. CONCLUSION: The automated algorithm can be used to reduce BH artifact in conventional CT and improve CT-MPI accuracy particularly by removing regions of reduced estimated flow which might be misinterpreted as flow deficits.

The role of acquisition and quantification methods in myocardial blood flow estimability for myocardial perfusion imaging CT.

In this work, we clarified the role of acquisition parameters and quantification methods in myocardial blood flow (MBF) estimability for myocardial perfusion imaging using CT (MPI-CT). We used a physiologic model with a CT simulator to generate time-attenuation curves across a range of imaging conditions, i.e. tube current-time product, imaging duration, and temporal sampling, and physiologic conditions, i.e. MBF and arterial input function width. We assessed MBF estimability by precision (interquartile range of MBF estimates) and bias (difference between median MBF estimate and reference MBF) for multiple quantification methods. Methods included: six existing model-based deconvolution models, such as the plug-flow tissue uptake model (PTU), Fermi function model, and single-compartment model (SCM); two proposed robust physiologic models (RPM1, RPM2); model-independent singular value decomposition with Tikhonov regularization determined by the L-curve criterion (LSVD); and maximum upslope (MUP). Simulations show that MBF estimability is most affected by changes in imaging duration for model-based methods and by changes in tube current-time product and sampling interval for model-independent methods. Models with three parameters, i.e. RPM1, RPM2, and SCM, gave least biased and most precise MBF estimates. The average relative bias (precision) for RPM1, RPM2, and SCM was ⩽11% (⩽10%) and the models produced high-quality MBF maps in CT simulated phantom data as well as in a porcine model of coronary artery stenosis. In terms of precision, the methods ranked best-to-worst are: RPM1 > RPM2 > Fermi > SCM > LSVD > MUP [Formula: see text] other methods. In terms of bias, the models ranked best-to-worst are: SCM > RPM2 > RPM1 > PTU > LSVD [Formula: see text] other methods. Models with four or more parameters, particularly five-parameter models, had very poor precision (as much as 310% uncertainty) and/or significant bias (as much as 493%) and were sensitive to parameter initialization, thus suggesting the presence of multiple local minima. For improved estimates of MBF from MPI-CT, it is recommended to use reduced models that incorporate prior knowledge of physiology and contrast agent uptake, such as the proposed RPM1 and RPM2 models.