Introduction
The proven effectiveness of injectable cabotegravir (CAB‐LA) is higher than that of any other HIV prevention intervention ever trialled or implemented, surpassing medical male ...circumcision, condoms and combination antiretroviral treatment. Based on our own analyses and experience with the South African oral pre‐exposure prophylaxis (PrEP) programme, we review the supply and demand side factors that would need to be in place for a successful rollout of CAB‐LA, and delineate lessons for the launch of other long‐acting and extended delivery (LAED) antiretroviral drugs.
Discussion
On the supply side, CAB‐LA will have to be offered at a price that makes the drug affordable and cost‐effective to low‐ and middle‐income countries, especially those with high HIV prevalence. An important factor in lowering prices is a guaranteed market volume, which in turn necessitates the involvement of large funders, such as PEPFAR and the Global Fund, and a fairly rapid scale‐up of the drug. Such a scale‐up would have to involve speedy regulatory approval and WHO pre‐qualification, swift integration of CAB‐LA into national guidelines and planning for large enough manufacturing capacity, including the enabling of local manufacture. On the demand side, existing demand for HIV prevention products has to be harnessed and additional demand created, which will be aided by designing CAB‐LA programmes at the primary healthcare or community level, and involving non‐traditional outlets, such as private pharmacies and doctors’ practices.
Conclusions
CAB‐LA could be the game changer for HIV prevention that we have been hoping for, and serve as a useful pilot for other LAEDs. A successful rollout would involve building markets of a guaranteed size; lowering the drug's price to a level possibly below the cost of production, while also lowering the cost of production altogether; harnessing, creating and sustaining demand for the product over the long term, wherever possible, in national programmes rather than single demonstration sites; and establishing and maintaining manufacturing capacity and supply chains. For this, all parties have to work together—including originator and generic manufacturers, donor organizations and other large funders, and the governments of low‐ and middle‐income countries, in particular those with high HIV prevalence.
Work-up of thyroid nodules remains challenging. Fine-needle aspiration (FNA) has been shown to be the most cost-effective way to select patients for surgery with sensitivities of 54%–90% and ...specificities of 60%–96% for the detection of malignant lesions. Ultrasound-based real-time elastography (RTE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules. A meta-analysis was performed to assess the overall performance of RTE for the differentiation of thyroid nodules.
Literature databases were searched. The inclusion criteria for studies were the use of FNA cytology histopathology of surgical specimens as the diagnostic reference standard and assessment of sensitivity and specificity of RTE. The meta-analysis was performed using an inverse variance method and the Der Simonian and Laird Random effect estimator in case of established heterogeneity.
Eight studies that included a total of 639 thyroid nodules were analyzed. The overall mean sensitivity and specificity for the diagnosis of malignant thyroid nodules by RTE of the eight studies was 92% confidence interval 88–96 and 90% confidence interval 85–95, respectively. A significant heterogeneity was found for specificity of the different studies.
RTE has a high sensitivity and specificity in the evaluation of thyroid nodules. This technique might be useful in conjunction or even instead of FNA to select patients with thyroid nodules for surgery.
Introduction
In recent years, many countries have adopted evidence‐based budgeting (EBB) to encourage the best use of limited and decreasing HIV resources. The lack of data and evidence for hard to ...reach, marginalized and vulnerable populations could cause EBB to further disadvantage those who are already underserved and who carry a disproportionate HIV burden (USDB). We outline the critical data required to use EBB to support USDB people in the context of the generalized epidemics of sub‐Saharan Africa (SSA).
Discussion
To be considered in an EBB cycle, an intervention needs at a minimum to have an estimate of a) the average cost, typically per recipient of the intervention; b) the effectiveness of the intervention and c) the size of the intervention target population. The methods commonly used for general populations are not sufficient for generating valid estimates for USDB populations. USDB populations may require additional resources to learn about, access, and/or successfully participate in an intervention, increasing the cost per recipient. USDB populations may experience different health outcomes and/or other benefits than in general populations, influencing the effectiveness of the interventions. Finally, USDB population size estimation is critical for accurate programming but is difficult to obtain with almost no national estimates for countries in SSA. We explain these limitations and make recommendations for addressing them.
Conclusions
EBB is a strong tool to achieve efficient allocation of resources, but in SSA the evidence necessary for USDB populations may be lacking. Rather than excluding USDB populations from the budgeting process, more should be invested in understanding the needs of these populations.
Policy discussions about the feasibility of massively scaling up antiretroviral therapy (ART) to reduce HIV transmission and incidence hinge on accurately projecting the cost of such scale-up in ...comparison to the benefits from reduced HIV incidence and mortality. We review the available literature on modelled estimates of the cost of providing ART to different populations around the world, and suggest alternative methods of characterising cost when modelling several decades into the future. In past economic analyses of ART provision, costs were often assumed to vary by disease stage and treatment regimen, but for treatment as prevention, in particular, most analyses assume a uniform cost per patient. This approach disregards variables that can affect unit cost, such as differences in factor prices (i.e., the prices of supplies and services) and the scale and scope of operations (i.e., the sizes and types of facilities providing ART). We discuss several of these variables, and then present a worked example of a flexible cost function used to determine the effect of scale on the cost of a proposed scale-up of treatment as prevention in South Africa. Adjusting previously estimated costs of universal testing and treatment in South Africa for diseconomies of small scale, i.e., more patients being treated in smaller facilities, adds 42% to the expected future cost of the intervention.
In economic analyses of HIV interventions, South Africa is often used as a case in point, due to the availability of good epidemiological and programme data and the global relevance of its epidemic. ...Few analyses however use locally relevant cost data. We reviewed available cost data as part of the South African HIV Investment Case, a modelling exercise to inform the optimal use of financial resources for the country's HIV programme.
We systematically reviewed publication databases for published cost data covering a large range of HIV interventions and summarised relevant unit costs (cost per person receiving a service) for each. Where no data was found in the literature, we constructed unit costs either based on available information regarding ingredients and relevant public-sector prices, or based on expenditure records.
Only 42 (5%) of 1,047 records included in our full-text review reported primary cost data on HIV interventions in South Africa, with 71% of included papers covering ART. Other papers detailed the costs of HCT, MMC, palliative and inpatient care; no papers were found on the costs of PrEP, social and behaviour change communication, and PMTCT. The results informed unit costs for 5 of 11 intervention categories included in the Investment Case, with the remainder costed based on ingredients (35%) and expenditure data (10%).
A large number of modelled economic analyses of HIV interventions in South Africa use as inputs the same, often outdated, cost analyses, without reference to additional literature review. More primary cost analyses of non-ART interventions are needed.
Introduction
As prevalence of undiagnosed HIV declines, it is unclear whether testing programmes will be cost‐effective. To guide their HIV testing programmes, countries require appropriate metrics ...that can be measured. The cost‐per‐diagnosis is potentially a useful metric.
Methods
We simulated a series of setting‐scenarios for adult HIV epidemics and ART programmes typical of settings in southern Africa using an individual‐based model and projected forward from 2018 under two policies: (i) a minimum package of “core” testing (i.e. testing in pregnant women, for diagnosis of symptoms, in sex workers, and in men coming forward for circumcision) is conducted, and (ii) core‐testing as above plus additional testing beyond this (“additional‐testing”), for which we specify different rates of testing and various degrees to which those with HIV are more likely to test than those without HIV. We also considered a plausible range of unit test costs. The aim was to assess the relationship between cost‐per‐diagnosis and the incremental cost‐effectiveness ratio (ICER) of the additional‐testing policy. The discount rate used in the base case was 3% per annum (costs in 2018 U.S. dollars).
Results
There was a strong graded relationship between the cost‐per‐diagnosis and the ICER. Overall, the ICER was below $500 per‐DALY‐averted (the cost‐effectiveness threshold used in primary analysis) so long as the cost‐per‐diagnosis was below $315. This threshold cost‐per‐diagnosis was similar according to epidemic and programmatic features including the prevalence of undiagnosed HIV, the HIV incidence and a measure of HIV programme quality (the proportion of HIV diagnosed people having a viral load <1000 copies/mL). However, restricting to women, additional‐testing did not appear cost‐effective even at a cost‐per‐diagnosis of below $50, while restricting to men additional‐testing was cost‐effective up to a cost‐per‐diagnosis of $585. The threshold cost per diagnosis for testing in men to be cost‐effective fell to $256 when the cost‐effectiveness threshold was $300 instead of $500, and to $81 when considering a discount rate of 10% per annum.
Conclusions
For testing programmes in low‐income settings in southern African there is an extremely strong relationship between the cost‐per‐diagnosis and the cost‐per‐DALY averted, indicating that the cost‐per‐diagnosis can be used to monitor the cost‐effectiveness of testing programmes.
Acoustic Radiation Force Impulse (ARFI)-Imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate ...sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE).
ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules ≥5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging.
One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy.
ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.
Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with ...thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules.
The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15).
The IA between the 3 observers was only fair for TIRADS categories 2-5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1-4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92-100% of patients with TIRADS-2 had benign lesions, while 28-42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92-100% for TIRADS using TIRADS-categories 4&5 and 96-98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11-42% of nodules were in TIRADS-categories 2&3, as compared to 58-60% with ES-1&2.
IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules.
Introduction
A number of antiretroviral HIV prevention products are efficacious in preventing HIV infection. However, the sexual and reproductive health needs of many women extend beyond HIV ...prevention, and research is ongoing to develop multi‐purpose prevention technologies (MPTs) that offer dual HIV and pregnancy protection. We do not yet know if these products will be an efficient use of constrained health resources. In this paper, we estimate the cost‐effectiveness of combinations of candidate multi‐purpose prevention technologies (MPTs), in South Africa among general population women and female sex workers (FSWs).
Methods
We combined a cost model with a static model of product impact based on incidence data in South Africa to estimate the cost‐effectiveness of five candidate co‐formulated or co‐provided MPTs: oral PrEP, intravaginal ring, injectable ARV, microbicide gel and SILCS diaphragm used in concert with gel. We accounted for the preferences of end‐users by predicting uptake using a discrete choice experiment (DCE). Product availability and protection were systematically varied in five potential rollout scenarios. The impact model estimated the number of infections averted through decreased incidence due to product use over one year. The comparator for each scenario was current levels of male condom use, while a health system perspective was used to estimate discounted lifetime treatment costs averted per HIV infection. Product benefit was estimated in disability‐adjusted life years (DALYs) averted. Benefits from contraception were incorporated through adjusting the uptake of these products based on the DCE and through estimating the costs averted from avoiding unwanted pregnancies. We explore the additional impact of STI protection through increased uptake in a sensitivity analysis.
Results
At central incidence rates, all single‐ and multi‐purpose scenarios modelled were cost‐effective among FSWs and women aged 16–24, at a governmental willingness‐to‐pay threshold of $1175/DALY averted (range: $214–$810/DALY averted among non‐dominant scenarios), however, none were cost‐effective among women aged 25–49 (minimum $1706/DALY averted). The cost‐effectiveness of products improved with additional protection from pregnancy. Estimates were sensitive to variation in incidence assumptions, but robust to other parameters.
Conclusions
To the best of our knowledge, this is the first study to estimate the cost‐effectiveness of a range of potential MPTs; suggesting that MPTs will be cost‐effective among higher incidence FSWs or young women, but not among lower incidence older women. More work is needed to make attractive MPTs available to potential users who could use them effectively.
Autoimmune polyglandular syndrome (APS-2: autoimmune Addison's disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ ...destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.
APS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)
D
for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR.
Pro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend - (p = 0.1). In vitro treatment with 1,25(OH)
D
reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03).
1,25(OH)
D
regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.
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