HIV Treatment as Prevention: Modelling the Cost of Antiretroviral Treatment��State of the Art and Future Directions

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.     

Xpert?MTB/RIF for the Diagnosis of Tuberculosis in a Remote Arctic Setting: Impact on Cost and Time to Treatment Initiation

Background

Tuberculosis (TB) remains a significant health problem in the Canadian Arctic. Substantial health system delays in TB diagnosis can occur, in part due to the lack of capacity for onsite microbiologic testing. A study recently evaluated the yield and impact of a rapid automated PCR test (Xpert®MTB/RIF) for the diagnosis of TB in Iqaluit (Nunavut). We conducted an economic analysis to evaluate the expected cost relative to the expected reduction in time to treatment initiation, with the addition of Xpert®MTB/RIF to the current diagnostic and treatment algorithms used in this setting.

Methods

A decision analysis model compared current microbiologic testing to a scenario where Xpert®MTB/RIF was added to the current diagnostic algorithm for active TB, and incorporated costs and clinical endpoints from the Iqaluit study. Several sensitivity analyses that considered alternative use were also considered. We estimated days to TB diagnosis and treatment initiation, health system costs, and the incremental cost per treatment day gained for each individual evaluated for possible TB.

Results

With the addition of Xpert®MTB/RIF, costs increased while days to TB treatment initiation were reduced. The incremental cost per treatment day gained (per individual investigated for TB) was $164 (95% uncertainty range $85, $452). In a sensitivity analysis that considered hospital discharge after a single negative Xpert®MTB/RIF, the Xpert®MTB/RIF scenario was cost saving.

Interpretation

Adding Xpert®MTB/RIF to the current diagnostic algorithm for TB in Nunavut appears to reduce time to diagnosis and treatment at reasonable cost. It may be especially well suited to overcome some of the other logistical barriers that are unique to this and other remote communities.     

Metabolic Syndrome and Nephrolithiasis Risk: Should the Medical Management of Nephrolithiasis Include the Treatment of Metabolic Syndrome?

This article reviews the relationship between metabolic syndrome (MetS) and nephrolithiasis, as well as the clinical implications for patients with this dual diagnosis. MetS, estimated to affect 25% of adults in the United States, is associated with a fivefold increase in the risk of developing diabetes, a doubling of the risk of acquiring cardiovascular disease, and an increase in overall mortality. Defined as a syndrome, MetS is recognized clinically by numerous constitutive traits, including abdominal obesity, hypertension, dyslipidemia (elevated triglycerides, low high-density lipoprotein cholesterol), and hyperglycemia. Urologic complications of MetS include a 30% higher risk of nephrolithiasis, with an increased percentage of uric acid nephrolithiasis in the setting of hyperuricemia, hyperuricosuria, low urine pH, and low urinary volume. Current American Urological Association and European Association of Urology guidelines suggest investigating the etiology of nephrolithiasis in affected individuals; however, there is no specific goal of treating MetS as part of the medical management. Weight loss and exercise, the main lifestyle treatments of MetS, counter abdominal obesity and insulin resistance and reduce the incidence of cardiovascular events and the development of diabetes. These recommendations may offer a beneficial adjunctive treatment option for nephrolithiasis complicated by MetS. Although definitive therapeutic recommendations must await further studies, it seems both reasonable and justifiable for the urologist, as part of a multidisciplinary team, to recommend these important lifestyle changes to patients with both conditions. These recommendations should accompany the currently accepted management of nephrolithiasis.Key words: Nephrolithiasis, Metabolic syndrome, Uric acid nephrolithiasisMetabolic syndrome (MetS), as defined by the National Cholesterol Education Program and the Adult Treatment Panel III in 2001 (and updated in 2005), represents a growing medical problem affecting more than 22% of US adults.^1–4 It is associated with an almost fivefold increase in the risk of developing diabetes and a doubling of the risk of acquiring cardiovascular disease.⁵ MetS is a clinical disorder defined by the presence of at least three of the following criteria: central obesity (abdominal girth > 102 cm [40 in] men and > 88 cm [35 in] women), low high-density lipoprotein (HDL) cholesterol (< 40 mg/dL in men and < 50 mg/dL in women), hypertriglyceridemia (> 150 mg/dL), hypertension (blood pressure > 130/85 mm Hg), and elevated fasting glucose (> 100 mg/dL).^2,4 The development of MetS appears to result from a complex interaction of genetics, phenotypic visceral fat accumulation (central obesity), insulin resistance, and sedentary behavior.^5,6 Beyond cardiometabolic risks, MetS has a wide range of long-term complications, including nonalcoholic fatty liver disease, polycystic ovarian syndrome, obstructive sleep apnea, hypogonadism, lipodystrophy, microvascular disease, and chronic renal disease.⁶ An important urologic complication of MetS, not routinely cited, is nephrolithiasis.^6–8Nephrolithiasis continues to be a major cause of morbidity and healthcare spending.⁹ A history of kidney stones is approximately twice as common in individuals with three criteria for MetS and three times as common in those with five criteria for MetS, as compared with those with none.¹⁰ These trends were confirmed in a large-scale, nationwide study of 30,448 Japanese patients with urolithiasis, who demonstrated that MetS was associated with a significantly increased risk of hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia, independent of age and sex.¹¹ Additionally, patients with a history of nephrolithiasis are significantly more likely to have multiple risk factors for cardiovascular disease, premature atherosclerosis, and cardiovascular events.^10,12,13 It is unknown whether this is primarily a reflection of factors associated with nephrolithiasis, such as obesity, hypertension, or glucose intolerance/diabetes, or due to components of MetS, such as insulin resistance.¹⁴ The current American Urological Association (AUA) guidelines on the medical management of kidney stones suggests a need for future research on advising patients to exercise and lose weight, but does not make definitive recommendations on these lifestyle changes.¹⁵     

The Prevalence of HIV-1 Drug Resistance among Antiretroviral Treatment Na?ve Individuals in Mainland China: A Meta-Analysis

Background

Surveillance of drug resistance in antiretroviral treatment-naïve patients in China is needed to ensure optimal treatment outcomes and control of the human immunodeficiency virus (HIV) epidemic.

Methods

A systematic literature search was conducted in English and Chinese through PubMed (English), China National Knowledge Infrastructure (Chinese), Chinese Biomedical Literature Database (Chinese), and Wanfang (Chinese). Random effects models were used to calculate the pooled prevalence of transmitted drug resistance and subgroup analyses examined prevalence estimates across time periods, study locations, and study populations.

Results

Analysis of data from 71 studies (47 in Chinese and 24 in English) yielded a pooled prevalence of transmitted HIV drug resistance to any antiretroviral drug class of 3.64% (95% confidence interval [CI]: 3.00%–4.32%). Rates were significantly high at initial stage of free ART program from 2003 to 2005 (5.18%, 95%CI: 3.13%–7.63%), and were much lower among studies conducted in 2006–2008 (3.02%, 95%CI: 2.03%–4.16%). A slight increase was observed again in the most recent study period from 2009 to 2012 (3.68%, 95%CI: 2.78%–4.69%). Subgroup analysis revealed highest prevalence levels of transmitted drug resistance in Beijing city, and Henan and Hubei provinces (above 5%), and although differences in prevalence rates among risk groups were negligible, men who have sex with men were unique in their relatively large portion of protease inhibitor resistance, a second-line drug of limited availability in China.

Conclusions

Overall prevalence of transmitted HIV drug resistance in China is classified as “low” by the World Health Organization. However regional and temporal variability suggest a more complex epidemic for which closer HIV drug resistance surveillance is needed. A nationwide HIV drug resistance surveillance system to monitor both treatment-experienced and treatment-naïve patients will be a cornerstone to ensure the effectiveness of treatment scale-up, particularly as China seeks to expand a national policy of antiretroviral treatment as prevention.     

How Should the Impact of Different Presentations of Treatment Effects on Patient Choice Be Evaluated? A Pilot Randomized Trial

Background

Different presentations of treatment effects can affect decisions. However, previous studies have not evaluated which presentations best help people make decisions that are consistent with their own values. We undertook a pilot study to compare different methods for doing this.

Methods and Findings

We conducted an Internet-based randomized trial comparing summary statistics for communicating the effects of statins on the risk of coronary heart disease (CHD). Participants rated the relative importance of treatment consequences using visual analogue scales (VAS) and category rating scales (CRS) with five response options. We randomized participants to either VAS or CRS first and to one of six summary statistics: relative risk reduction (RRR) and five absolute measures of effect: absolute risk reduction, number needed to treat, event rates, tablets needed to take, and natural frequencies (whole numbers). We used logistic regression to determine the association between participants'' elicited values and treatment choices. 770 participants age 18 or over and literate in English completed the study. In all, 13% in the VAS-first group failed to complete their VAS rating, while 9% of the CRS-first group failed to complete their scoring (p = 0.03). Different ways of weighting the elicited values had little impact on the analyses comparing the different presentations. Most (51%) preferred the RRR compared to the other five summary statistics (1% to 25%, p = 0.074). However, decisions in the group presented the RRR deviated substantially from those made in the other five groups. The odds of participants in the RRR group deciding to take statins were 3.1 to 5.8 times that of those in the other groups across a wide range of values (p = 0.0007). Participants with a scientific background, who were more numerate or had more years of education were more likely to decide not to take statins.

Conclusions

Internet-based trials comparing different presentations of treatment effects are feasible, but recruiting participants is a major challenge. Despite a slightly higher response rate for CRS, VAS is preferable to avoid approximation of a continuous variable. Although most participants preferred the RRR, participants shown the RRR were more likely to decide to take statins regardless of their values compared with participants who were shown any of the five other summary statistics.

Trial Registration

Controlled-Trials.com ISRCTN85194921     

Diagnosis and Treatment of Lymphocutaneous Sporotrichosis: What Are the Options?

Lymphocutaneous sporotrichosis is the most common clinical form of cutaneous sporotrichosis. Caused by a complex of dimorphic fungi called Sporothrix schenckii complex, it is an occupational disease, present especially in tropical and subtropical areas, and has been reported in all continents. Diagnosis is established by isolation of the causative agent. Therapy of choice for lymphocutaneous sporotrichosis is itraconazole, and in developing countries, potassium iodide solution. In general, the lymphocutaneous form is considered a mild benign form of the disease, and the majority of cases respond well to treatment in about 3–4 months of therapy. In this paper, we have made a general review of the disease, especially of the epidemiology, clinical features and diagnosis of the lymphocutaneous form, as well as a brief analysis of the advantages and disadvantages of diverse treatments.     

Temporal Structure in Cooperative Interactions: What Does the Timing of Exploitation Tell Us about Its Cost?

Exploitation in cooperative interactions both within and between species is widespread. Although it is assumed to be costly to be exploited, mechanisms to control exploitation are surprisingly rare, making the persistence of cooperation a fundamental paradox in evolutionary biology and ecology. Focusing on between-species cooperation (mutualism), we hypothesize that the temporal sequence in which exploitation occurs relative to cooperation affects its net costs and argue that this can help explain when and where control mechanisms are observed in nature. Our principal prediction is that when exploitation occurs late relative to cooperation, there should be little selection to limit its effects (analogous to “tolerated theft” in human cooperative groups). Although we focus on cases in which mutualists and exploiters are different individuals (of the same or different species), our inferences can readily be extended to cases in which individuals exhibit mixed cooperative-exploitative strategies. We demonstrate that temporal structure should be considered alongside spatial structure as an important process affecting the evolution of cooperation. We also provide testable predictions to guide future empirical research on interspecific as well as intraspecific cooperation.     

Current Status in Diagnosis of Scedosporium Infections: What Is the Impact of New Molecular Methods?

Scedosporium species are increasingly encountered as fungal pathogens. Species identification is important due to species-specific differences in epidemiology, antifungal susceptibility and virulence. Histology and culture-based identification are hampered by their low sensitivity and specificity. The use of new selective media has improved the recovery rate from clinical samples. Molecular methods, including multiplex PCR, PCR-RFLP analysis, DNA sequencing, oligonucleotide arrays, real-time PCR, rolling circle amplification, are increasingly used for species identification. Most recently, Matrix-Assisted Laser Desorption-Time of Flight Mass Spectrometry has been successfully applied as a tool for rapid identification of clinically relevant Scedosporium species. This review aims to summarize the methods currently used to guide the clinical microbiology laboratory in the selection of the most appropriate identification techniques. This will aid the laboratory in making a fast and reliable diagnosis that enables the clinician to make correct treatment choices.     

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.