Patient access to chronic medications during the Covid-19 pandemic: Evidence from a comprehensive dataset of US insurance claims.

Patient access and adherence to chronic medications is critical. In this work, we evaluate whether disruptions related to Covid-19 have affected new and existing patients' access to pharmacological therapies without interruption. We do so by performing a retrospective analysis on a dataset of 9.4 billion US prescription drug claims from 252 million patients from May, 2019 through August, 2020 (about 93% of prescriptions dispensed within those months). Using fixed effect (conditional likelihood) linear models, we evaluate continuity of care, how many days of supply patients received, and the likelihood of discontinuing therapy for drugs from classes with significant population health impacts. Findings indicate that more prescriptions were filled in March 2020 than in any prior month, followed by a significant drop in monthly dispensing. Compared to the pre-Covid era, a patient's likelihood of discontinuing some medications increased after the spread of Covid: norgestrel-ethinyl estradiol (hormonal contraceptive) discontinuation increased 0.62% (95% CI: 0.59% to 0.65%, p<0.001); dexmethylphenidate HCL (ADHD stimulant treatment) discontinuation increased 2.84% (95% CI: 2.79% to 2.89%, p<0.001); escitalopram oxalate (SSRI antidepressant) discontinuation increased 0.57% (95% CI: 0.561% to 0.578%, p<0.001); and haloperidol (antipsychotic) discontinuation increased 1.49% (95% CI: 1.41% to 1.57%, p<0.001). In contrast, the likelihood of discontinuing tacrolimus (immunosuppressant) decreased 0.15% (95% CI: 0.12% to 0.19%, p<0.001). The likelihood of discontinuing buprenorphine/naloxone (opioid addiction therapy) decreased 0.59% (95% CI: 0.55% to 0.62% decrease, p<0.001). We also observe a notable decline in new patients accessing these latter two therapies. Most US patients were able to access chronic medications during the early months of Covid-19, but still were more likely to discontinue their therapies than in previous months. Further, fewer than normal new patients started taking medications that may be vital to their care. Providers would do well to inquire about adherence and provide prompt, nonjudgmental, re-initiation of medications. From a policy perspective, opioid management programs seem to demonstrate a robust ability to manage existing patients in spite of disruption.

Challenges of access to kidney care for children in low-resource settings.

Kidney disease is a global public health concern across the age spectrum, including in children. However, our understanding of the true burden of kidney disease in low-resource areas is often hampered by a lack of disease awareness and access to diagnosis. Chronic kidney disease (CKD) in low-resource settings poses multiple challenges, including late diagnosis, the need for ongoing access to care and the frequent unavailability of costly therapies such as dialysis and transplantation. Moreover, children in such settings are at particular risk of acute kidney injury (AKI) owing to preventable and/or reversible causes - many children likely die from potentially reversible kidney disease because they lack access to appropriate care. Acute peritoneal dialysis (PD) is an important low-cost treatment option. Initiatives, such as the Saving Young Lives programme, to train local medical staff from low-resource areas to provide care for AKI, including acute PD, have already saved hundreds of children. Future priorities include capacity building for both educational purposes and to provide further resources for AKI management. As local knowledge and confidence increase, CKD management strategies should also develop. Increased awareness and advocacy at both the local government and international levels will be required to continue to improve the diagnosis and treatment of AKI and CKD in children worldwide.

Managing a Renal Transplant Programme During the COVID-19 Pandemic: Practical Experience from a Singapore Transplant Centre.

INTRODUCTION: Coronavirus Disease 2019 (COVID-19) has significantly affected the way healthcare is delivered in Singapore. Healthcare services such as renal transplantation had to rapidly adjust and meet the needs to (1) protect patients and staff, (2) ramp up, conserve or redeploy resources while (3) ensuring that critical services remained operational. This paper aims to describe the experience of the renal transplant programme at the Singapore General Hospital (SGH) in responding to the risks and constraints posed by the pandemic. METHODS AND MATERIALS: This is a review and summary of the SGH renal transplant programme's policy and protocols that were either modified or developed in response to the COVID-19 Pandemic. RESULTS: A multi-pronged approach was adopted to respond to the challenges of COVID-19. These included ensuring business continuity by splitting the transplant team into different locations, adopting video and tele-consults to minimise potential patient exposure to COVID-19, streamlining work processes using electronic forms, ensuring safe paths for patients who needed to come to hospital, ring-fencing and testing new inpatients at risk for COVID-19, enhancing precautionary measures for transplant surgery, ensuring a stable supply chain of immunosuppression, and sustaining patient and staff education programmes via video conferencing. CONCLUSIONS: Though the COVID-19 pandemic has reduced access to kidney transplantation, opportunities arose to adopt telemedicine into mainstream transplant practice as well as use electronic platforms to streamline work processes. Screening protocols were established to ensure that transplantation could be performed safely, while webinars reached out to empower patients to take precautions against COVID-19.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

How Did the War Affect Organ Transplantation in Syria?

Since 2011, the Syrian conflict has destroyed much of the country's infrastructure. The deteriorating humanitarian situation has involved health workers and facilities. In 2010, before the war, 385 kidney transplants were performed in Syria. This number declined to 154 in 2013 (60% less) before increasing to 251 transplants in 2018, which is still 35% less than the number of transplants performed before the war. In addition, the number of operational kidney transplant centers has decreased from 8 in 2010, distributed over 3 cities, to only 4 in 2013, all located in Damascus, which increased to 6 centers in 2019. Interestingly, with regard to type of living donor, the percentage of unrelated kidney donors has decreased by 20% for unclear reasons. Another alarming statistic is that more than 50% of kidney transplant physicians and surgeons are no longer practicing transplant medicine in their centers, either because they have left the country or because their centers had become nonoperational. Since the war, free and timely provision of immunosuppressive drugs for all patients in all provinces has been a leading challenge for health authorities and transplant patients. This difficulty has led to adverse medical consequences for patients. A project to initiate liver transplant came to a halt because of complex reasons but mainly because foreign trainers could not visit Syria. Although the autologous bone marrow transplant program had slowed until recently, it has become more active, involving both autologous and allogeneic transplants. The deceased-donor program is still not available in Syria; the war has just reinforced the many reasons that prevented the start of this program before the conflict. The commitment of transplant teams despite these large challenges continues to be extraordinary. The Syrian conflict has affected all aspects of organ transplant, paralyzing new projects and negatively affecting existing programs.

Renal transplant patients' preference for the supply and delivery of immunosuppressants in Wales: a discrete choice experiment.

BACKGROUND: Prescribing policy recommendations aimed at moving immunosuppressant prescribing for renal transplant patients from primary to secondary care may result in benefits of increased safety and reduced cost. However, there is little evidence of patients' preferences for receiving their immunosuppressant therapy from hospitals compared to community dispensing. The aim of this study was to elicit patient preferences for different service configurations focusing in particular on home delivery versus collection of medication from hospital. METHODS: A discrete choice experiment was administered to 265 renal transplant patients in North Wales. Respondents were presented 18 pairwise choices, labelled as either home delivery or hospital collection, and described by the attributes: frequency of supply, waiting time (for delivery or collection) and method of ordering (provider contact, patient contact via phone, patient contact electronically). Data were analysed using a random-effects logit model and marginal rates of substitution calculated based on the waiting time attribute. RESULTS: A response rate of 63% was achieved, with 5332 usable observations from 150 respondents. Method of delivery (ß coefficient 1.21; 95% confidence interval 1.05 to 1.38), frequency of supply (0.05; 0.03 to 0.08) waiting time (-0.00, -0.00 to -0.00), provider contact (desirable) (0.20; 0.12 to 0.27), patient contact by telephone (desirable) (0.09; 0.01 to 0.17) and patient contact electronically (undesirable) (-0.292; -0.37 to -0.21) were statistically significant (p < 0.05). Results indicate that patients are willing to increase waiting time by nearly 10 h to have a home delivery service. CONCLUSION: Patients indicate a clear preference for a home delivery service. They prefer providers to make contact when new immunosuppressant supplies are required and show preference against ordering medication electronically. A policy for secondary care prescribing and hospital collection of medicines does not align with this preference.

Teva Pharmaceuticals v. Sandoz: availability of generic glatiramer acetate and the impact to patent litigation claim construction.

In the upcoming case of Teva Pharmaceuticals v. Sandoz, the U.S. Supreme Court will address how much deference the appellate court should afford to a trial court's claim construction ruling. The effect of this decision will be far-reaching, as how claims are construed can determine whether a patent is infringed or not infringed, valid or invalid.

Rabbit antithymocyte globulin treatment in childhood acquired severe aplastic anemia.

Acquired severe aplastic anemia (SAA) is a life threatening bone marrow failure characterized by pancytopenia and hypocellular bone marrow. Matched sibling donor is not available for majority of the patients and many children receive immunosuppressive therapy (IST). Although horse antithymocyte globuline (ATG) is the preferred option, our patients received rabbit ATG; since horse ATG is not available in Turkey. We reviewed the medical records of children with SAA who were treated with rabbit ATG, cyclosporine, and granulocyte colony stimulating factor (GCSF) between 2006 and 2012. Fifteen children with SAA aged between 1.5 and 17 years received rabbit ATG as first line treatment. Only two of them showed partial response and the others did not give any response at 3rd, 6th, and 12th months after the first course of IST. The second course of ATG was given to 8 of the patients; Rabbit ATG at the same dosage was used for 3 of them, and others were given horse ATG. None of the patients responded to the second course of ATG. Invasive fungal infection (IFI) which was seen in 80% of the patients was the most significant problem. Overall survival rate was 60%. The median time between the diagnosis and initiation of IST was 57 (range; 29-144) days. This delay might be significantly contributed to unresponsiveness. In our series, the use of rabbit ATG was not effective for these patients as first line treatment modality. Response rate was very low and the incidence of fungal infections was very high in the SAA patients who received rabbit ATG.

The efficacy of rabbit antithymocyte globulin with cyclosporine in comparison to horse antithymocyte globulin as a first-line treatment in adult patients with severe aplastic anemia: a single-center retrospective study.

Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with severe aplastic anemia (SAA) ineligible for allogeneic stem cell transplantation. Recently, rabbit ATG with cyclosporine A has been used as a first-line IST regimen in patients with SAA because of unavailability of horse ATG. We retrospectively analyzed adult SAA patients who were treated with horse ATG (n=46) or rabbit ATG (n=53) between Feb 2001 and May 2010 to compare hematologic response and survival. Overall response rates at 3, 6, 12, and 18 months were similar in both the horse and rabbit ATG groups: 28.3 versus 35.8 % (P=0.421), 39.1 versus 45.3 % (P=0.537), 45.7 versus 49.1 % (P=0.735), and 47.8 versus 50.9 % (P=0.757), respectively. The complete response (CR) rate at 6 months in the horse ATG was significantly superior in comparison with the rabbit ATG (13.0 versus 1.9 %, P=0.031). But CR rates became similar in both groups after 6 months: 17.4 versus 11.3 % (P=0.387) at 12 months and 21.7 versus 22.6 % (P=0.914) at 18 months. Lymphocyte depletion after ATG was more profound and protracted in the rabbit ATG group compared to the horse ATG group. Overall survival (P=0.460) and failure-free survival (P=0.911) were not significantly different between the two groups. Our retrospective study demonstrated that the efficacy of first-line IST with rabbit ATG is similar to that with horse ATG. However, the time from treatment to CR was longer with rabbit ATG than with horse ATG, partly due to more profound and protracted lymphocyte depletion.

Disruptions in the supply of medications used in transplantation: implications and management strategies for the transplant clinician.

Drug shortages are a threat to patient care and public health, and the number of drugs on shortage is growing at an exponential rate. The major therapy areas affected by these shortages are oncology, anti-infective, cardiovascular and central nervous system. However, drugs utilized in the transplant patient population have not been exempt, and can have significant influence on posttransplant outcomes. The purpose of this review is to discuss the current and historical solid organ transplant-related disruptions in the supply of medications and implications on patient care and safety. Transplant centers should be armed with an implementation plan when imperative transplant-related drugs such as tacrolimus, mycophenolate, or antithymocyte globulin go on shortage. This plan should provide steps to manage the shortage, and provide effective therapeutic alternatives.

Temporary discontinuation of immunosuppressive treatment and renal graft rejection: experience of a center in Venezuela

In some Latin American countries, discontinuation of treatment when immunosuppressive drugs are unavailable can cause late renal graft loss. This retrospective study reports the frequency and consequences of interrupted treatment at a single center in Venezuela. In 2005 and 2006, we evaluated the medical records of and interviewed 303 patients (181 males) followed for more than one year after renal transplantation done between 1973 and 2005. Noncompliance for > 1 week was reported by 124 patients; 107 (86.3 percent) instances were due to unavailability of immunosuppressive drugs at the institution (institutional noncompliance), and the remainder were due to voluntary noncompliance. Acute rejection episodes were about three times as frequent among voluntary noncompliers as institutional noncompliers, probably because voluntary noncompliance lasted longer (mean 42.7 ± standard deviation of 14.1 days) than institutional noncompliance (18.5 ± 11.2 days, P < 0.001). Graft loss occurred in 63.6 percent (7/11) of the episodes of voluntary noncompliance and in 33.3 percent (10/30) of the episodes of institutional noncompliance. Institutional noncompliance represents a preventable cause of graft loss in some transplantation programs in developing countries.

En algunos países de América Latina, la interrupción del tratamiento cuando no se dispone de los medicamentos inmunosupresores puede causar la pérdida tardía del trasplante renal. Este estudio retrospectivo informa la frecuencia y las consecuencias de la interrupción del tratamiento en un centro en Venezuela. Se entrevistaron 303 pacientes (181 de ellos del sexo masculino) que tenían un seguimiento de más de un año después del trasplante renal y se evaluaron sus historias clínicas. Ciento veinticuatro pacientes informaron haber interrumpido el tratamiento por más de 1 semana; en 107 (86,3 por ciento) casos el motivo fue no disponer de los medicamentos inmunosupresores en la institución (incumplimiento institucional) y el resto se debió a incumplimientos voluntarios. Los episodios de rechazo agudo fueron cerca de tres veces más frecuente en los incumplidores voluntarios que en los incumplidores institucionales, probablemente porque el incumplimiento voluntario duró más (42,7 ± 14,1 días [desviación estándar]) que el institucional (18,5 ± 11,2 días; P < 0,001). La pérdida del trasplante ocurrió en 63,6 por ciento (7/11) de los incumplimientos voluntarios y en 33,3 por ciento (10/30) de los incumplimiento institucionales. El incumplimiento institucional es una causa evitable de pérdida del órgano transplantado en algunos programas de trasplante en países en desarrollo.

Temporary discontinuation of immunosuppressive treatment and renal graft rejection. Experience of a center in Venezuela.

In some Latin American countries, discontinuation of treatment when immunosuppressive drugs are unavailable can cause late renal graft loss. This retrospective study reports the frequency and consequences of interrupted treatment at a single center in Venezuela. In 2005 and 2006, we evaluated the medical records of and interviewed 303 patients (181 males) followed for more than one year after renal transplantation done between 1973 and 2005. Noncompliance for>1 week was reported by 124 patients; 107 (86.3%) instances were due to unavailability of immunosuppressive drugs at the institution (institutional noncompliance), and the remainder were due to voluntary noncompliance. Acute rejection episodes were about three times as frequent among voluntary noncompliers as institutional noncompliers, probably because voluntary noncompliance lasted longer (mean 42.7+/-standard deviation of 14.1 days) than institutional noncompliance (18.5+/-11.2 days, P<0.001). Graft loss occurred in 63.6% (7/11) of the episodes of voluntary noncompliance and in 33.3% (10/30) of the episodes of institutional noncompliance. Institutional noncompliance represents a preventable cause of graft loss in some transplantation programs in developing countries.

Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis.

Approximately 10-20% of infants in industrialized countries experience atopic dermatitis. In recent decades topical corticosteroids have been the first-choice therapy for treatment of flares. However, this form of therapy may induce skin atrophy, especially after application to facial lesions or with long-term use. Thus, development of new anti-inflammatory topical agents for the treatment of childhood atopic dermatitis was needed. The topical calcineurin inhibitors tacrolimus and pimecrolimus have an effect on various cells of the cutaneous immune system, specifically on T cells, by inhibiting the phosphatase calcineurin and preventing the transcription of proinflammatory cytokines. In several clinical studies of children and adults with atopic dermatitis, topical calcineurin inhibitors were found to be effective both on the face and the trunk and extremities, in both short- and long-term treatment regimens. Tachyphylaxis or rebound were not observed. In most patients an improvement of their eczema occurred during the first week of treatment, as measured by subjective and objective clinical signs of atopic dermatitis. Treatment significantly reduced the incidence of flares and the need for corticosteroids in children and adults. Treatment success, commonly defined as 'excellent improvement' or 'clearing of all lesions', was observed in more than one-third of all children treated with 0.03% or 0.1% tacrolimus or 1% pimecrolimus. Topical application of pimecrolimus and tacrolimus does not lead to significant blood concentrations of these agents in the majority of children with atopic dermatitis, and any increase in blood concentrations decreases after a few days of therapy. No changes in laboratory parameters were observed in short- and long-term studies in patients with atopic dermatitis. The most common adverse effect following the application of topical calcineurin inhibitors is mild to moderate symptoms of irritation such as burning, erythema and pruritus, which occurred in up to 20% of all children treated with tacrolimus and 10% of children treated with pimecrolimus, and usually faded after a few days. In contrast to topical corticosteroids, calcineurin inhibitors do not induce skin atrophy, even after long-term use. Topical calcineurin inhibitors have been proven to be effective and have a good safety profile during short-term and long-term use for up to 1 year with pimecrolimus and up to 4 years with tacrolimus. Given the lack of extensive experience with use of topical calcineurin inhibitors over longer periods, regular use of these agents, particularly in children, should be undertaken only after careful consideration of individual cases. Sun protection should also be advised.

Kidney transplantation in a developing economy: challenges and initial report of three cases at Ile Ife.

BACKGROUND: Kidney transplantation (KT) is globally adjudged the best alternative treatment for end stage renal disease (ESRD) in preference to life-long dialysis. This form of therapy was hitherto unavailable in Nigeria until our hospital and a private hospital embarked on a KT programme despite our depressed economy, and inadequate facilities. We present the initial report of KT performed in our hospital and the challenges of KT in our developing society. CASE REPORTS: Three patients with ESRD had living related KT between June 2002 and April 2003. The first patient died with functioning graft six and a half months post transplantation from complications of Diabetes mellitus and sepsis, while the remaining two still enjoy a good quality of life 35 months post transplantation. There were problems with procurement and monitoring of immunosuppressive drugs in the three patients. This report also illustrates the common causes of ESRD in Nigeria and some of the complications of KT. To our knowledge, these are the first reported cases of KT in Nigeria. CONCLUSION: Kidney transplantation is cost effective and offers a good quality of life for ESRD patients. Poverty, inadequate facilities and lack of donors are major problems facing KT in our society. Although KT requires high technical and material resources, with proper training, commitment and adequate funding, it is feasible, safe and cheaper on a long term basis for the management of patients with ESRD in a developing economy like ours. There is a need for government funding of KT programmes in developing countries.

[Cyclosporin A eyedrops: manufacturing, toxicity, pharmacokinetics and indications in 2000]. / Collyre à la cyclosporine A: fabrication, toxicité, pharmacocinétique et indications en l'an 2000.

INTRODUCTION: Cyclosporin eye-drops allow local immunoregulation without systemic side effects and is an alternate to local steroids. In this article we review specific problems of product setup and clinical studies published over the past 20 years. PRODUCT SETUP: The main problems in eye-drop preparation are sterility, pH, particles, and its lipophilic properties. Numerous excipients have been tested including oil solvents, alphacyclodextrin, collagen shields, liposomes, polyester nanocapsules, but documentation on stability of the molecule is inadequate. TOXICITY: Epithelial toxicity is well known and is probably mainly due to the excipient. No endothelial toxicity has been described in vivo. Repeated doses lead to uveal reactions in animals, which could limit the indications for intraocular diseases. PHARMACOKINETICS: Bioavailability is mainly limited by the lipophilic properties. Oil excipients, the most widely used, lead to good corneal penetration but low intraocular concentrations. Cyclosporin bioavailability is improved when using hydrophilic excipients. INDICATIONS: Every ocular surface disease that involves cytokines is a potential indication for cyclosporine eyedrops: keratoconjunctivitis sicca, vernal keratitis, adjuvant therapy of filtering surgery, stromal herpes keratitis, immunity limbal keratitis, and Thygeson's keratitis. There is biological evidence of efficacy, and encouraging results from many studies, yet few have tested a large number of patients. A large multicenter study on dry eye is currently in progress.