Kenneth Bender

An examination of Medicaid prior authorization policies for medication treatment of attention-deficit/hyperactivity disorder (ADHD) finds policies are inconsistent across states, which could influence whether treatments are consistent with, or differ from recommended practices.

Rachel Hulkower, JD, MSPH, Public Health Analyst, Cherokee Nation Assurance, Public Health Law Program, Office for State, Tribal, Local and Territorial Support, Arlington, Virginia, and colleagues point out that ADHD treatment recommendations are not always followed.

"When best-practice recommendations are compared with indicators of clinical practice, it appears that current practices and best practices for pediatric ADHD treatment are misaligned," Hulkower and colleagues indicate.

They note that the American Academy of Pediatrics (AAP) recommends evidence-based parent and/or teacher-administered behavior therapy as first-line treatment for preschool-aged children, with medication reserved if behavior therapy fails to substantially improve the child's functioning and there is moderate to severe continued disturbance in the child's function. A combination of such therapy with medication is recommended for older children.

Some of the highest rates of ADHD diagnosis are among children with public health insurance, however, investigators suggest that states' Medicaid policies and prior authorization requirements could have a substantial impact of how this condition is treated.

"Some state Medicaid programs have implemented policies to try to manage the use of ADHD medications," explain the investigators. "These policies include prescription medication prior authorization policies and prescription drug lists that restrict coverage approvals to patients of a certain age or require additional provider involvement before payment is granted. These policies may guide physicians toward preferred pediatric ADHD treatments."

"The NCBDDD (National Center on Birth Defects and Developmental Disabilities) has identified Medicaid prior authorization policy interventions as a set of strategies that may control the use of ADHD medication among patients diagnosed with ADHD and may guide clinicians towards referral for behavior therapy," Hulkower said, elaborating in an interview reported in Public Health Law.

To characterize the states' Medicaid pediatric ADHD medication prior authorizations, the investigators conducted a cross-sectional mapping study of states' policies as of November 1, 2015. The data on policy characteristics and authorization criteria included data on age restrictions and fail-first behavior therapy requirements.

The investigators report, among their findings, that 27 state Medicaid programs have prior authorization policies for ADHD medications prescribed to children and adolescents, 16 of which were applicable only to children <6 years of age. In 2 states, Medicaid coverage is expressly denied for ADHD medication prescriptions for patients younger than specified age: Minnesota denies all ADHD medications for children <3 years; Texas denies immediate-release medications <3 years, and denies extended-release and non-stimulant formulations for children <6 years.

Twenty-five states have policies that list criteria for approval; with the most common approval criterion, found in 23 states, a documented ADHD diagnosis. Less common criteria include: ruling out other causes for symptoms; ADHD symptoms persisting for a specified duration; patient impairment demonstrated in social environments, and the administration of a psychological evaluation.

Several of the states' policy ask the prescriber to confirm that an alternative treatment has been considered, and 7 state policies ask whether non-medication treatments such as behavior therapy had been attempted before the requested medication coverage. One state, Florida, requires the prescriber demonstrate not only that non-medication treatments are considered, but that an adequate trial failed to improve a patient's symptoms.

Hulkower indicated that the database developed from this study, available to the public, will next be analyzed in conjunction with Medicaid claims data for diagnosis and treatment of ADHD with prescription medications and psychological services to ascertain effects on ADHD treatment patterns.

"Research has not yet examined how prior authorization policies impact receipt of the recommended first-line treatment for these families, which is behavior therapy," Hulkower told MD Magazine.  "Evaluation of the impact of prior authorization policies on behavior therapy rates would document whether prior authorization policies are effectively supporting best practices for young children with ADHD."

The assessment of Medicaid prior authorization policies for medication treatment of ADHD was published in the November/December issue of 

This article was originally published by 

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Study finds that ADHD treatment recommendations are not always followed.

Inconsistent Prior Authorization Affects Attention-Deficit/Hyperactivity Disorder Treatment

Serologic detection of hepatitis C virus antigen (HCV-Ag) could replace the previous detection standard of molecular HCV-RNA in the era of direct-acting antivirals (DAAs), as DAA effectiveness in treating HCV is not predicted by baseline HCV-RNA levels, and successful treatment is no longer marked by absence of residual HCV-RNA.

"To simplify treatment monitoring, hepatitis C core antigen is emerging as a new tool for diagnosis and treatment monitoring in chronic HCV infection,” wrote principle investigator Pietro Andreone, MD, Department of Medical and Surgical Sciences, University of Bologna, Bologna Italy, and colleagues.

Andreone, and lead author Elisabetta Loggi, PhD, currently at the UOC Patologica Clinica, Fermo, Italy, elaborated on the advantages of applying the serologic testing of HCV-Ag in a statement to 

"Certainly, the main advantage is the general workflow simplification: the automated HCV-Ag testing doesn't require sophisticated laboratory facilities, specialized technicians, has a much faster turnaround time and lower costs," Andreone and Loggi said.

Although the HCV-Ag testing has a lower level of sensitivity than HCV-RNA detection, Andreone and Loggi posed the question of whether there is still a need for virological testing with high sensitivity in the DAA era.

The change to DAA treatment from pegylated interferon-based protocols has obviated the need for baseline levels of RNA in order to categorize the patient or to tailor therapy. Also, successful treatment is no longer marked by an absence of HCV-RNA, but by sustained virologic response (SVR).  In addition, there is no longer a "futility/stop treatment" measure from HCV-RNA that is used with DAA regimens.

"A residual viremia during the treatment is currently disregarded, as it does not imply a modification of treatment schedule,” Andreone and Loggi said.

To ascertain the clinical utility of the less costly and more accessible HCV-Ag detection method for monitoring treatment response compared to HCV-RNA, the investigators obtained both values periodically through DAA treatment of 96 consecutive, all-genotype patients with chronic HCV infection presenting to University of Bologna associated outpatient clinics between June 2013 and December 2015.

The investigators found expected patterns. There was a very rapid decrease in HCV-RNA, with negative detection increasing from mean of 16% after 2 weeks, to 55% after 4 weeks, and 99% after 8 weeks of treatment.  The kinetics of HCV-Ag was expectedly different, with 63% negative after 2 weeks and then a slower progression during treatment to 74% after 4 weeks and 83% after 8 weeks.

At the end of treatment, however, all patients except 1 with breakthrough viremia were negative for both HCV-RNA and HCV-Ag.

"Our recent work, in agreement with other similar experiences, showed a general clinical equivalence between HCV-Ag and HCV-RNA monitoring," Andreone and Loggi said. "Both present a similar kinetic disappearance from serum during DAA treatment, despite the lower sensitivity of HCV-Ag, which does not seem to limit the performance of the test."

The researchers opined that HCV-Ag is a strong candidate for simplified, cost-saving virological testing for HCV, and should be implemented “both as index of viral replication and to assess the response to pharmacological treatment.”

Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods

Automated HCV antigen testing has a much faster turnaround time and lower costs.

Hepatitis C Antigen Testing Could Simplify, Improve Treatment

Ribavirin (RBV) continues to be a necessary adjunct to direct-acting antiviral (DAA) regimens for difficult-to-cure hepatitis C virus (HCV) infection. A new large cohort study has confirmed the RBV steady-state serum levels that correspond to high rates of efficacy and low adverse effect.

Faydra Lieveld, MD, University Medical Center Utrecht, The Netherlands, and Marjolein van Tilborg, MD, PhD, Erasmus MC University Medical Center, The Netherlands, co-lead authors on behalf of the HepNed Study Group, determined the RBV steady-state plasma level at 8 weeks that correspond to a sustained virologic response (SVR) to the RBV-DAA regimen at 12 weeks.

"RBV has not left the therapeutic arena and still used as an additive under certain circumstances such as presence of cirrhosis, genotype 3 infection, presence of resistance-associated substitutes, previous antiviral treatment failure and/or in specific DAA regimens to increase treatment efficacy," researchers wrote.

In an essay commenting on the HepNed Study Group findings, Martin Lagging, MD, PhD and Jesper Waldenström, MD, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden, elaborated on the role of RBV.

"In the setting of decompensated cirrhosis (Child-Pugh B or C), RBV likely will remain a pivotal component of HCV therapy as protease inhibitors should not be used and re-treatment options are limited," they wrote.

Lagging and Waldenström illustrated that point by citing the ASTRAL-4 trial of sofosbuvir and velpatasvir (Epclusa) treatment of HCV genotype 1-6 infected patients with decompensated cirrhosis, in which the highest SVR rate was achieved in those additionally receiving RBV.

Lieveld, vanTilborg, and colleagues identified 183 patients treated with DAAs plus RBV from 4 Dutch academic medical centers. Eighty-five percent of the patients were characterized as difficult-to-cure, with such characteristics as previous treatment experience, HCV genotype 3 and/or cirrhosis.

Most were treated with a sofosbuvir-based regimen, and the majority (89%) achieved SVR at 12 weeks.

The median RBV steady-state plasma level attained at 8 weeks was 2.66mg/L (95% CI; 1.95-3.60) with a median dose of 12.9mg/kg/day (11.2-14.7). Multivariable analyses revealed that a higher RBV steady-state plasma level was an independent predictor of SVR (OR 1.79; 95% CI; 1.09-2.93). 

The investigators reported that the optimal RBV lowest level for achieving SVR was 2.28mg/L and the optimal ceiling to attain efficacy while minimizing the incidence of hemolytic anemia was 3.61mg/L.

Their findings counter a lack of association between RBV steady-state plasma levels and SVR found in a previous study, but argue that this is likely to due to the smaller size of that study (N=47), that cohort predominately comprised of genotype 1-infected, non-cirrhotic patients, and the retrospective analysis of the RBV plasma samples.

"Our study represents a large real-world cohort of mainly difficult-to-cure patients on various DAA combinations with prospectively analyzed plasma samples and SVR rates similar to clinical trials and real world cohorts," researchers wrote. 

Lagging and Waldenström accepted the investigators' recommended therapeutic range of 2.28-3.61mg/L for optimal dosing of RBV with DAAs in treating HCV infection. They also suggested an additional step to reduce the occurrence of  hemolytic anemia: screening for patients who are more refractory to the adverse effect (approximately one-third) by virtue of carrying genetic variants entailing reduced inosine triphosphate pyrophosphatase (ITPase) activity.

 "Based on these findings, in patients continuing to receive ribavirin containing treatment, it may be of interest to tailor therapy by means of on-treatment monitoring of ribavirin concentrations, and/or performing pre-treatment ITPA genetic profiling in order to optimize the likelihood of achieving SVR while minimizing the risk of adverse effects," Lagging and Waldenström concluded.

Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C—infected patients treated with direct-acting antivirals

Alimentary Pharmacology and Therapeutics 

Ribavirin steady-state serum levels correspond to high rates of efficacy and low adverse effect from direct-acting antiviral drugs for difficult-to-treat hepatitis C virus.

Ribavirin Remains a Key Factor in Successful Treatment of Hepatitis C

The successful treatment of hepatitis C virus genotype 6 (HCV-GT6) with a non-interferon-based fixed dose oral regimen of ledipasvir and sofosbuvir (LDV/SOF) bodes well for treating HCV in Southeast Asia, where newer pangenotypic agents are not available to treat this region's most prevalent genotype.

"While there are now other new meds that work the same or just slightly better for GT 6, LDV/SOF may remain the most cost-efficient for resource limited regions where most of these GT 6 patients are — Vietnam, Myanmar, Cambodia, Laos, Southern China, Thailand and Indonesia," Mindie Nguyen, MD, Professor of Medicine, GI and Hepatology, Liver Transplant, Stanford University Medical Center, told 

Nguyen and colleagues identified 60 Asian and foreign-born patients with HCV-GT6 at 4 treatment centers in the US. The 20 patients who were treatment-naive and without cirrhosis received open-labeled LDV 90mg/SOF 400mg orally once daily for 8 weeks, and 40 patients with cirrhosis and/or previous treatment failure were treated for 12 weeks.

Among the patients receiving 12 weeks of treatment, approximately 70% had cirrhosis and almost 40% had a history of prior HCV treatment. Two of these patients had decompensated cirrhosis and 3 had hepatocellular carcinoma (HCC).  The most common HCV-GT6 subtypes in the study cohort were 6c (43.4%) and 6a/b (21.7%).

Nguyen and colleagues described the trial as the first prospective study conducted with all oral, interferon-free fixed dose LDV/SOF combination for HCV GT6 patients to examine the efficacy of using the shorter 8-week treatment regimen, and the first to include patients with prior treatment failure, HCC, and cirrhosis with hepatic decompensation.

The investigators reported that 95% of those in the 8-week treatment group achieved sustained virologic response at 12 weeks (SVR12), with the 1 patient failing to respond having taken the medication for only 1 to 2 weeks. SVR12 was also achieved in 95% of the 12-week treatment group.

"For patients who do not have cirrhosis or prior treatment failure, 8 weeks of LDV/SOF appears to give similar cure rates as 12 weeks for patients with more advanced disease, which can mean a 33% cost savings for these patients," Nguyen said.

In addition to achieving SVR12, there was a significant decrease in patients' liver enzymes in both 8- and 12-week treatment groups, and increased albumin levels in those having failed previous treatment with and without cirrhosis. The investigators were encouraged by this indication that the treatment not only cleared the virus but also improved liver function in a short amount of time.

"This result deserves following over an extended period of time to determine the long-term, clinical outcomes especially for the incidence of HCC amongst this population," researchers wrote.

The response to treatment in these patients also suggested to the investigators that treatment should not be withheld because of the presence of HCC, particularly for patients who are wait listed for liver transplantation (LT). 

"HCV treatment prior to liver transplant with the all oral direct acting antivirals provides the best health outcomes and is the most cost-effective strategy for the treatment of HCV for patients with HCC or DCC (decompensated cirrhosis) waitlisted for LT," researchers wrote.

The assessment of 8 versus 12 weeks of LDV/SOF treatment of HCV genotype 6 was published in the December issue of the American Journal of Gastroenterology.

Oral regimen of ledipasvir and sofosbuvir for hepatitis C virus shows improved treatment outcomes.

8-Week Oral Hepatitis C Genotype 6 Therapy Shows Efficacy

A large cohort study found that use of acetaminophen for 29 days or more during pregnancy is associated with a two-fold risk of attention-deficit/hyperactivity disorder (ADHD) developing in offspring.

The study used records from the Norwegian Mother and Child Cohort Study (MoBa), drawn from the Norwegian Patient Registry, to assess outcome for 112,973 offspring born between 1999 and 2009, including 2,246 who developed ADHD. An invitation to participate sent to pregnant women in Norway in conjunction with routine ultrasound examinations at local hospitals was accepted by 25,242 mothers and 75,217 fathers.

Eivind Ystrom, PhD, Norwegian Institute of Public Health, Oslo, Norway and colleagues point to earlier studies which have suggested the association, but in which they found important limitations, including possible residual confounding.

"In contrast to research in previous studies, we were able to adjust for indications of acetaminophen use and parental symptoms of ADHD," the researchers wrote. "We were furthermore able to analyze maternal use of acetaminophen before pregnancy as a negative control and to estimate the effect of paternal use before pregnancy on offspring ADHD."

The investigators noted some conditions for which acetaminophen is indicated can potentially increase risk of neurodevelopmental disorders independent of that treatment, including fever, inflammation and autoimmunity. Their interest in determining and controlling for paternal pre-pregnancy use of acetaminophen was based on preclinical evidence of acetaminophen having endocrine disruption effects, and the possibility of male germ-line epigenetic effects.

The investigators sent self-report questionnaires to mothers and fathers at approximately 18 weeks of gestation, and to mothers later in pregnancy and after delivery. Medical records data for the offspring were gathered from the MoBa study when children were 6 months old, 1.5 years old and 3 years old. 

Documentation of ADHD diagnoses in the records referenced the 

International Classification of Diseases, 10th Revision

In addition to ascertaining the gestational time, duration and amount of acetaminophen use, the questionnaires elicited the conditions treated with acetaminophen and other medications used, histories of smoking and alcohol use, and symptoms of anxiety and depression.

Ystrom and colleagues found that treating fever or infection with acetaminophen for more than 8 days during pregnancy was associated with risk for ADHD increasing with the number of days of exposure. 

Acetaminophen used for 29 days or more had a two-fold risk for offspring to receive a diagnosis of ADHD from specialist health services (HR = 2.20; 95%; CI = 1.50-3.24). The risk was similar across the trimesters of exposure. In addition, there was a similar risk associated with paternal use of acetaminophen prior to pregnancy.

The investigators noted that the associations persisted after adjusting for acetaminophen use before pregnancy and for parental symptoms of ADHD.

“We had the advantage of having medication data separately for each indication, allowing us to account for confounding by each indication in a stratified model," researchers wrote. "Our ability to adjust for parental symptoms of ADHD represents a considerable improvement compared to previous study designs."

In commentary accompanying the study, Mark Wolraich, MD, University of Oklahoma, credited the advantage of large data sets for the investigators eliminating some previous confounders in establishing the association.

"With so many factors contributing to the condition, it becomes difficult to further identify any additional contributing factors with any certainty," Wolraich wrote. "The techniques employed by Ystrom et al, in their article demonstrate how it is possible to more specifically examine the possible association between prenatal exposure to acetaminophen and ADHD."

The large cohort study examining prenatal exposure to acetaminophen and risk of ADHD was published in the November issue of 

Acetaminophen use for 29 days or more during pregnancy linked to a significant risk of attention-deficit/hyperactivity disorder.

Pregnant Mothers Who Use Acetaminophen May Have Children With ADHD

A review of infections in patients with multiple sclerosis (MS) finds an inherent risk from the related disabilities, and the possibility of increased risk from disease-modifying therapies (DMT) with implications for treatment choice.

Elisabeth Gulowsen Celius, MD, Professor, Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway explained this possible adverse effect of treatment for MS to 

"The challenge with infections is even greater now that we also have drugs approved for progressive MS," Celius said. "With advancing age and disability, the risk of infections in general increases and treating these patients with immunomodulatory drugs further increases this risk."

Celius cites previous studies finding that patients with MS have an increased risk of infections and of more severe infections, as well as a higher utilization of intensive care and higher mortality rate than the general population.  The increased risk associated with having MS has been largely attributed to disturbances in bladder function, predisposing to urinary tract infections and pneumonia.

Infections can exacerbate the course of MS, and in one study a relative risk ratio of 1.3 for relapse of MS was documented in a 4-week post-viral infection period. Other studies have demonstrated an increased risk of relapse after influenza and Epstein-Barr virus infections, and have suggested that peripheral infections can induce neuroinflammation and clinical relapses.

Celius distinguished between the mechanisms of the immunomodulatory and/or immunosuppresive treatments and their relative potential for increasing risk of infections.  She noted that drugs inducing a reduction in normal T-cell or monocyte function could increase the risk of bacterial, viral, parasitic and viral functions. Drugs causing a reduction in neutrophils could lead to an increased risk of bacterial and fungal infections, according to Celius.

Paticular risks that were identified include progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) treatment of patients having JC-virus seropositivity. 

Celius attributes the association, albeit rare, to the drug blocking entry of B and T cells to the central nervous system, "accounting for the reduced immune surveillance of the brain."

Fingolimod (Gilenya) was found to have possible association with selective reactivation of herpes virus infections, although Celius notes it did not appear to interfere with the immune response against cytomegalovirus and Epstein-Barr. Alemtuzumab (Lemtrada) has been linked to cases of opportunistic infections such as listeria and pneumocystis pneumonia, which Celius suggested is "most probably related to the transient depletion of both adaptive and the innate immune system."

Celius identified 2 agents that were not associated with risk of infections: glatiramer acetate (Copaxone) and teriflunomide (Aubagio).  She notes that Leflunomide (Arava) for rheumatoid arthritis is metabolized to teriflunomide, and has been shown to inhibit Epstein-Barr.

"Thus, possible anti-viral properties of teriflunomide may indicate that teriflunomide is a treatment option in patients with recurrence of disease (MS) activity after PML," Celius said.

Celius concluded her review by advising that the choice of DMT in MS should be “guided by the drugs' specific mechanism of action and the drug-specific risk of infection."

"Screening for infections pre-treatment and extreme vigilance during treatment is required," Celius said.

Infections in patients with multiple sclerosis: Implications for disease-modifying therapy and implications for disease-modifying therapy

Treating aging patients with immunomodulatory drugs further increases the risk of infections.