Real-world analysis of adverse event rates after initiation of ibrutinib among Medicare beneficiaries with chronic lymphocytic leukemia.

BACKGROUND: The first-generation BTK inhibitor ibrutinib is a standard-of-care therapy in the treatment of chronic lymphocytic leukemia (CLL) despite potential side effects that often lead to discontinuation. METHODS: This study used 2013-2019 claims data to describe the incidence rate of adverse events (AEs) among elderly Medicare beneficiaries newly initiating ibrutinib for CLL. RESULTS: The final sample contained 11,870 Medicare beneficiaries with CLL (mean age 77.2) newly initiating ibrutinib, of whom 65.2% discontinued over mean follow-up of 2.3 years. The overall incidence rate of AEs was 62.5 per 1000 patient-months for all discontinuers and 32.9 per 1000 patient-months for non-discontinuers. Discontinuers had a higher incidence rate of AEs per 1000 patient-months compared with non-discontinuers for all AEs examined, including infection (22.8 vs. 14.5), atrial fibrillation (15.1 vs. 7.0), anemia (21.9 vs. 14.5), and arthralgia/myalgia (19.5 vs. 13.6). CONCLUSION: In this first real-world study of a national sample of elderly US patients treated with ibrutinib, we found a clear unmet need for improved management of ibrutinib-related AEs and/or new treatments to improve real-world outcomes in patients with CLL.

Adverse Events and Economic Burden Among Patients Receiving Systemic Treatment for Mantle Cell Lymphoma: A Real-World Retrospective Cohort Study.

BACKGROUND/AIM: Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs. PATIENTS AND METHODS: Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy. RESULTS: Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month. CONCLUSION: Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.

Update on HIV prevention and preexposure prophylaxis.

HIV preexposure prophylaxis (PrEP) is an opportunity for clinicians to curb the 40,000 HIV infections occurring annually in the United States. PrEP is medication used by HIV-negative patients to reduce their risk of acquiring the virus. This article provides a baseline understanding of PrEP indications, prescribing, and monitoring, including a review of previously approved medication and an update on newly approved drugs, including emtricitabine/tenofovir alafenamide (F/TAF). Sexual and gender minorities are often underrepresented in the literature about PrEP, but clinicians should address risk focused on specific behaviors rather than population-level characteristics. As one of few professions with prescriptive authority, PAs have an obligation to understand and manage PrEP.

Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis B: can the fracture risk assessment tool identify those at greatest risk?

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is an established nucleotide analogue in the treatment of chronic hepatitis B. Bone mineral density loss has been described in TDF-treated patients with human immunodeficiency virus infection, but limited data exist for patients with chronic hepatitis B. Dual X-ray absorptiometry (DEXA) was used to determine bone mineral density changes in TDF-exposed patients. We evaluated the accuracy of the Fracture Risk Assessment Tool (FRAX) as an alternative to DEXA in clinical practice. METHODS: A total of 170 patients were studied: 122 were exposed to TDF, and 48 were controls. All patients underwent DEXA, and demographic details were recorded. FRAX scores (before and after DEXA) were calculated. RESULTS: TDF was associated with a lower hip T score (P = .02). On univariate and multivariate analysis, advancing age, smoking, lower body mass index, and TDF exposure were independent predictors of low bone mineral density. In addition, the pre-DEXA FRAX score was an accurate predictor of the post-DEXA FRAX treatment recommendation (100% sensitivity and 83% specificity), area under the curve 0.93 (95% CI, .87-.97, P < .001). CONCLUSIONS: TDF-treated patients with chronic hepatitis B have reduced bone mineral density, but the reduction is limited to 1 anatomical site. Age and advanced liver disease are additional contributing factors, underlining the importance of multifactorial fracture risk assessment. FRAX can accurately identify those at greatest risk of osteoporotic fracture.

[Assessment of mitochondrial toxicity induced by zidovudine and adefovir dipivoxil in rats].

OBJECTIVE: To explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system. METHODS: Twelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope. RESULTS: No significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats. CONCLUSION: Significant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.

[Analysis of adherence and efficiency when replacing an antiretroviral therapy with efavirenz-emtricitabine-tenofovir in a single daily dose]. / Análisis del cambio en la adherencia y eficiencia del tratamiento antirretroviral con el uso de efavirenz-emtricitabina-tenofovir en dosis única diaria.

OBJECTIVE: To analyse whether the change of antiretroviral therapy to efavirenz/emtricitabine/tenofovir in a single daily dose (EETu) increases adherence and maintains effectiveness, and establish the cost increase caused by the change. METHODS: An observational, retrospective, and intra-subject study, performed in the outpatient dispensing unit. The study period was 1 year (6 months before and 6 months after the change). Computer dispensing records and days of hospitalisation during the study period were reviewed, and the difference in treatment adherence calculated. To determine the effectiveness of treatment, viral load and CD4 lymphocytes data before and after the change were reviewed. The cost before and after treatment for each patient was determined, and therefore the annual cost increase and the incremental cost per patient. RESULTS: The study included 127 patients. The difference in adherence was 0.6%. The percentage of poor adherence was 35.4% and 40.9% before and after the treatment change, respectively. The levels of CD4 lymphocytes and viral load did not change significantly with treatment. The economic analysis revealed an annual increase of 25,374.60 and €199.80 per patient. CONCLUSIONS: The use of EETu did not improve the control of HIV infection in terms of effectiveness and adherence, and resulted in increased economic costs. Therefore, its choice as antiretroviral treatment will have to be based on criteria other than those described above.

What primary care providers need to know about preexposure prophylaxis for HIV prevention: a narrative review.

As HIV prevalence climbs globally, including more than 50 000 new infections per year in the United States, we need more effective HIV prevention strategies. The use of antiretrovirals for preexposure prophylaxis (PrEP) among high-risk persons without HIV is emerging as one such strategy. Randomized, controlled trials have demonstrated that once-daily oral PrEP decreased HIV incidence among at-risk men who have sex with men and African heterosexuals, including serodiscordant couples. An additional randomized, controlled trial of a topical pericoital antiretroviral microbicide gel decreased HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population. The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee reviewed these studies and additional data in May 2012 and voted to advise the approval of oral tenofovir-emtricitabine for PrEP in high-risk populations. On 16 July 2012, the FDA recommended that this combination medication be approved for use as PrEP in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic.

Risk factors for suboptimal vitamin D levels among adults with HIV attending an inner-city clinic of New Orleans, Louisiana.

BACKGROUND: Vitamin D insufficiency and deficiency are highly prevalent in populations with HIV, but there is limited data on predictors for suboptimal levels. METHODS: To determine risk factors for Vitamin D insufficiency/deficiency, 185 charts were retrospectively reviewed. RESULTS: Proportions with Vitamin D levels < 10 ng/ml, 10 - 20 ng/ml, 20 - 30 ng/ml and > 30 ng/ml were 14.6%, 44.8%, 24.9%, and 15.7%, respectively. Bivariate analysis showed that Vitamin D levels < 20 ng/ml were associated with a lower albumin level (p =.02), female gender (p = .0003), and African-American (AA) race (p = .0001). Tenofovir exposure showed borderline significance (p = .09). AA race was the only significant factor in multivariate modeling. CONCLUSIONS: Vitamin D insufficiency/deficiency was high. AA race was an independent risk factor. Although not significant, obese persons with a poorer nutritional status and possibly those on tenofovir may also be at higher risk.

L-selectin and P-selectin are novel biomarkers of cervicovaginal inflammation for preclinical mucosal safety assessment of anti-HIV-1 microbicide.

A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.

Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B, in accordance with the licensed indication, based upon the evidence submission from Gilead to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included two international randomised controlled trials (RCTs) comparing tenofovir with adefovir, and a mixed treatment comparison (MTC) using Bayesian methodology to compare tenofovir with other nucleos(t)ide analogues using direct and indirect RCT evidence. There were no statistically significant differences between tenofovir and adefovir in overall adverse events although, in hepatitis B 'e' antigen (HBeAg)-positive patients, there was a higher incidence of mild nausea in the tenofovir treatment group. The primary outcome, 'complete response', was a composite end point defined as histology response and hepatitis B virus DNA below 400 copies/ml. For both HBeAg-positive and HBeAg-negative patients, a significantly greater proportion had a complete response after 48 weeks with tenofovir than with adefovir. There was no statistically significant difference in histological response in either group of patients compared with adefovir. The MTC could only generate results for HBeAg positive nucleos(t)ide naive patients as there was insufficient evidence for other subgroups. The probability of achieving undetectable HBV DNA with tenofovir was found to be significantly higher than that for all other treatments considered in the analysis at the 0.05 level. The analysis demonstrated that there is a 98% probability that tenofovir is the most potent nucleos(t)ide in terms of this outcome. The manufacturer's submission concluded that tenofovir is a cost-effective option as first-line treatment. For HBeAg-positive patients, tenofovir followed by lamivudine has an incremental cost-effective ratio (ICER) of 9940 pounds per quality-adjusted life-year (QALY) gained, compared with lamivudine followed by tenofovir. A more appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,619 pounds per QALY gained, compared with lamivudine followed by tenofovir. For HBeAg-negative patients, tenofovir followed by lamivudine has an ICER of 9811 pounds per QALY gained, compared with best supportive care. A more clinically appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,854 pounds per QALY gained, compared with tenofovir followed by lamivudine. The ERG uncovered a number of errors in the submission and these ICERs approximately doubled when the analysis was corrected and reran. The guidance issued by NICE on 22 July 2009 states that tenofovir disoproxil, within its marketing authorization is recommended as an option for the treatment of people with chronic HBe-Ag-positive or HBe-Ag-negative hepatitis B in whom antiviral treatment is indicated.

Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa.

BACKGROUND: Most first-line antiretroviral therapy regimens in Africa include stavudine (d4T), despite the high incidence of toxicities related to it. We estimated the cost and cost-effectiveness of switching from d4T to tenofovir disoproxil fumarate (TDF) in South Africa. METHODS: A model was developed to estimate the proportion of patients in a hypothetical cohort who experienced d4T- and TDF-related events over the 2 years after antiretroviral therapy initiation. Transition probabilities, event and drug costs, and utility losses were estimated from primary data and the literature. Outcomes included incremental cost, incremental cost-effectiveness ratio per quality-adjusted life year gained, and threshold prices for TDF. RESULTS: After 2 years, 82.5% of the d4T scenario cohort remained on d4T, 16.6% had switched to AZT, 0.8% had died, and 414 events that did not lead to a drug change had occurred. In the TDF scenario, 97.5% of the cohort remained on TDF. At a baseline cost of TDF of $17.00/month, the incremental cost of the TDF scenario was $128/patient/year and the incremental cost-effectiveness ratio was $9007 per quality-adjusted life year gained. The change to TDF would be cost neutral for the government at a price of $6.17/month and highly cost effective at a price of $12.94/month. CONCLUSIONS: At a TDF price of $17.00/month, savings on d4T toxicity management will offset roughly 20% of the higher price of TDF. The price of TDF would have to fall substantially to make the change cost neutral for South Africa in budgetary terms, but it would be highly cost effective at a price only slightly less than what is currently available.

Assessment of adverse events associated with antiretroviral regimens for postexposure prophylaxis for occupational and nonoccupational exposures to prevent transmission of human immunodeficiency virus.

OBJECTIVE: To assess adverse events associated with antiretroviral regimens for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP), with a particular focus on the treatment combination of zidovudine, lamivudine, and tenofovir (ZDV-3TC-TDF). METHODS: Retrospective chart review for individuals who received HIV PEP for occupational and nonoccupational exposure, and multivariate analyses to identify risk factors for noncompletion of PEP and adverse events associated with PEP. SETTING: University of Rochester Health Service Occupational Health Program and University of Rochester AIDS Center. PARTICIPANTS: Healthcare workers who received HIV PEP for occupational exposure from January 1, 1999, to December 31, 2004, and individuals who received HIV PEP for nonoccupational exposure from January 1, 2002, to December 31, 2004.Results. We found increased rates of nausea among subjects who received treatment with ZDV-3TC-TDF and subjects who received treatment with zidovudine, lamivudine, and indinavir (ZDV-3TC-IDV). Analyses showed that female sex was a risk factor for nausea. Compared with subjects who received treatment with ZDV-3TC-TDF, subjects who received treatment with ZDV-3TC-IDV were less likely to not complete the HIV PEP for occupational exposure. CONCLUSION: Preventive treatment of adverse events may be necessary to ensure completion of HIV PEP.

A systematic review and economic evaluation of adefovir dipivoxil and pegylated interferon-alpha-2a for the treatment of chronic hepatitis B.

Standard treatments for chronic hepatitis B (CHB) include interferon-alpha (IFN-alpha) and lamivudine (LAM), but these are associated with adverse effects and viral resistance, respectively. The aim of this systematic review and economic evaluation was to assess the clinical effectiveness and cost-effectiveness of two alternative drugs for the treatment of adults with CHB: adefovir dipivoxil (ADV) and pegylated IFN-alpha-2a. We searched electronic databases, including Cochrane Systematic Reviews and Medline, for literature that met criteria defined in a research protocol. Retrieved articles were independently assessed for inclusion by two reviewers. We developed a Markov state transition model to estimate the cost-effectiveness (cost-utility) of pegylated IFN-alpha-2a and of ADV compared with nonpegylated IFN-alpha-2a, LAM and best supportive care. Seven randomized controlled trials and two systematic reviews met the inclusion criteria for our review of clinical effectiveness. ADV was significantly more effective than placebo or ongoing LAM in reducing levels of hepatitis B virus (HBV) DNA. Rates of hepatitis B e antigen (HBeAg) seroconversion were higher among patients receiving ADV than either placebo or ongoing LAM. Patients treated with pegylated IFN-alpha-2a, either as monotherapy or in combination with LAM, showed significantly reduced HBV DNA levels compared with patients treated with LAM monotherapy. HBeAg seroconversion rates at follow-up were significantly higher for pegylated IFN-alpha-2a patients than for those receiving LAM monotherapy. Results of our cost-effectiveness analysis demonstrate that incremental costs per quality adjusted life year (QALY) for a range of comparisons were between 5,994 and 16,569 British Pound, and within the range considered by NHS decision-makers to represent good value for money.

[Assessment of renal abnormalities in 107 HIV patients treated with tenofovir]. / Evaluation de la tolérance rénale du ténofovir dans une cohorte de 107 patients.

OBJECTIVES: The objectives of our study were to assess frequency, severity and outcome of renal abnormalities, as well as to determine the risk of developing hypophosphataemia in HIV-infected patients receiving tenofovir. METHODS: An observational study was conducted in real-life conditions, during a 6-month period, in 107 HIV patients receiving tenofovir. RESULTS: Mild-to-moderate hypophosphataemia (<0.77 mmol/L) occurred during follow-up, at least once in 43% of patients and at least twice in 27%. Antiretroviral therapy including ritonavir + lopinavir was significantly associated with the occurrence of hypophosphataemia (relative risk = 2.6; p = 0.03). Frequency of abnormal proteinuria was 22%. CONCLUSION: Creatinine clearance, phosphataemia, proteinuria and glycosuria should be closely monitored in patients receiving tenofovir therapy.

T-20 and adefovir for salvage therapy -- expect no miracles.

AIDS: T-20, a fusion inhibitor comprised of a portion of the gp41 protein, lowers viral loads by as much as 97 percent. Because T-20 confers no cross-resistance with currently used antivirals, T-20 is a good candidate for use as a salvage therapy. T-20 is planned to be administered by subcutaneous infusion pump to 72 patients who are NNRTI-naive and have failed indinavir, ritonavir, or nelfinavir. Initially, T-20 will be given alone, then in combination with efavirenz and nelfinavir plus either saquinavir or ritonavir. Concerns that HIV can easily become resistant to T-20, as observed in cell cultures, would potentially leave some trial participants with limited treatment options. Gilead Sciences, manufacturers of adefovir, has enlarged the access program for adefovir to include individuals who have failed two nucleoside analogs and at least one protease inhibitor. Gilead strongly recommends that study participants routinely have kidney tests, as higher doses of the drug have produced signs of Fanconi-like syndrome.^ieng