Prevalence and Characteristics of Self-Reported Hypothyroidism and Its Association with Nonorgan-Specific Manifestations in US Sarcoidosis Patients: A Nationwide Registry Study

Little is known about the prevalence, clinical characteristics and impact of hypothyroidism in patients with sarcoidosis. We aimed to determine the prevalence and clinical features of hypothyroidism and its relation to organ involvement and other clinical manifestations in patients with sarcoidosis. We conducted a national registry-based study investigating 3835 respondents to the Sarcoidosis Advanced Registry for Cures Questionnaire between June 2014 and August 2019. This registry is based on a self-reported, web-based questionnaire that provides data related to demographics, diagnostics, sarcoidosis manifestations and treatment. We compared sarcoidosis patients with and without self-reported hypothyroidism. We used multivariable logistic regression and adjusted for potential confounders to determine the association of hypothyroidism with nonorgan-specific manifestations. 14% of the sarcoidosis patients self-reported hypothyroidism and were generally middle-aged white women. Hypothyroid patients had more comorbid conditions and were more likely to have multiorgan sarcoidosis involvement, especially with cutaneous, ocular, joints, liver and lacrimal gland involvement. Self-reported hypothyroidism was associated with depression (adjusted odds ratio (aOR) 1.3, 95% CI 1.01–1.6), antidepressant use (aOR 1.3, 95% CI 1.1–1.7), obesity (aOR 1.7, 95% CI 1.4–2.1), sleep apnoea (aOR 1.7, 95% CI 1.3–2.2), chronic fatigue syndrome (aOR 1.5, 95% CI 1.2–2) and was borderline associated with fibromyalgia (aOR 1.3, 95% CI 1–1.8). Physical impairment was more common in patients with hypothyroidism. Hypothyroidism is a frequent comorbidity in sarcoidosis patients that might be a potentially reversible contributor to fatigue, depression and physical impairment in this population. We recommend considering routine screening for hypothyroidism in sarcoidosis patients especially in those with multiorgan sarcoidosis, fatigue and depression

Intracellular Pharmacokinetics of Once versus Twice Daily Zidovudine and Lamivudine in Adolescents▿ ‡

Zidovudine (ZDV) and lamivudine (3TC) metabolism to triphosphates (TP) is necessary for antiviral activity. The aims of this study were to compare ZDV-TP and 3TC-TP concentrations in adolescents receiving twice daily (BID) and once daily (QD) regimens and to determine the metabolite concentrations of ZDV and 3TC during chronic therapy on a QD regimen. Human immunodeficiency virus-infected patients (12 to 24 years) taking ZDV (600 mg/day) and 3TC (300 mg/day) as part of a highly active antiretroviral therapy regimen received QD and BID regimens of ZDV and 3TC for 7 to 14 days in a crossover design. Serial blood samples were obtained over 24 h on the QD regimen. Intracellular mono-, di-, and triphosphates for ZDV and 3TC were measured. The median ratio of BID/QD for ZDV-TP predose concentrations was 1.28 (95% confidence interval [CI] = 1.00 to 2.45) and for 3TC-TP was 1.12 (95% CI = 0.81 to 1.96). The typical population estimated half-lives (± the standard error of the mean) were 9.1 ± 0.859 h for ZDV-TP and 17.7 ± 2.8 h for 3TC-TP. Most patients had detectable levels of the TP of ZDV (24 of 27) and 3TC (24 of 25) 24 h after dosing, and half-lives on a QD regimen were similar to previously reported values when the drugs were given BID. Lower, but not significantly different, concentrations of ZDV-TP were demonstrated in the QD regimen compared to the BID regimen (P = 0.056). Although findings were similar between the BID and QD groups, the lower concentrations of ZDV and the number of patients below the level of detection after 24 h suggests that ZDV should continue to be administered BID

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV

Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy

BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants \u3e or =14 days to /r therapy, and doses were modified to maintain LPV predose concentrations \u3e1 microg/mL and area under the curve (AUC) /mL. RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group

Pharmacokinetics of High-Dose Lopinavir-Ritonavir with and without Saquinavir or Nonnucleoside Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pediatric and Adolescent Patients Previously Treated with Protease Inhibitors▿ †

Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m2 orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m2 p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m2 p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log10, with a median maximal decrease in viral load of −1.57 log10 copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) μg·h/ml and median LPV trough concentration (Ctrough) of 10.8 (range, 4.1 to 25.3) μg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) μg·h/ml and the median SQV Ctrough was 2.1 (range, 0.2 to 4.1) μg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach