Reinitiation Of Therapy Research Articles

Expansion and Contraction of HIV-Specific CD4 T Cells with Short Bursts of Viremia, but Physical Loss of the Majority of These Cells with Sustained Viral Replication

Chronic infection with the HIV results in poor HIV-specific CD4 T cell proliferation, but more recent analyses using intracellular cytokine staining demonstrated that IFN-gamma-producing, HIV-specific CD4 T cells can be detected for years in HIV-infected subjects. Because it is not known whether the majority of HIV-specific T cells are lost or become dysfunctional, we examined the kinetics of the T cell response over an extended period of time using a panel of 10 HLA-DR tetramers loaded with HIV p24 peptides. Tetramer+ CD4 T cells were present at a relatively high frequency during acute infection, but the size of these populations substantially contracted following suppression of viral replication. Short-term cessation of antiretroviral therapy resulted in a burst of viral replication and concomitant expansion of tetramer+ CD4 T cells, and these populations again contracted following reinitiation of therapy. The kinetics with which these cell populations contracted were characteristic of effector T cells, a conclusion that was supported by their phenotypic (CCR7-CD45RA-) and functional properties (IFN-gamma+). Continued high-level viremia resulted in the physical loss of the majority of tetramer+ CD4 T cells, and the decline of HIV p24-specific CD4 T cells occurred more rapidly and was more substantial than the reduction of total CD4 T cell numbers. We conclude that the population of HIV p24-specific CD4 T cells is initially responsive to changes in the levels of viral Ags, but that the majority of these cells are lost in a setting of chronic viremia.

Successful Initiation of Combined Therapy with Valproate Sodium Injection and Divalproex Sodium Extended‐release Tablets in the Epilepsy Monitoring Unit

Patients in epilepsy monitoring units (EMUs) often require aggressive initiation or reinitiation of therapy before discharge. We developed a simple dosing scheme using valproate sodium injection (VPA-IV) and divalproex sodium extended-release (VPA-ER) tablets to minimize the time required for initiation of therapy, without increasing the likelihood of seizures and adverse effects. We identified 42 patients in the EMU, naïve to VPA-IV and VPA-ER, for whom one of the discharge AEDs included divalproex sodium. On the day of discharge, patients were loaded with 20 mg/kg VPA-IV at 6 mg/kg/min, followed by approximately 20 mg/kg VPA-ER within 1 h. The discharge daily dose of VPA-ER was identical to the dose given after the IV load. We assessed tolerability and seizure occurrence during infusion, at 1 h, 4 h, and 1 week after discharge. All patients tolerated the VPA-IV dose followed by VPA-ER. Four patients reported mild nausea, and two patients reported mild dizziness within 4 h. No seizures or significant changes in heart rate or blood pressure occurred within 4 h, and all patients were discharged the same day. All patients denied systemic complaints at 1 week, and five had seizures during the week after discharge. All patients had improved seizure frequencies at the end of the first week. VPA-IV is well tolerated and convenient for rapid loading in the EMU. When promptly followed by VPA-ER, seizure control remains excellent.

Split-dosing of subcutaneous alpha and beta interferon reduces local cutaneous complications

RATIONALE: Interferon (IFN) therapy for multiple sclerosis (MS) and hepatitis C (HepC) is associated with severe local adverse effects.METHODS: We studied the efficacy of a split-dosing regimen for subcutaneous interferons. A MS patient receiving recombinant IFN1β 9×106 units on alternate days and a HepC patient receiving pegylated IFNα2a 180mcg weekly were referred for evaluation. Erythematous lesions evolving into necrotic ulcers presented 6 weeks after IFN1β injection. Pruritic hive-like lesions developed 2 hours after IFNα2a injection. No improvement occurred with alternate injection sites. Therapy was discontinued. Prick/intradermal skin tests and incremental challenge were performed in the HepC patient due to rapid onset of reaction. Prick tests were done with undiluted IFNα2A (180mcg/1cc), histamine (6mg/ml) and saline controls. Intradermal skin testing was performed with IFNα2A diluted in saline (1:100 concentration), histamine and saline controls. Subcutaneous incremental challenge began with undiluted IFNα2A 18mcg. Trials of split-dosing, half the standard dose given at two separate sites, were initiated in both patients. The patients were followed for site reactions over subsequent weeks after therapy re-initiation.RESULTS: No immediate or delayed hypersensitivity or irritant reaction was observed after skin testing and challenge with IFNα2a. Split dosing of interferons significantly reduced the severity of reactions and permitted the continued use of these drugs.CONCLUSION: Given the efficacy of interferon therapy and the frequency of cutaneous side-effects, an alternative dosing regimen in patients with severe local complications should be considered. RATIONALE: Interferon (IFN) therapy for multiple sclerosis (MS) and hepatitis C (HepC) is associated with severe local adverse effects. METHODS: We studied the efficacy of a split-dosing regimen for subcutaneous interferons. A MS patient receiving recombinant IFN1β 9×106 units on alternate days and a HepC patient receiving pegylated IFNα2a 180mcg weekly were referred for evaluation. Erythematous lesions evolving into necrotic ulcers presented 6 weeks after IFN1β injection. Pruritic hive-like lesions developed 2 hours after IFNα2a injection. No improvement occurred with alternate injection sites. Therapy was discontinued. Prick/intradermal skin tests and incremental challenge were performed in the HepC patient due to rapid onset of reaction. Prick tests were done with undiluted IFNα2A (180mcg/1cc), histamine (6mg/ml) and saline controls. Intradermal skin testing was performed with IFNα2A diluted in saline (1:100 concentration), histamine and saline controls. Subcutaneous incremental challenge began with undiluted IFNα2A 18mcg. Trials of split-dosing, half the standard dose given at two separate sites, were initiated in both patients. The patients were followed for site reactions over subsequent weeks after therapy re-initiation. RESULTS: No immediate or delayed hypersensitivity or irritant reaction was observed after skin testing and challenge with IFNα2a. Split dosing of interferons significantly reduced the severity of reactions and permitted the continued use of these drugs. CONCLUSION: Given the efficacy of interferon therapy and the frequency of cutaneous side-effects, an alternative dosing regimen in patients with severe local complications should be considered.

Imatinib mesylate in chordoma.

To the authors' knowledge, no effective medical therapy currently is available for advanced chordoma. Imatinib mesylate is a tyrosine kinase inhibitor targeting platelet-derived growth factor receptor-beta (PDGFRB), BCR-ABL, and KIT. Six patients with advanced chordoma were treated with imatinib mesylate at a dose of 800 mg daily. In all patients, the tumor was found to be positive for PDGFRB, and in four patients PDGFRB was shown to be phosphorylated/expressed. After a treatment period of > or = 1 year, overt tumor liquefaction was evident on computed tomography (CT) scan in the first patient. In previous months, a decrease in contrast enhancement on magnetic resonance imaging (MRI) and a decrease in glucose uptake on positron emission tomography (PET) were detected. Similar signs on MRI and PET were observed in subsequent patients, who had a shorter treatment period. One of these patients initially was removed from therapy and then was readmitted to therapy because of difficulties with regard to tumor response assessment; 1 month after the reinitiation of therapy, an overt decrease in tumor density was visible on CT scan in this patient. In four of five symptomatic patients, a subjective improvement was observed early in the course of treatment. The first patient died after 17 months, with a sizeable, mostly liquefied mass. Another patient died early, apparently of unrelated causes. The remaining patients were on therapy at the time of last follow-up. Imatinib mesylate has been found to have antitumor activity in patients with chordoma. This activity might be mediated by inactivation of PDGFRB. Tumor response manifests through patterns that are similar to those observed in patients with gastrointestinal stromal tumors who respond to molecular-targeted therapy, but evolves more slowly. The benefit to the patient entailed by this pattern of tumor response in chordoma needs to be elucidated, but may be limited in the presence of significant local disease.

Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients.

To determine the effect of treatment interruptions (TI) on the evolution and persistence of drug-resistant viruses in chronically HIV-1-infected suppressed patients. The emergence of viral resistance to combination antiretroviral therapy was monitored in 11 suppressed chronically HIV-1-infected patients undergoing from one up to four sequential TI (a total of 25 TI), by genotyping of the virus for known mutations in the genes for protease and reverse transcriptase. Resistance assays were performed at the first viral rebound > 100 copies/ml. All subjects achieved resuppression of HIV-1 under the same antiretroviral therapy, regardless of the number of TI. Five of eleven patients showed no development of resistance. In the remaining six patients, the following patterns of mutations associated with viral resistance were found: one mutation (K70R), which was observed in one patient during the 1st TI and persisted during follow-up; two mutations (L90M, M184V), which were observed in four patients during the 1st TI and were intermittently present or lost following extended TI, treatment reinitiation and/or during subsequent TI; and evolution of two mutations (M184V, K219E) observed in two patients. These two mutations were not present during the 1st TI and were subsequently lost following therapy reinitiation or during the next TI. Detection of drug resistance during TI by virus genotyping assays does not predict failure to resuppress after antiretroviral therapy reinitiation nor persistence of a resistant viral population during extended interruptions or subsequent TI.

Evolution of HIV-1 multidrug-resistant genotypes during combination therapy and after the cessation of antiretroviral drugs.

Evolution of HIV-1 multidrug-resistant genotypes during combination therapy and after the cessation of antiretroviral drugs.

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients.

To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n = 67), HIV-infected patients (n = 57) had significant increases in the number and fraction of dividing CD4(+) and CD8(+) T cells. Higher percentages of dividing CD4(+) and CD8(+) T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4(+) T cell counts. Marked reductions in CD4(+) and CD8(+) T cell proliferation were seen in 11/11 patients 1-12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16-72 weeks). Decreases in naive T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4(+) and CD8(+) T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9/9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation.

Cyclical breast pain and swelling in relation to differing patterns of suppression of ovarian activity with the luteinizing hormone-releasing hormone analogue buserelin acetate: case report

The presenting complaints of an amenorrhoeic (after hysterectomy with ovarian preservation) woman were cyclical breast pain and swelling. These showed synchronicity with fluctuations in E2 levels. Both ovarian activity and symptoms initially responded to (after lag periods of approximately 40 days) daily SC injections of the LH-RH analogue buserelin acetate. After a break in treatment, the interval between reinitiation of therapy and suppression of E2 levels was prolonged markedly, ovarian function being apparently resistant even to very large doses of the analogue.

Discontinuation of chronic diuretic therapy in stable congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy

To assess the feasibility of diuretic discontinuetion in patients with stable congestive heart failure (CHF) and to identify risk factors for subsequent development of congestion, a prospective, 12-week clinical trial of unmasked diuretic withdrawal was conducted with continuation of background CHF therapy and double-blind randomization to placebo or lisinoprl. Forty-one patients with a history of CHF and continuous diuretic use for ≥3 months had all diuretic therapy discontinued, and therapy with lisinopril 5 mg (target 20 mg)/day (n = 20) or placebo (n = 21) begun the next day. A diuretic was restarted if new or worsening CHF symptoms and signs developed. Twelve patients (299% did not require diuretic reinitiation at any time during follow-up, whereas 29 (71%) restarted diuretic therapy after a median of 15 days (range 2 to 42). Fourteen patients taking lisinopril and 15 taking placebo required diuretic drugs (p = NS). The baseline daily furosemide dose of >40 mg, a left ventricular ejection fraction ≤0.27, and history of systemic hypertension were independently predictive of early diuretic reinitintion by Cox proportional-hazards analysis. The probability of remaining diurstic-free after 6 weeks was 71% if none of these criteria were present. This trial demonstrates the feasibility of discontinuing diuretic drugs in certain patients with stable CHF and predicts those patients likely to require reinitiation of therapy. Diuretic withdrawal may be warranted when the furosemide dose is ≤40 mg/day, left ventricular ejection fraction is >0.27 and when no history of systemic hypertension is present.