Management of dyslipidaemia in HIV-infected patients receiving antiretroviral therapy

Dyslipidaemia associated with the treatment of HIV infection, particularly with the use of protease inhibitors (PIs), can raise cholesterol and triglyceride (TG) levels to the thresholds indicated for intervention. Recent evidence from epidemiological studies has shown that there are correlations between antiretroviral drug use and increased risks for, and incidences of, cardiovascular disease, including myocardial infarction and coronary heart disease. The primary goals of dyslipidaemia therapy for HIV patients are reductions of both low-density lipoprotein cholesterol (LDL-C) and markedly elevated TG levels. Dietary strategies and exercise programs may be tried, although these have shown inconsistent results. The two options for drug therapy are switching antiretroviral agents and using lipid-lowering drugs. Each approach is associated with advantages and limitations, and the need to maintain viral suppression must be balanced with the need to treat abnormal lipid levels. Most drug switches replace the PI component with drugs from another antiretroviral class. Selection of drug therapy for lipid lowering depends on the type of dyslipidaemia predominating and the potential for drug interactions. The use of the statins pravastatin and atorvastatin is recommended for the treatment of patients with elevated LDL-C levels and gemfibrozil or fenofibrate for patients with elevated TG concentrations. Development of new PIs with more favourable effects on the lipid profile should be of benefit.     

Estimates of intracellular delay and average drug efficacy from viral load data of HIV-infected individuals under antiretroviral therapy

We analyse viral load data of five patients under ritonavir monotherapy using a model of HIV dynamics under antiretroviral therapy that includes both drug pharmacokinetics and the intracellular delay from the time of cell infection to viral production. Using this approach we separate pharamacokinetic from intracellular delays, and obtain new estimates of intracellular delay and the antiviral efficacy of ritonavir. We find the average intracellular delay to be 1 day, in agreement with experiments. The average viral generation time is now estimated at 2 days, resulting in approximately 180 replication cycles per year. The model also reveals that ritonavir monotherapy is approximately 65% as efficacious as a recently used potent four-drug therapy, suggesting that selection for drug resistance may be facilitated by the relatively low efficacy of individual drugs, contributing in part to the inherent limitations of current therapies in combating HIV-1 infection.     

Effect of fluconazole on viability of Candida albicans over extended periods of time.

The treatment of chronic mycoses may expose the infecting organisms to antimicrobial agents for extended periods of time. It is possible that an azole antifungal drug such as fluconazole, with primarily fungistatic activity in standard in vitro susceptibility tests, might be able to damage the fungal cells and reduce their viability over prolonged incubations under nonproliferating conditions. To test this possibility, Candida albicans yeast cells were exposed to various concentrations of fluconazole in RPMI 1640 tissue culture medium for 4 h at 37 degrees C, washed free of the drug, and then incubated at 37 degrees C for a 28-day period; enumeration of the remaining CFU at various times during this period revealed no increased loss of viability for the fluconazole-exposed organisms. However, when fluconazole was added to the organisms maintained in distilled water (with or without pretreatment with the drug), a marked reduction of viability was found. At 14 days of incubation with two strains of C. albicans, negative cultures were found for 7 of 10 and 10 of 11 samples, respectively, containing 1.0 microgram of fluconazole per ml versus 0 of 10 and 1 of 11 control samples (P of < 0.01 and 0.001, respectively). The effect of fluconazole on fungal viability under these conditions became noticeable at approximately 7 days and was greater when the samples were incubated at 37 degrees C rather than 25 degrees C. These findings suggest that fluconazole may have fungicidal effects on fungal cells during prolonged exposures under conditions in which the organisms are prevented from proliferating by lack of nutrients.     

HIV-infected mothers' foci of concern during the viral testing of their infants.

The objective of this study was to explore HIV-infected mothers' most worrisome concerns during their infants' HIV viral testing. A total of 20 HIV-infected women consented to one antepartum and five postpartum study visits clustered around infant HIV viral testing time points. Content analysis was used to categorize maternal responses about their concerns. The majority (80%) of mothers identified infant health as the most worrisome concern during the prenatal and early postpartum periods. This concern declined after the second infant viral test result but rebounded before obtaining the final viral test. Once the final viral test result was known, the majority (60%) of mothers identified psychosocial issues as most worrisome. Maternal health did not surpass infant health or psychosocial issues as a primary concern. The primary concern of the HIV-infected mothers in this study was infant health during the infant viral testing period. Maternal health issues remained secondary to infant health and psychosocial issues as major concerns several months after infant viral testing was completed.     

Real-time nucleic acid sequence-based amplification assay to quantify changes in mitochondrial DNA concentrations in cell cultures and blood cells from HIV-infected patients receiving antiviral therapy

BACKGROUND: To study the clinical relevance of changes in mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) attributable to HIV infection and/or combination antiretroviral therapy (cART), a high-throughput molecular assay to quantify mtDNA is required. METHODS: We developed a quantitative real-time duplex nucleic acid sequence-based amplification assay in which both mtDNA and nuclear DNA are simultaneously amplified in 1 tube. The assay could accurately quantify mtDNA in a range of 15-1500 copies of mtDNA per 2 genomic copies with an intrarun variation of 11% and an interrun variation of 16%. We compared this real-time assay with the lactate/pyruvate ratios in fibroblasts incubated with glucose and exposed to zalcitabine. Additionally, we studied the effects of platelet contamination and the in vivo effects of cART on mtDNA in PBMCs from a small group of patients. RESULTS: Decreases in mtDNA preceded the increase in lactate/pyruvate ratios and vice versa when zalcitabine was eliminated from the culture. Platelets affected the mtDNA in PBMCs if >5 platelets per PBMC were present. Within 12 weeks, mtDNA increased and remained increased in PBMCs from patients on continuous treatment with zidovudine/lamivudine/indinavir therapy (P = 0.03), but increased if patients were switched to stavudine/didanosine therapy (P = 0.008). CONCLUSION: After drug exposure, the mtDNA assay can detect changes in mtDNA concentrations in cell lines and PBMCs, when properly controlled for platelet effects, earlier than traditional assays.     

Stavudine, lamivudine plus novel protease inhibitor therapy in antiretroviral-naive HIV-infected individuals treated for 24 weeks

Preliminary results are presented from a dose-comparison trial of the regimen stavudine/lamivudine plus the novel protease inhibitor, ABT-378/ritonavir, given to 101 antiretroviral-naive, human immunodeficiency virus (HIV)-infected subjects for > or = 24 weeks. The HIV-1 RNA had decreased to <400 copies/ml in 94% of patients and CD4 cell count had increased by approximately 160 cells/mm3 at 24 weeks. The regimen was well tolerated and merits further study.     

95例进行一线抗病毒治疗的艾滋病患者发生耐药的影响因素分析

目的 探讨95例进行一线抗病毒治疗的艾滋病(AIDS)患者发生耐药的影响因素.方法 选取95例进行一线抗病毒治疗的AIDS患者,收集其基本病例资料,分析性别、年龄、婚姻状况、感染途径等与耐药的关系,判断影响耐药的因素.结果 通过性传播,治疗前CD4+计数越少,AIDS确诊到治疗间隔越长,患者的耐药情况就越严重;感染肝炎...     

Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B

BACKGROUND: The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined. METHODS: We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry. RESULTS: Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders (P = 0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients. CONCLUSIONS: Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.     

Using viral load, CD4+ levels, and clinical response to guide antiviral therapy for HIV

The decision to start or modify antiviral therapy in patients with human immunodeficiency virus (HIV) infection is not based on any single factor. Although HIV RNA levels are the primary guide to therapy, the CD4+ count and clinical response are also important.     

Clinical significance of cytokine level and T-cell lymphocyte response to B and C hepatic viral antigens in patients with type C and B+C hepatitis receiving antiviral therapy

The authors studied the levels of cytokines (interleukin (IL)-1, IL-2, IL-4, IL-6, and interferon-gamma (IFN-gamma)) and cell response to HBV and HCV in the dynamics in patients with acute mixed hepatitis (B+C) who recovered or became chronically ill, as well as before and after treatment of hepatitis C. Patients who later recovered had high levels of IL-2 and IFN-gamma during the acute phase of the disease, and displayed T-lymphocyte sensitization to HbeAg, Hbcore Ag, and the non-structural protein HCV NS3. A significant elevation of IL-2 level and, especially, IFN-gamma level, as well as the appearance of T-lymphocyte response to HCV NS3, HCVcore Ag, and HCV NS4 was observed during antiviral therapy.     

The effects of interleukin-2 therapy on the viral reservoir in HIV+ patients.

The initial idea that potent antiretroviral therapies could eradicate HIV infection within a few years of treatment has been recently challenged by the demonstration that the viral reservoir persists in the peripheral blood and in the lymphoid tissue. For this reason, an alternative approach based on the use of interleukin-2 has been developed. This cytokine, in fact, may be able to activate infected cells, promoting viral integration and replication, making HIV susceptible to antiretroviral treatments; this fact may ultimately contribute to the eradication of the virus itself. The measurement of the viral reservoir appears therefore essential to monitor the effects of combination therapies. We summarize here the technical approaches that have been used to quantitatively assess the HIV reservoir. We also show that the prolonged use of IL-2 in association with antiretroviral drugs promotes a reduction of the viral reservoir, but is unable to eradicate HIV, even after two years of therapy. The available in vitro and in vivo data do not exclude the fact that IL-2 may have a future in the treatment of HIV infection, though new therapeutic approaches using different strategies are required to clarify this issue.     

Assessment of the values of immune response mediators in patients with acute hepatitis C receiving combined antiviral therapy

The spectrum ofcytokines was studied in 32 patients with acute hepatitis C (AHC) on combined antiviral therapy (A VT) with realdiron plus ribavirin and in 30 patients with acute HCVinfection on basic therapy (control group). The content of immune response mediators in blood serum was measured by immune enzyme assay using test systems produced by Proteinovy Konntur (Saint Petersburg). AHC patients on A VT displayed a more prominent decrease in the levels of interleukins (IL-1beta, IL-6), tumor necrosis factor-alpha (TNF-alpha) vs. controls during the second week of treatment. This fact may be explained by antifibrotic effect of interferon-alpha, (IF-alpha) and ribavarin, which is connected with suppression of hepatic stellate cells. Upon the completion of the treatment, patients with AHC displayed a significant increase in IL-2, IF-alpha, and IF-beta levels due to natural biological mechanisms of interaction between antiviral mechanisms and the human organism. In addition to antiviral action, certain immunoregulative effects of AVT were noted. The significant increase in IL-2, IF-alpha, and IF-beta during the second week of AVT in patients with a stable virusological response demonstrated a high effector potential of Th 1 lymphocytes, which favored suppression of active viral replcation, and viral elimination.     

Efficacy and safety of once-daily,extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain

Background: Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla? ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23–31% of the study populations). Methods: Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0–10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. Results: In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. Conclusion: In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD’s safety and tolerability profiles were similar to other opioid analgesics.     

Medicinal chemistry of nucleoside phosphonate prodrugs for antiviral therapy

Considerable attention has been focused on the development of phosphonate-containing drugs for application in many therapeutic areas. However, phosphonate diacids are deprotonated at physiological pH and thus phosphonate-containing drugs are not ideal for oral administration, an extremely desirable requisite for the treatment of chronic diseases. To overcome this limitation several prodrug structures of biologically active phosphonate analogues have been developed. The rationale behind the design of such agents is to achieve temporary blockade of the free phosphonic functional group until their systemic absorption and delivery, allowing the release of the active drug only once at the target. In this paper, an overview of acyclic and cyclic nucleoside phosphonate prodrugs, designed as antiviral agents, is presented.     

An improved method for monitoring efficacy of anti-retroviral therapy in HIV-infected individuals: a highly sensitive HIV p24 antigen assay.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured by a highly sensitive HIV p24 antigen-capture enzyme-linked immunosorbent assay (ELISA) in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) otherwise negative for HIV p24 antigen measured by a commercial antigen-capture ELISA. The assays were performed at baseline and at several intervals during treatment with either zidovudine (ZDV) or dideoxyinosine (ddl). To further enhance the rate of antigen detection, serum was pretreated with hydrochloric acid to denature antibody in immune complexes. Utilizing this assay system, we monitored these patients for drug efficacy. HIV p24 antigen levels obtained by using this sensitive assay decreased in 3 of 8 patients receiving ZDV during 8 weeks of ZDV treatment. Similarly, ddl administration was associated with a decrease of HIV p24 antigen levels in 3 of 5 patients. Thus, the use of the highly sensitive HIV p24 antigen assay permitted the monitoring of surrogate HIV p24 antigen as a measure of efficacy of anti-retroviral therapy in all of these patients who were otherwise HIV p24 antigen-negative at the onset of anti-retroviral therapy.