Lipid disorders in antiretroviral-naive patients treated with lopinavir/ritonavir-based HAART: frequency, characterization and risk factors

OBJECTIVES: The aim of this study was to evaluate the frequency, characteristics and risk factors of lipid changes associated with lopinavir/ritonavir treatment in antiretroviral-naive patients. METHODS: A prospective cohort of 107 antiretroviral-naive HIV-infected patients was followed for 12 months after starting lopinavir/ritonavir-based highly active antiretroviral therapy. RESULTS: At 12 months, percentages of patients with hypercholesterolaemia and hypertriglyceridaemia were 17.4% and 40%, respectively. Mean increases in total cholesterol and triglycerides were 40.7 and 73.3 mg/dL. There was a significant increase in both low-density and high-density (HDL) cholesterol, and no increase in the total cholesterol/HDL ratio (from 4.16 at baseline to 4.49 after 12 months). Baseline cholesterol > 200 mg/dL and triglycerides > 150 mg/dL were independent risk factors for dyslipidaemia, while hepatitis C coinfection appeared to be protective. CONCLUSIONS: Patients with elevated lipid values at baseline have the greatest risk of developing hypercholesterolaemia and hypertriglyceridaemia after starting lopinavir/ritonavir. Antiretroviral-naive patients coinfected with hepatitis C have a low risk of developing hyperlipidaemia after starting lopinavir/ritonavir.     

Optimum combination therapy regimens for HIV/HCV infection

HIV-HCV co-infection mostly affects intravenous drug users, in whom prevalence has tended to decrease in recent years, while it has increased in men who have sex with men, with occurrence of acute hepatitis C. Hepatitis C has a poorer prognosis in patients co-infected with HIV, as clinical progression is faster and degree of hepatic fibrosis is greater. However, optimized ARV treatment is clearly associated with slower progression to hepatic complications. Interactions between HCV and HIV drugs are numerous, which underlines the importance of pharmacological advice for HIV-treated patients before they start HCV treatment. In HIV-HCV co-infection, treatment of hepatitis C has to be offered as in mono-infected patients (US and European countries) or to all patients (French guidelines). In most patients, HCV eradication is achieved with different DAA associations, the choice and duration being driven by HCV genotype, hepatic fibrosis stage, and whether patients have been previously treated or not.     

Impact of steady-state lopinavir plasma levels on plasma lipids and body composition after 24 weeks of lopinavir/ritonavir-containing therapy free of thymidine analogues

OBJECTIVES: To study the impact of lopinavir/ritonavir-containing therapy on plasma lipids and body fat of HIV-infected adults and to assess whether lopinavir plasma levels at steady state are correlated with plasma lipids and body fat after 24 weeks. METHODS: Patients had their antiretroviral therapy switched to an antiretroviral regimen containing lopinavir/ritonavir plus one or two non-thymidine analogues. Body composition was assessed by dual energy X-ray absorptiometry at baseline and at week 24 and an intensive pharmacokinetic (PK) 12 h profile was performed at week 2. RESULTS: Twenty-six patients were included. Plasma triglycerides (from 206 mg/dL to 261 mg/dL, P = 0.09) and total cholesterol (from 201 to 206 mg/dL, P = 0.03) increased from baseline to week 24. There was a significant rise in total fat (from 10.9 to 11.9 kg, P = 0.02) and limb fat (from 3.8 to 4.4 kg, P = 0.02) from baseline to week 24. We did not find any correlation between PK lopinavir levels and changes over time for triglycerides, cholesterol or body fat composition. CONCLUSIONS: There was an increase in plasma triglycerides and total cholesterol levels and a gain in both total and limb fat at 24 weeks, but these changes were not correlated with lopinavir plasma levels.     

Interaction between HIV-1 and HCV infections: towards a new entity?

Since human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same modes of transmission, HIV-HCV co-infected patients are relatively common. Until recently, the clinical course of HCV in co-infected patients was overshadowed by the high morbidity and mortality of HIV disease. Recent reductions in morbidity and mortality among HIV-infected patients due to the advent of highly active antiretroviral therapy (HAART), have contributed to the emergence of HCV as a significant viral pathogen in this population. This article reviews the current evidence on the epidemiology and clinical implications of an interaction between HIV-1 and HCV infections.     

安徽、河南、山西3省自愿咨询检测人群HIV/HCV共感染及HCV基因亚型初步分析

目的了解目前我国安徽、河南、山西3省自愿咨询检测(VCT)人群HIV感染者中HIV/HCV共感染率及HCV亚型的分布情况。方法对来自安徽、河南、山西3省VCT人群中HIV阳性样本进行HCV抗体检测并对HCV阳性的样本进行HCVC/E1区RT-PCR扩增、基因测序,分析HCV的亚型分布。结果在HIV阳性的382份样本中,检出HCV阳性215份,3省VCT人群HIV感染者中HIV/HCV共感染率平均为56.3%,安徽、河南、山西3省分别为50.0%、59.3%、42.9%。其中,经血传播人群的HIV/HCV共感染率为72.1%,经性传播人群为33.3%,其它途径人群为36.6%。HCV PCR扩增成功98份,1b亚型69份(70%),2a亚型28份(29%),3a亚型1份(1%)。结论安徽、河南、山西VCT人群具有较高的HIV/HCV共感染率;经性传播人群HIV/HCV共感染率高于国外水平;HIV/HCV共感染对HCV亚型分布无显著影响。     

CD81和趋化因子CC受体5与丙型肝炎合并人类免疫缺陷病毒感染的相关性研究

目的 检测外周血CD4＋及CD8＋T淋巴细胞表面CD81、CCR5的表达,探讨与丙型肝炎病毒（HCV）单纯感染、人类免疫缺陷病毒（HIV）单纯感染和HCV/HIV合并感染的关系.方法 采用流式细胞术,检测HCV感染组（n=21）、HIV感染组（n=14）、HCV/HIV感染组（n=28）及正常对照组（n=30）人外周血CD4＋及CD8＋T淋巴细胞表面CD81和CCR5的表达.结果 与正常对照组相比,外周血CD4＋T淋巴细胞表面CD81,在HCV感染组表达变化不明显,而在HIV感染组和HCV/HIV合并感染组中低表达;CD8＋T淋巴细胞表面CD81,在HCV感染组、HIV感染组和HCV/HIV合并感染组中都呈高表达.外周血CD4＋T和CD8＋T淋巴细胞表面CCR5,在HIV感染组高表达,而在HCV感染组和HCV/HIV合并感染组中低表达.结论 HCV/HIV合并感染中,影响外周血CD4＋及CD8＋T淋巴细胞表面CCR5表达的主要因素是HCV感染;而合并感染对CD4＋及CD8＋T淋巴细胞表面CD81的表达,其影响作用是不相同的.     

Pegylated-IFNα2a for HIV/hepatitis C virus coinfected patients: out with the old,in with the new

Introduction: Liver disease is a major burden in patients co-infected with HIV and hepatitis C virus (HCV). From the time of its approval, pegylated-IFNα-2a (pegIFN-α2a) has played a major role in treatment of HCV in HIV/HCV co-infection.

Areas covered: This article briefly summarizes the epidemiology of HCV/HIV co-infection, the pharmacokinetic, and pharmacodynamic properties of pegIFN-α2a. Results from clinical trials investigating therapies containing pegIFN-α2a for HIV/HCV co-infected patients will be discussed with a focus on efficacy and safety.

Expert opinion: PegIFN-α2a has improved rates of sustained virologic response for co-infected patients. In combination with direct-acting antivirals (DAA), the disparity between mono- and co-infected patients is beginning to disappear. For the first time, IFN-free regimens are available in clinical practice. It is unlikely that pegIFN-α2a will continue to be a critical component in treatments for HCV in the general co-infected population.     

HIV and hepatitis C co-infection

HIV/HCV co-infection is emerging as a major cause of morbidity and mortality in the 21st century. This editorial reviews the prevalence of co-infection, the factors involved in acquisition of HCV, and the influence of co-infection on disease progression. We examine the results of the major co-infection trials including APRICOT, ACTG 5071 and RIBAVIC. These trials, in association with emerging evidence for future therapies currently undergoing investigation, have led to increased hope of treatment success in co-infected individuals.     

Impact of HIV on HCV, GBV-C/HGV, and HBV infection

To investigate influence of HIV co-infection on HCV, we examined 58 Japanese hemophiliacs with chronic hepatitis C(CHC) including 25 patients co-infected with HIV. HCV RNA levels and liver function were not affected statistically by the presence of HIV. Further studies are necessary to evaluate the impact of HIV on the prognosis of CHC in hemophiliacs. We were the first to report a beneficial effect of GBV-C/HGV infection on the course of HIV disease and many studies were confirmed our results. Discussions of these important issues such as impact of HIV on GBV-C/HGV and HBV have been performed in this paper.     

HCV RNA对HIV合并HCV感染者高效抗逆转录病毒治疗的影响

目的 探讨HCV RNA对HIV和HCV合并感染者接受高效抗反转录病毒治疗(highlyactive antiretroviral therapy,HA.ART)后疗效、肝脏功能和血脂的影响.方法 招募我国河南既往有偿供血人群中接受HAART治疗的HIV/HCV合并感染者275例,每6个月随访一次,定期检测HCVRNA、HIV RNA、CD+4T淋巴细胞计数、肝脏功能指标和血脂等实验室指标,采用卡方检验、成组设计秩和检验比较HCV RNA阳性组和HCV RNA阴性组HAART治疗后HIV病毒抑制率、免疫学应答、肝损伤和血脂的差异.结果 HAART治疗6月以上患者中,HCV RNA阳性组和HCV RNA阴性组HIV完全抑制率差异无统计学意义(45.6%vs.38.5%,x2=1.150,P>0.05);HAART治疗前(286个/μ1 vs.209个/μ1,z=0.734,P=0.463)、治疗后6个月(310个/μ1 vs.362个/μ1,z=0.562,P=0.574)、12个月(378个/μl vs.289个/μ1,Z=1.091,P=0.275)、18个月(363个/μ1 vs.288个/μ1,z=1.435,P=0.151)、24个月(413个/μ1 vs.348个/μ1,z=0.939,P=0.348)CD+4;T淋巴细胞计数在HCV RNA阳性组和HCV RNA阴性组间差异无统计学意义.HCV HNA阳性组血清ALT(55.0 U/L vs 29.5 U/L,Z=6.789,P<0.01)、AST(46.0 U/L vs.33.0 U/L,Z=4.890,P<0.01)、TBIL(9.3 mmol/L vs.7.2 mmol/L,z=3.748,P<0.01)水平显著高于HCV RNA阴性组;HCV RNA阳性组HAART治疗后发生肝损伤的风险显著高于HCV RNA阴性组(调整后优势比aOR=3.8,P<0.01).HIV/HCV合并感染者HCV RNA阳性组TG水平显著低于HCV RNA阴性组(1.2 mmol/Lvs.1.4 mol/L,Z=1.936,P=0.043)、而HDL-C水平显著高于HCV RNA阴性组(1.5 mmol/L vs.1.3 mmol/L,z=2.251,P=0.024).结论 HCV RNA对HIV/HCV合并感染者HAART治疗后HIV病毒抑制率无影响,亦不影响HAART治疗后CD+4淋巴细胞的恢复;HCV RNA是HIV/HCV合并感染者HAART治疗后肝损伤的独立危险因素,但可能减轻HAART治疗引起的血脂异常.     

HAART attenuates liver fibrosis in patients with HIV/HCV co-infection: fact or fiction?

Since highly active antiretroviral therapy (HAART) has significantly improved survival in patients with HIV, liver disease from hepatitis C virus (HCV) infection is now an important cause of morbidity and mortality in such a cohort. Studies assessing liver fibrosis in an HIV/HCV cohort are beset with methodological flaws and heterogeneity of the study population, precluding definite conclusions. Nonetheless, recent data (albeit from retrospective studies) do suggest that HAART can attenuate liver fibrosis in the co-infected cohort with fibrosis progression rates comparable to the mono-infected patients. This is especially true for those patients whose HIV was diagnosed after 1996 and for whom HAART is associated with successful viral suppression. The mechanism/s underlying this favourable course of events however remain speculative but could be related to immune restoration-induced changes in inflammatory and fibrogenic cytokines or to a direct effect of HAART on hepatic fibrosis. Therefore with the current available evidence it seems unjustifiable to defer HAART in those that need it because of concerns regarding potential hepatotoxicity as the benefits (both from the HIV and HCV viewpoint) probably outweigh any potential risks. Nonetheless, this issue can only be unequivocally resolved by better designed prospective studies.     

Resolving hyperlipidemia after liver transplantation in a patient with primary sclerosing cholangitis

A 64-year-old man with primary sclerosing cholangitis (PSC) and resultant liver failure presented to our hospital with severe dyslipidemia (total cholesterol, 525 mg/dL; low-density lipoprotein (LDL) cholesterol, 489 mg/dL; high-density lipoprotein (HDL) cholesterol, 13 mg/dL; triglycerides, 114 mg/d) and coronary artery disease. The abnormal lipid profile of patients with cholestatic liver disease, such as PSC, includes an abnormal atherogenic LDL called lipoproteinX. The patient's dyslipidemia persisted despite treatment with a statin. Lipids normalized only after liver transplantation (total cholesterol, 135 mg/dL; LDL cholesterol, 60 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; triglycerides, 130 mg/dL). To the best of our knowledge, the dramatic improvement in the lipid profile after liver transplantation represents the first such published report for PSC. The recognition of dyslipidemia and atherosclerosis in those with cholestatic liver disease and the normalization of lipid profile after liver transplantation warrant further study. We present a review of dyslipidemia in cholestatic liver disease, its relationship to atherosclerosis, and its treatment.     

Faldaprevir (BI 201335) for the treatment of hepatitis C in patients co-infected with HIV

Chronic HCV infection affects 130–170 million individuals worldwide and there are currently 34 million people living with HIV/AIDS. The aim of treatment of HCV is the elimination of the virus (sustained virological response). With development of drugs that specifically target HCV replication, direct-acting agents, sustained virological response rates have dramatically changed for genotype 1 infections. Challenges in the use of direct-acting agents in patients with HIV/HCV co-infection include the potential for drug–drug interactions between HIV and HCV drugs, additional drug toxicities and the need for therapy with IFN-α. Faldaprevir (FDV), previously known as BI 201335, is a second-wave HCV NS3/4A protease inhibitor with highly potent in vitro activity against HCV GT-1a/1b and improved pharmacokinetics suitable for once-daily dosing. FDV is currently in Phase III development. This article will review the pharmacology and pharmacodynamics of FDV, the efficacy and safety of the drug and explore possible future developments in the management of chronic hepatitis C infection, focusing on HIV/HCV co-infected patients.     

Ciprofibrate treatment decreases non-high density lipoprotein cholesterol and triglycerides and increases high density lipoprotein cholesterol in patients with Frederickson type IV dyslipidemia phenotype

OBJECTIVE: The combination of hypertriglyceridemia and low high density lipoprotein (HDL) cholesterol is one of the most common lipid abnormalities. Thus, the aim of this study was to determine the effects of ciprofibrate on lipid profile in patients with Frederickson's type IV dyslipidemia phenotype. RESEARCH DESIGN AND METHODS: Seventy-five patients with type IV dyslipidemia were assigned at random to 1 of 2 therapeutic options: group A (control), American Heart Association (AHA) Step II diet and physical activity; and group B, AHA diet, physical activity, and ciprofibrate 100 mg daily for 8 weeks. The lipid profile of all patients was determined at baseline and after therapeutic intervention. RESULTS: Patients in group B (treated with ciprofibrate) compared with group A (control) had significantly higher reductions in total cholesterol (downward arrow 14.2% vs. downward arrow 4.8%; P < 0.02), triglycerides (downward arrow 38.0% vs. downward arrow 21.6%; P < 0.007), very low density lipoprotein cholesterol (downward arrow 38.0% vs. downward arrow 21.6%; P < 0.007), non-HDL cholesterol (downward arrow 20.5% vs. downward arrow 7.1%; P < 0.007), and total cholesterol/high density cholesterol ratio (downward arrow 25.6% vs. downward arrow 9.4%; P < 0.01). The ciprofibrate group had a significantly higher increase in HDL cholesterol levels compared with the other group (upward arrow 25.0% vs. upward arrow 9.6%, P < 0.02). CONCLUSIONS: Ciprofibrate treatment effectively reduced triglyceride-rich particles and non-HDL cholesterol, and significantly increased HDL cholesterol, proving its effectiveness in patients with low HDL cholesterol and type IV Frederickson's hyperlipidemia.     

Comparing a novel equation for calculating low-density lipoprotein cholesterol with the Friedewald equation: A VOYAGER analysis

Treating elevated low-density lipoprotein cholesterol (LDL-C) to risk-stratified target levels is recommended in several guidelines. Thus, accurate estimation of LDL-C is required. LDL-C is typically calculated using the Friedewald equation: (total cholesterol) – (non-high-density lipoprotein cholesterol [non-HDL-C]) – (triglycerides [TGs]/5). As the equation uses a fixed value equal to 5 as a divisor for TGs, it does not account for inter-individual variability, often resulting in underestimation of risk and potentially undertreatment. It is specifically inapplicable in patients with fasting triglycerides ≥400 mg/dL. A novel method of LDL-C calculation was derived and validated by Martin et al.: (non-HDL-C) – (triglycerides/adjustable factor). This equation uses an adjustable factor, the median TG:very-low-density lipoprotein cholesterol ratio in strata defined by levels of TG and non-HDLC, as divisor for TGs, and the adjustable factor ranging from 3 to 12 has been shown to provide more accurate estimates of LDL-C compared with the Friedewald equation using a direct assay as the gold standard.We used 70,209 baseline and on-treatment lipid values from the VOYAGER meta-analysis database to determine the difference in calculated LDL-C values using the Friedewald and novel equations. In patients with TGs <400 mg/dL, LDL-C values calculated using the novel equation were plotted against those calculated using the Friedewald equation. The novel equation generally resulted in LDL-C values greater than the Friedewald calculation, with differences increasing with decreasing LDL-C levels; 23% of individuals who reached a LDL-C target of 70 mg/dL with the Friedewald equation did not achieve this target when the novel equation was used to calculate LDL-C; these figures were 8% and 2% for <100 mg/dL and < 130 mg/dL targets, respectively. In patients with triglycerides ≥400 mg/dL, in whom the Friedewald equation is not valid, lipid values calculated using the novel equation were compared with those obtained by β-quantification. Values calculated with the novel equation did not appear to be closely related with those calculated by β-quantification in these patients. In conclusion, the novel equation provides a higher estimation of exact LDL-C values than the Friedewald equation, particularly in patients with low LDL-C levels, which may result in undertreatment of some patients whose LDL-C was calculated using the Friedewald method. However, neither may be suitable for patients with TG ≥400 mg/dL.     

中国HCV/HIV合并感染者T淋巴细胞表面CD81、CXCR3表达的研究

目的探讨T淋巴细胞表面受体CD81、CXCR3，在丙肝病毒（HCV）单纯感染，艾滋病病毒（HIV）单纯感染和HCV／HIV合并感染过程中的表达及意义。方法采用流式细胞术，检测HCV感染组（n=21），HIV感染组（n=14），HCV／HIV感染组（n=28）及正常对照组（n=30）人外周血CD4^＋T淋巴细胞和CD8^＋T淋巴细胞表面CD81、CXCR3的表达。结果HIV感染组及HCV／HIV合并感染组CD4^＋T细胞表面CD81、CXCR3表达显著降低（P〈0．001），CD8^＋T细胞表面CD81、CXCR3表达显著升高（P〈0．001）；HCV感染组CD4^＋及CD8^＋T细胞表面CXCR3表达轻度升高但差异不显著，CD81在CD4^＋T细胞表面轻度升高而在CD8^＋T细胞表面明显升高（P〈0．01）。结论中国HCV／HIV合并感染患者外周血T淋巴细胞表面受体CD81、CXCR3，在CD4^＋T细胞表面表达降低，而在CD8^＋T细胞表面表达升高。     

The SWITCHMRK studies: substitution of lopinavir/ritonavir with raltegravir in HIV-positive individuals

Protease inhibitors potently suppress HIV viral load but are often associated with metabolic disturbances such as dyslipidemias and lipodystrophy. In addition to exercise, diet modification and anti-lipid therapies, one potential management strategy for HIV-positive patients with dyslipidemia is to switch any antiretrovirals that may be exacerbating the condition to more lipid-neutral drugs. The SWITCHMRK studies examined the effects of substituting lopinavir/ritonavir, a protease inhibitor known to cause dyslipidemias, with the integrase inhibitor raltegravir. Participants who switched from lopinavir/ritonavir to raltegravir experienced an improvement in cholesterol and triglycerides at 12 weeks; however, a large proportion of patients in the raltegravir arms did not maintain HIV virologic suppression at less than 50 copies/ml at week 24. Further analyses are underway to determine why more patients in the raltegravir arms experienced increased virologic failure and to determine whether switching lopinavir/ritonavir with raltegravir may be appropriate for specific subgroups of patients.     

Adding HCV treatment to HIV treatment in HIV-HCV coinfected patients: the impact on the different dimensions of fatigue and self-reported side effects

Hepatitis C virus (HCV) infection is frequent among human immunodeficiency virus (HIV)-infected patients, and is often associated with disabling symptoms such as fatigue. The purpose of this study was to assess the effect of HCV treatments on the perceived physical, cognitive, and psychosocial impact of fatigue (Fatigue Impact Scale) among HIV-HCV coinfected patients. A cross-sectional survey was conducted among 223 adult coinfected patients being followed-up in two clinical centers located in the south of France. Analysis was focused on patients who answered a self-administered questionnaire and who were being treated for their HIV infection (n=139). The cognitive, physical, and psychosocial impact of fatigue was significantly worse in patients also receiving HCV treatment (n=24) than in those receiving HIV treatment only (n=115). Along with depression, the number of self-reported treatment-related side effects was independently associated with fatigue scores after adjustment for all other characteristics. This number was significantly higher among patients on HCV treatment than among those who were not (relative risk [95% confidence interval]=1.4 [1.1; 1.7], P=0.002). In particular, skin or hair problems and general symptoms such as loss of appetite, loss of weight, fever, and headache were more prevalent among these patients. In conclusion, the combination of HIV and HCV treatments results in more self-reported side effects that exacerbate the perceived impact of fatigue among HIV-HCV coinfected patients. Effective follow-up of HCV-treated HIV-coinfected patients should, therefore, include close consideration and management of patients' subjective experience with treatments to reduce the burden of HCV-associated fatigue.