Current pharmacotherapy for the treatment of dyslipidemia associated with HIV infection

ABSTRACT

Introduction: Cardiovascular disease is an important cause of morbidity and mortality in persons with human immunodeficiency virus (PWH). The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in PWH compared to uninfected persons. Dyslipidemia is a critical link in the pathogenesis of ASCVD in PWH. Chronic inflammation associated with HIV infection may drive both dyslipidemia and ASCVD.

Areas covered: The authors review the evidence for using lipid-lowering therapy in PWH and includes an overview of the utility and complexity of using statins in PWH, in particular, drug interactions, safety, and efficacy. In addition, data covering alternate therapies like omega-3 fatty acids, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors are reviewed.

Expert opinion: Dyslipidemia is a common problem in PWH. The risk of ASCVD is higher in PWH. Lipid-lowering therapy reduces the risk of ASCVD, but clinical endpoint trials are lacking in PWH. Statin therapy is the mainstay of primary prevention for ASCVD. The timing of when to initiate primary prevention with statins in PWH is unclear. Beyond statins, there are limited data that other lipid-lowering agents have utility in PWH. Ongoing trials like the REPRIEVE trial will inform the community about the optimal approach to lipid-lowering therapy in PWH.     

Hepatitis B and C viral load changes following initiation of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection

Chronic infection with either hepatitis B (HBV) or hepatitis C virus (HCV) is frequently present in patients seropositive for human immunodeficiency virus (HIV) because of shared routes of transmission. With the advent of highly active antiretroviral therapy (HAART) regimens capable of controlling HIV replication and dramatically prolonging the survival of HIV-infected patients, the impact of co-morbid infections such as HBV and HCV has come into focus. Several studies have monitored HBV or HCV viral loads following initiation of HAART, with disparate results. The effects of HAART on hepatitis B and C plasma viral loads (n = 9 and 32, respectively) and on liver enzyme levels were studied in a large cohort of prospectively studied subjects with advanced stage HIV disease. Comparing the mean pre- and post-HAART levels, there was an estimated increase of (a) 1.40 log(10) from 4.83 to 6.24 log(10) for HBV plasma viral load (P = 0.07), (b) 0.74 log(10) from 6.38 to 7.12 log(10) for HCV plasma viral load (P = 0.001), and (c) 19.4 U/L from 37.4 to 56.8 U/L for serum alanine aminotransferase (P < 0.001). While the number of subjects co-infected with HIV and HBV was limited, these data collected in a population of advanced stage HIV-infected patients raises questions regarding the interactions of these viruses with each other and the host immune system and has implications regarding the order in which antiviral therapies are initiated.     

Fenretinide inhibits HIV infection by promoting viral endocytosis

HIV fusion is mediated by the sequential interaction of the viral envelope glycoprotein with cellular receptors at the plasma membrane. We have previously reported that the upregulation of cellular ceramide levels following fenretinide treatment inhibits HIV fusion. As ceramide facilitates the internalization of a variety of microbes, we hypothesized that it may also promote the engulfment of HIV virions. Hence, we analyzed the effect of fenretinide treatment on virus binding and uptake. We observed that virus binding is not altered by fenretinide treatment. The distribution of HIV receptors was also unchanged. In contrast, virus uptake showed a significant increase. We have determined that fenretinide treatment promotes the internalization of virions from the plasma membrane and the accumulation of virus in the endocytic fraction of HeLa cells. This effect of fenretinide appears to be specific for virus as the endosomal accumulation of gp120, transferrin and horse-radish peroxidase was not increased. Notably, fenretinide increased the infectivity of influenza virus, which fuses in the endosomal compartment upon low pH activation. Our data suggest that fenretinide treatment effectively inhibits HIV infection by re-directing the virus to the endocytic pathway.     

Factors associated with frequent and infrequent HIV testing.

Drug user treatment clients with 5 or more HIV tests (frequent testees N=43) and 0-2 HIV tests (infrequent testees-N = 56) were compared on demographic characteristics, risk behaviors, perceived risk of HIV infection to self, involvement with family members, and psychological functioning. Extreme groups of HIV testees did not differ on any variables other than an index of perceived vulnerability to HIV infection (e.g., " You think that you really could get AIDS"). That measure of felt vulnerability was not correlated significantly with needle or sexual risk behaviors, family involvement, psychological functioning or other measures of perceived risk. It was reasoned that, in a community in which both dangers and protective behaviors are widely understood, frequent testees experience a generalized and heightened concern unrelated to specific behaviors or characteristics.     

Pharmacogenetics of the lipodystrophy syndrome associated with HIV infection and combination antiretroviral therapy

INTRODUCTION: Antiretroviral drugs have been associated with several toxicities that limit their success. Of the chronic toxicities, the lipodystrophy syndrome is of special concern due to the metabolic alterations that can accompany it. Why some patients treated with a particular antiretroviral regimen develop lipodystrophy, while others do not, is a medical mystery, but it has been suggested that individuals may (or may not) have a genetically conditioned predisposition. Pharmacogenetics is the science that studies how the genetic composition of individuals can give rise to interindividual variations in response to drugs and drug toxicity. AREAS COVERED: This article reviews the published investigations on the association between host genetic determinants in treated HIV-infected patients and the presence of lipodystrophy. Studies were identified through a PubMed database search. Case-control and longitudinal studies into pharmacogenetic association were selected. Areas covered include the data on the genetic variants of mitochondrial parameters, cytokines, adipokines, proteins involved in adipocyte biology and proteins involved in stavudine metabolism. EXPERT OPINION: Most studies provide inconsistent data due to partial genetic evaluation, different assessment of lipodystrophy and low number of patients evaluated. The pharmacogenetics of lipodystrophy in HIV-infected patients treated with antiretroviral drugs still belongs in the research laboratory.     

人类免疫缺陷病毒感染者抗病毒治疗期间病毒载量与免疫学指标的关系

目的 探讨人类免疫缺陷病毒(HIV)感染者抗病毒治疗期间病毒载量(VL)与免疫学指标的关系.方法 建立前瞻性研究队列,选取2018年1月至2019年1月在保定市人民医院治疗的确认为HIV-1感染阳性的感染者200例为研究对象,给予替诺福韦(TDF)+拉米夫定(3TC)+依非韦伦(EFV)高效抗反转录病毒治疗(HAART...     

Cytomegalovirus infection in patients with HIV infection

Cytomegalovirus (CMV) is responsible for the most common viral opportunistic infection in persons with acquired immunodeficiency virus syndrome (AIDS). Clinical disease due to CMV has been recognized in up to 40% of patients with advanced HIV disease. The most common presentation is retinitis, although colitis, esophagitis, pneumonitis and neurological disorders are also reported frequently. CMV retinitis is usually diagnosed clinically, and serological testing for CMV immunoglobulin is useful to support the diagnosis. Parts of the gastrointestinal tract (esophagus and colon) are the most common extraocular sites of CMV infection in AIDS patients. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. Ganciclovir is associated mainly with hematological toxicity, while foscarnet and cidofovir are nephrotoxic. Intravitreal injections with these antiviral agents are also effective, but inconvenient, and there is a need for repeated injections. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but the occurrence of contralateral ocular and extraocular disease is a serious concern. New agents, as for example an anti-sense agent against CMV, appear promising.     

Rhabdomyolysis associated with human immunodeficiency virus (HIV) infection.

A case study is given of a 25-year old woman with rhabdomyolysis associated with HIV infection. The presenting symptoms were a 1-week history of backache, gross swelling of both hands and feet, and weakness and marked pain in most muscle groups; 3 days before admission the urine was black and she was unable to walk. Multiple, firm 1-2 cm lymph nodes were revealed during examination. White blood cell count (WBC) was 22,000/microliter with 12 pc lymphocytes, 7.3 pc monocytes, and 80.5 pc polymorphonuclear leukocytes. Hemoglobin concentration was 15.8 g/deciliter; platelet count was 124,000/microliter with a Westergren ESR of 109 mm/h. An antinuclear antibody test was negative. Serum concentration of urea was 3.8 mmol/liter, creatinine 42 microliter/liter, sodium 128 mmol/liter, and potassium 5.9 mmol/liter. Microscopic examination of urine revealed WBC 100/HPF, red blood cells 20/HBF, and granular casts. The dipstick test showed blood land protein in the urine. Electromyography showed inflammatory myopathy. Creatine Kinase (CK) concentration was 2359 IU/liter and lactate dehydrogenase concentration 1000 IU/liter. Hemolysis was present from clinical or laboratory signs. The patient tested HIV positive by ELISA (Abbott) and Western blot (Dupont). Treatment consisted of administration of 60 mg/day of prednisolone orally. Over 2 weeks, swelling of limbs was reduced and CK concentration was reduced to 931 IU/liter. The patient was discharged and did not keep a follow-up appointment. The patient did not have a history of other predisposing conditions, only HIV infection and persistent muscle weakness and inflammatory myopathy. There is evidence from other patient studies of myopathy associated with HIV infection and polymyositislike illness. In this case study, the patient may have had a acute form of polymyositis, or acute viral myositis such as occurs with echo, influenza, coxsackie, and other viral infections. A detailed viral investigation was not performed. HIV infection may have directly infected myocytes or immunosuppression predisposing to acute myositis by other pathogens. HIV-related muscle disease should include rhabdomyolysis.     

Prescribing issues in elderly individuals living with HIV

ABSTRACT

Introduction: Combined antiretroviral therapy has transformed HIV infection into a chronic disease thus people living with HIV (PLWH) live longer. As a result, the management of HIV infection is becoming more challenging as elderly experience age-related comorbidities leading to complex polypharmacy and a higher risk for drug-drug or drug–disease interactions. Furthermore, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing or inappropriate prescribing and consequently to adverse drug reactions and the subsequent risk of starting a prescribing cascade.

Areas covered: This review discusses the demographics of the aging HIV population, physiological changes and their impact on drug response as well as comorbidities. Particular emphasis is placed on common prescribing issues in elderly PLWH including drug–drug interactions with antiretroviral drugs. A PubMed search was used to compile relevant publications until February 2019.

Expert opinion: Prescribing issues are highly prevalent in elderly PLWH thus highlighting the need for education on geriatric prescribing principles. Adverse health outcomes potentially associated with polypharmacy and inappropriate prescribing should promote interventions to prevent harm including medication reconciliation, medication review, and medication prioritization according to the risks/benefits for a given patient. A multidisciplinary team approach is recommended for the care of elderly PLWH.     

Neurocognition in individuals co-infected with HIV and hepatitis C

Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area.     

Multiple polyexponentials and quasipolynomials as empirical nonlinear regression models: a case study with HIV viral load data

Measurements of HIV1-RNA plasma concentrations are an important method of assessing patient response to anti-HIV1 treatment, and in most clinical trials of such treatments HIV1-RNA levels are assessed at regular intervals of time. HIV1-RNA levels in successfully treated patients tend to follow a standard pattern of biphasic decline-a rapid early decline in viral load, followed by a period of slower decline or a steady level. Fitting nonlinear regression models to these patterns of declining HIV1-RNA levels can be of value in comparing different treatment regimes and in predicting treatment outcome. Simple exponential-decline models can give an adequate fit to the typical pattern of HIV1-RNA decline, but we have explored the extent to which curve-fitting can be improved by using two novel nonlinear model forms. Specifically, we describe the fitting of multiple polyexponential and quasipolynomial forms to longitudinal HIV1-RNA plasma data collected in two recent trials of the novel anti-HIV1 treatment Fuzeon. We comment on the practicalities of fitting these nonlinear models, and compare the fit using various criteria.     

851例HIV/AIDS患者抗病毒治疗后病毒载量和CD4+T淋巴细胞检测结果分析

目的 了解郑州市851例HIV/AIDS患者抗病毒治疗后免疫重建效果及病毒抑制情况,分析病毒载量与CD4+T淋巴细胞的相关性.方法 采集HIV/AIDS患者的外周血用于CD4+T淋巴细胞的计数,分离血浆后采用荧光探针法检测病毒载量(VL).应用SPSS 22.0对数据进行统计分析.结果 抗病毒治疗后,58.99％患者C...     

No reduction of HCV viral load in HIV patients co-infected with HCV genotype 1 during a 30 days course of nitazoxanide monotherapy

There are two new drugs approved and several in development for treatment of chronic HCV; among them nitazoxanide (NTZ). Twelve HIV/HCV genotype 1 co-infected patients were enrolled prospectively to receive a 30 days course of oral NTZ 500 mg bid. This therapy was well tolerated in this group of HIV patients co-infected with HCV genotype 1. Nevertheless no changes in HCV viral load were observed during treatment in none of the patients evaluated. This data suggests that despite the promising results reported for HCV genotype 4 mono-infected patients, NTZ exhibit poor activity as monotherapy in HIV/HCV co-infected patients with genotype 1.     

The efficacy of viral capsid inhibitors in human enterovirus infection and associated diseases

Enteroviruses are members of picornavirus family which causes diverse and severe diseases in humans and animals. Clinical manifestations of enterovirus infections include fever, hand, foot, and mouth disease, and herpangina. Enteroviruses also cause potentially severe and life-threatening infections such as meningitis, encephalitis, myocarditis, polio-like syndrome, and neonatal sepsis. With the emergence of enterovirus all over the world as the major causative agent of HFMD fatalities in recent years and in the absence of any effective anti-enteroviral therapy, there is clearly a need to find a specific antiviral therapy. Steps such as viral attachment, uncoating, viral RNA replication, and protein synthesis in the replication cycle can serve as potential targets for antiviral agents. Agents targeted at viral protein 1 (VP1), a relatively conserved capsid structure mediating viral adsorption and uncoating process, is of great potential to be anti-enterovirus drugs. Recently, considerable efforts have been made in the development of antiviral compounds targeting the capsid protein of enterovirus. This review summarizes the development of small molecules targeting enteroviral capsid protein as effective antiviral therapy.     

Treatment of HIV infection with raltegravir

Background: Raltegravir, an inhibitor of the HIV-1 integrase enzyme, is now available for the treatment of drug-resistant virus. Objective: To establish raltegravir as an effective addition to the existing antiretroviral armamentarium by reviewing pharmacokinetics, efficacy, safety and tolerability. Methods: Data from pharmacokinetic, Phase II and III clinical trials were reviewed. Results/conclusions: Results from clinical trials indicate that raltegravir is safe and highly effective in the treatment of both antiretroviral-naïve and -experienced patients.