Emerging drug toxicities of highly active antiretroviral therapy for human immunodeficiency virus (HIV) infection

To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease. All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities; hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed. With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.     

Therapeutic drug monitoring in highly active antiretroviral therapy

Importance of the field: Despite the efficacy of combination antiretroviral therapy (ART), a large proportion of patients living with HIV/AIDS on ART does not achieve or maintain adequate virological suppression. Therapeutic drug monitoring (TDM) has been utilised to improve treatment outcomes of ART.

Areas covered in the review: The potential incorporation of TDM into the clinical HIV management is supported by the existing relationship between drug exposure and efficacy/toxicity, the high inter-patient variability pharmacokinetics, and the accurate, specific and rapid method for drug level determination. The current status of TDM in ART is reviewed in this article with discussions on its feasibility, potential use and limitations.

What the reader will gain: Mounting evidence from clinical trials has indicated the potential use of TDM in reducing the rates of treatment failure and adverse effect, avoiding the drug interactions, and special populations, such as children, pregnant women and patients with co-infections. TDM may play an important role even in resource-limited settings, to safeguard expanded use of bioequivalent generic antiretroviral drugs and avoid drug interactions with traditional Chinese medicines.

Take home message: TDM is still in the centre of controversy in that several critical issues need to be addressed, such as limited adherence assessment, inappropriate response predictors, insufficient validation of target concentration windows and lack of the quality control of assay. The utility of TDM will remain experimental until more data are obtained from large clinical trials showing the benefit of TDM.     

艾滋病合并结核病患者的抗结核治疗

艾滋病患者由于细胞免疫功能低下,极易发生各种机会感染。高效抗反转录病毒联合治疗（highly active antiretroviral therapy,HAART）在临床的广泛应用使艾滋病机会感染明显减少。然而,由于我国艾滋病患者确诊时大多处于疾病发病期,患者免疫功能严重缺陷,同时我国还有相当比例的艾滋病患者未能接受抗病毒治疗,部分患者由于依从性差、药物毒副作用、HIV耐药等原因致使抗病毒疗效并不理想。     

Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry,retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections

Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified ritonavir-boosted atazanavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, up to a five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use.From the Clinical EditorThis team of authors describes a novel method for macrophage folate receptor-targeted antiretroviral therapy. Atazanvir entry, retention, and antiretroviral activities were superior using the presented method, and so was its biodistribution, enabling a more efficient way to address human immunodeficiency virus infections, with a hoped for clinical application in the near future.     

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.     

Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Introduction: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial.

Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English.

Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations.     

Prevention and management of occupational exposures to human immunodeficiency virus (HIV)

Occupational exposure to blood and other potentially infectious body fluids places health care workers at risk for acquisition of bloodborne pathogens, including the human immunodeficiency virus (HIV). Utilizing appropriate techniques, personal protective equipment, and safer "sharp" technology can minimize the risk of these exposures. When exposure does occur, immediate evaluation and initiation of post-exposure prophylaxis, when indicated. can substantially reduce the risk of transmission of HIV. In this article, the basic concepts of exposure prevention and management are reviewed.     

Human immunodeficiency viruses and drug therapy: resistance and implications for antiretroviral therapy

Through a concerted effort to combat the human immunodeficiency virus (HIV) epidemic, researchers have made significant strides in molecular biology, virology, and immunology, which have resulted in an increased understanding of the complexities of this infection. The biggest obstacle to the success of current HIV therapy, however, is the emergence of viral resistance. Viral resistance is caused by mutations in the HIV-1 genome coding for structural changes in the target enzymes that can affect the binding or activity of the inhibitors. More information on the genetic basis of HIV resistance, mechanisms of viral variation, and therapeutic strategies for overcoming HIV resistance are needed. Sixty million people have been infected with HIV, 24 million have died, and it is projected that 200 million individuals will be infected by 2020.     

Therapeutic drug monitoring in children with HIV/AIDS

In this paper we present an overview on the use of TDM in the treatment of HIV-1-infected children. The processes of growth and development have a significant impact on drug metabolism. The use of TDM makes it possible to optimize plasma drug concentrations of antiretroviral drugs. This is important when one considers that the levels of viral suppression and drug toxicity in adults and children are associated with the plasma concentration of PIs and NNRTIs. Indeed, in clinical practice the use of TDM in the treatment of HIV-1-infected children has favorable results. However, there is a serious shortage of population reference values of antiretroviral medication in children. Targeting plasma drug levels in children to adult reference values may be insufficient because of the unique features of HIV infection in children. Apart from its primary function for dose optimization, TDM can also be used as a tool to assess adherence to antiviral medication. One should, however, be cautious to base assumptions on plasma levels alone because aberrant plasma levels may also be the result of other factors such as changes in nutritional habits, drug-drug interactions, or changing gastric motility. We conclude that TDM is a useful tool in the treatment of HIV-1-infected children. Additional data are needed to establish child-specific reference values and to assess the optimal method of TDM.     

治疗药物监测(TDM)与新抗癫痫药

治疗药物监测 (ＴｈｅｒａｐｅｕｔｉｃＤｒｕｇＭｏｎｉｔｏｒｉｎｇ ,ＴＤＭ)是近代临床药物治疗学最重大的进展之一 ,过去 30年间 ,ＴＤＭ对临床常用抗癫痫药 (ａｎｔｉｅｐｉｌｅｐｔｉｃｄｒｕｇ ,ＡＥＤ ,亦称老ＡＥＤ)的合理应用起了至关重要的指导作用[1] 。近几年又有数种新ＡＥＤ在美、欧和日本陆续上市。这些新ＡＥＤ大都是预先经过作用机制设计而人工合成的 ,较那些偶然发现的老ＡＥＤ有很多药代动力学 (ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ,ＰＫ)方面的优点 ,如蛋白结合率很低或者为零 ,与其他药物的ＰＫ相互作用较少等[2 ,3 ] …     

The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update

The use of highly active antiretroviral therapy (HAART) has considerably improved the quality of life and has increased the survival of HIV-infected individuals. Although HAART can successfully suppress viral replication in the long term, it is not without significant toxicity, which can seriously compromise treatment effectiveness. Moreover, the rapid rate of virus mutation and subsequent emergence of drug-resistant HIV variants threaten the longer-term efficacy of HIV treatment. The most common adverse effects caused by HAART include a metabolic syndrome with lipodystrophy, hyperlipidemia and insulin resistance, deterioration in the clinical status due to various exaggerated local and systemic inflammatory reactions during the immunerestoration disease, and various hepatic, peripheral and cardiac muscle, kidney, bone, bone marrow, retinal, ear, and skin toxicities. The heterogeneity in the organs affected by the different drugs and the morphological features observed in tissues in HAART-treated patients raise possible explanations including differential distribution or activation of these agents. Antiretroviral drugs from new classes, as well as new drugs from existing classes with favorable resistance and side effect profiles are in various stages of development. However, new tissue disorders will be certainly described in the future in patients treated with these drugs. The different pathophysiology of the main adverse effects and the less common known side effects of antiretroviral therapy against HIV are described here, with special emphasis on the histological features induced by HAART.     

Concurrent use of antiretrovirals and anticonvulsants in human immunodeficiency virus (HIV) seropositive patients

Seizure disorders may complicate HIV disease, either as a direct result of HIV or as a manifestation of a secondary opportunistic infection. Unless a reversible cause of seizure activity can be discerned, current treatment guidelines recommend the use of anticonvulsant drugs in these patients. The concurrent use of antiretrovirals and anticonvulsants is a poorly studied area. Controlled clinical trials examining drug-drug and drug-disease interactions in this area are scant, leaving clinicians a therapeutic dilemma in terms of drug selection. Most studies have been retrospective in nature. Generalized seizures appear to be most common and occur most frequently in patients with more severe disease as indicated by lower mean CD4(+) cell counts. In short follow-up periods, seizures appear to recur relatively frequently. Treatment of seizures in this population is hindered by a lack of clear data and numerous reports of drug-drug and drug-disease interactions. In order to best provide evidence-based care, controlled clinical trials are needed to discern which anticonvulsants are best suited for use in this population. Trials should also examine appropriate dose adjustments that may be warranted when anticonvulsants and antiretrovirals agents are used concurrently. Unless an identifiable and reversible cause of seizures is identified in this patient population seizures should be treated with standard therapy and close follow-up and monitoring. Newer anticonvulsants (i.e., gabapentin, tiagabine) with fewer drug interactions may be better alternatives when compared to older anticonvulsant agents. Clinicians might avoid valproic acid given some conflicting reports regarding potential for increasing viral replication.     

治疗性药物监测在高效抗反转录病毒疗法中的应用进展

在HIV病人的治疗中,高效抗反转录病毒疗法(HAART)在降低发病率和病死率方面都有积极作用。然而,用于HAART的抗反转录病毒药物(ARV)在体内代谢中多有相互影响,主要为彼此的抑制或拮抗作用。因此,HAART在临床应用于不同个体时多会有不同的临床效果和不良反应,用药剂量难以把握。治疗性药物监测(TDM)则可检测用药病人的ARV血浆浓度,在此基础上再结合临床疗效而对用药剂量作出调整。本文综述了TDM在HAART中的运用现状、存在问题以及发展前景。