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Advances in Biology, Bioengineering and Environment Management of Metabolic Side Effects of Antiretoviral Drugs in Patients Infected with Human Immunodeficiency Virus DANOIU SUZANA1, BIZDOACA NICU GEORGE2, DANOIU MIRCEA3, DANCIULESCU MIULESCU RUCSANDRA4 Department: 1Patophysiology; 2Mechatronics; 3Physiology; 4 Endocrinology. 1 University: University of Medicine and Pharmacy of Craiova; 2,3 University of Craiova; 4University of Medicine and Pharmacy, Bucharest. 1 Address: Petru Rares Street No 4, Craiova; 2,3A.I Cuza Street No 13, Craiova; 4 Dionisie Lupu Street No 37 Bucharest. COUNTRY: ROMANIA e-mail: [email protected]; 2 [email protected]; [email protected]; 4 [email protected] Abstract: - Acquired immunodeficiency syndrome (AIDS) is a human immune systemic disease caused by the human immunodeficiency virus (HIV). This condition reduces progressively the effectiveness of the immune system and leaves individuals susceptible to infection and tumors. Antiretroviral treatment reduces the mortality and the morbidity of HIV infection but the treatment is associated with increasing reports of metabolic abnormalities such as body fat abnormalities, impaired glucose metabolism and insulin resistance, and dyslipidemia. All these metabolic side effects of antiretroviral therapy combined with effect of HIV infection seem to play a key role in the increased cardiovascular risk of these patients. The modification of cardiovascular risk factors has become an important aspect of HIV management. All treatment strategies should emphasize cardiovascular risk reduction, focusing particularly on hypertension control and correction of glycemic parameters, and dyslipidemia. Switching antiretrovirals may result in improvements of cardiovascular risk factors, but special care must be taken to avoid virologic failure with such substitutions. The treatment of cardiovascular risk factors in HIV often involves polypharmacy, which increases the risk of suboptimal adherence and may compromise the benefit of antiretroviral drugs. Key-Words: - Acquired immunodeficiency syndrome, Antiretroviral treatment, Cardiovascular risk factors • Protease inhibitors inhibit the activity of protease, enzyme used by HIV to cleave nascent proteins for final assembly of new virons. • Integrase inhibitors inhibit the integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. • Fusion inhibitors which interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. • CCR5 inhibitors. C-C chemokine receptor type 5 known as CCR5 is a protein. HIV uses CCR5 or another protein, as a co-receptor to enter its target cells. A number of new HIV drugs have been designed to interfere with the interaction between CCR5 and HIV. Combinations of antiretroviral drugs create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs being taken arises, the other drugs continue to suppress reproduction of that mutation. Most current highly active antiretroviral therapy regimens consist of three drugs: 2 1 Introduction Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to infection and tumors [1]. AIDS is now a pandemic. In 2008, 33.400.000 people lived with the disease worldwide, and that AIDS killed 2 million people [2]. Antiretroviral treatment reduces the mortality and the morbidity of HIV infection. Antiretroviral drugs are classified by the phase of the retrovirus life-cycle that the drug inhibits [3]. Nucleoside and nucleotide reverse transcriptase inhibitors inhibit reverse transcription by being incorporated into the newly synthesized viral deoxyribonucleic acid (DNA) and preventing its further elongation. • Non-nucleoside reverse transcriptase inhibitors inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function. • ISBN: 978-960-474-261-5 146 Advances in Biology, Bioengineering and Environment nucleoside and nucleotide reverse transcriptase inhibitors + a protease inhibitor or a non-nucleoside reverse transcriptase inhibitors [4]. The use of antiretroviral therapy is associated with increasing reports of metabolic abnormalities such as body fat abnormalities, impaired glucose metabolism and insulin resistance, and dyslipidemia. reverse transcriptase inhibitors therapy. Decreases in mitochondrial RNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mitochondrial RNA and oxidation of fatty acids, whereas peroxisome proliferator-activated receptor gamma which is important for fatty acid storage and glucose metabolism differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 suggesting a central role for peroxisome proliferator-activated receptorgamma coactivator-1 in nuclear responses to mitochondrial dysfunction [11]. Genetic predisposition, gender, and age may be associated with increased lipodystrophy risk. 2 Body fat abnormalities Body fat abnormalities in patients receiving antiretroviral therapy, occurr in 30-50% in several large, prospective studies [5]. Body fat abnormalities include central fat accumulation, development of a dorsocervical fat pad and breast enlargement, as well as loss of peripheral subcutaneous fat. The combination of these morphologic changes and antiretroviral-associated metabolic derangements has been referred to as the lipodystrophy syndrome. Several elements contribute to lipodystrophy syndrome, supporting a multifactorial etiology [6]. Different classes of antiretroviral drugs are implicated both independently and synergistically in this process. Immune system dysfunction resulting from a sustained elevation of proinflammatory cytokines, mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitor and metabolic changes induced by protease inhibitor are all involved in the pathogenesis of lipodystrophy. Lipogenesis and lipolysis can be influenced by proinflammatory cytokines, such as tumour necrosis factor-alpha, that inhibit the former and stimulate the latter process [7,8]. There is now strong evidence that nucleoside reverse transcriptase inhibitors-induced mitochondrial toxicity plays a major role in the development of the lipoatrophic component of HIVassociated lipodystrophy syndrome [9,10]. Nucleoside analogues are effective in inhibiting HIV replication due to their high affinity for the viral enzyme reverse transcriptase (a viral DNA polymerase). Nucleoside analogues can also bind to other human DNA-polymerases, like DNA polymerase beta (necessary for repair of nuclear DNA) and mitochondrial DNA polymerase gamma, which is exclusively responsible for the replication of mitochondrial DNA. Lipodystrophy with peripheral fat wasting is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA content in patients with nucleoside reverse transcriptase inhibitors therapy. Mallon et al. found decreased transcription of mitochondrial ribonucleic acid (RNA) without significant depletion of mitochondrial DNA in patients in dual- nucleoside ISBN: 978-960-474-261-5 3 Insulin resistance intolerance and glucose Multiple mechanisms were involved to insulin resistance and glucose intolerance in the HIVinfected individual taking antiretroviral therapy: • impaired cellular glucose uptake due to inhibition of the Glut4 glucose transporter and glucose phosphorylation induced by protease inhibitors [12]. • the elevated blood levels of free fatty acids induced by both the fat accumulation and depletion components of lipodystrophy may interfere with cellular glucose transport through a reduction in the phosphorylation of insulin receptor substrate-1associated phosphatidylinositol 3-kinase, which results in impaired intracellular signaling and insulin resistance, especially in muscle and hepatic [13]. • HIV infection and antiretroviral-mediated disturbances in the quantity and distribution of fat may disrupt the normal cytokine regulation of glucose homeostasis. A correlation between low adiponectin levels and decreased peripheral subcutaneous fat has been reported [14]. 4 Dyslipidemia Abnormalities of lipid metabolism are common complications of HIV disease and HIV therapy. Prior to the availability of effective antiretroviral therapy, proatherogenic lipid profiles characterized by reduced levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but with appearance of small dense LDL (small dense LDL is proatherogenic because it is susceptible to oxidation particularly and can penetrate the endothelium and bind to intima proteoglycans more 147 Advances in Biology, Bioengineering and Environment any age is associated with improvements in health [4]. Dietary intervention. The guidelines of European AIDS Clinical Society included the following recommendations: dietary intervention should not interfere with the absorption of antiretroviral therapy, limit intake of fat (<30%), dietary cholesterol (<300 mg/day), but should emphasize intake of vegetables, high fibre fruits and grain products, emphasize consumption of fish and lean meat, intake of alcohol should be restricted (< 20-40 g/day) [4]. Exercise promotion. The guidelines of European AIDS Clinical Society included the following recommendations: promote active lifestyle to prevent and treat obesity, hypertension and diabetes, encourage self-directed moderate physical activity (take the stairs, cycle or walk to work, cycling, swimming etc), emphasize regular moderate-intensity rather than vigorous exercise, achieve cardiovascular fitness (30 minutes brisk walking > 5 days a week, maintain muscular strength and joint flexibility [4]. Among non-HIVinfected patients the Finnish Diabetes Prevention study [23], in which individualized counseling aimed at reducing weight, the total intake of fat, and saturated fat, and increasing the intake of fiber and physical activity, the risk of diabetes was decreased 58% among overweight patients with impaired glucose tolerance. Among HIV-infected patients, Roubenoff et al demonstrated a decrease in total abdominal fat, waist-to-hip ratio, body mass index, total cholesterol, and increased fitness and muscle strength with progressive cardiovascular and resistance training for one hour and 15 min three times a week, and a diet with total fat intake less than or equal to 30% of total calories, a saturated fat intake less than or equal to 10% of total calories, and a fiber intake greater than 25 g per day [24]. In contrast, a study of home-based progressive resistance training among HIV-infected women without dietary intervention improved waist circumference and cardiorespiratory fitness, but no effect was seen on blood pressure or lipids [25]. Another study of HIV-infected patients with dyslipidemia receiving a lipid-lowering diet followed 161 patients for 3 months and 70 patients for 6 months, and showed a significant decrease in total cholesterol and triglyceride levels in subjects with compliance [26]. effectively than large LDL, resulting in retention in the arterial wall) and increased triglyceride levels were reported [15]. Since the initiation of antiretroviral therapy, particularly with the use of protease inhibitors, elevations in triglycerides, LDL, and total cholesterol are seen commonly in practice. Protease inhibitors have been implicated as a major cause of the lipid abnormalities seen with antiretroviral therapy. Protease inhibitors inhibit the degradation of apolipoprotein B [16]. Apolipoprotein B is the primary apolipoprotein of LDL and there is considerable evidence that levels of apolipoprotein B are a better indicator of heart disease risk than total cholesterol or LDL. [17]. Medications with nucleoside reverse transcriptase inhibitors appear to have less of a tendency than protease inhibitors to cause dyslipidemia, particularly on a short-term basis bat lipoatrophy epidemiologically linked to the use of nucleoside reverse transcriptase inhibitors has been associated with increases in free fatty acid production and triglyceride levels [18]. Non-nucleoside reverse transcriptase inhibitors have effects on lipid levels, although not to the same degree as protease inhibitors and comperd with protease inhibitors, use of non-nucleoside reverse transcriptase class has been noted to result in generally higher HDL cholesterol levels [19,20]. All these metabolic side effects of antiretroviral therapy combined with effect of HIV infection seems to play a key role in the increased cardiovascular risk of these patients [21]. A prospective assessment of 23.490 patients from 11 cohorts on 3 continents (DAD Study) found that combination antiretroviral therapy was associated with a increase in the rate of myocardial infarction [22]. The modification of cardiovascular risk factors has become an important aspect of HIV management. The guidelines of clinical management of treatment of HIV infected adults in Europe elaborated by The European AIDS Clinical Society in 2009 included: life style intervention, prevention and management of lipodystrophy, diagnosis and management of type 2 diabetes, management of dyslipidemia [4]. 5 Life style intervention Smoking cessation. Much of the prior work documenting the impact of smoking on health. The high prevalence of smoking among HIV-infected patients and the particular health risks make interventions to promote smoking cessation imperative in this population. Quitting smoking at ISBN: 978-960-474-261-5 6. Prevention and management of lipodystrophy Because their pathogenic mechanisms differ, fat accumulation and fat depletion require different 148 Advances in Biology, Bioengineering and Environment glucose 73-110 mg/dl (4-6 mmol/l) according to The Guidelines of Clinical Management of Treatment of HIV Infected Adults of The European AIDS Clinical Society [4], Diet has an important role in the management of glycemia in diabetic patients [29]. therapeutic interventions.The prevention of lipoatrophy by switching antiretroviral drugs from nucleoside reverse transcriptase inhibitors to anothers regimens has been demonstrated to result in some improvement in subcutaneous adipose tissue.The management of lipoatrophy. Switching antiretrovirals therefore may result in modest improvements, but care must be exercised to avoid virologic failure with such substitutions. Pharmacological interventions to treat lipodistrophy have not been proven to be effective and may introduce new complications [4]. Plastic surgery has gained increasing attention in the HIV-infected community due to the limited efficacy of other therapeutic options. The prevention of lipohypertrophy has no proven strategy. Weight reduction of avoidance of weight gain may decrease visceral adiposity [4]. The management of lipohypertrophy. Dietary intervention and exercise may reduce visceral adiposity. Pharmacological interventions to treat lipohypertrophy have not been proven to be effective and may introduce new complications [4]. 8. Management of dyslipidemia Target levels for lipids parameters are to be used as guidance are not definitive. Guidelines of clinical management of treatment of HIV infected adults of European AIDS Clinical Society recomend the optimal target for LDL cholesterol < 80 mg/dl (2 mmol/l) and standard ≤ 115mg/dl (3 mmol/l) and for triglycerides, the optimal target is < 155 mg/dl (4 mmol/l) and standard ≤ 190 mg/dl (5 mmol/l) [4]. Higher LDL cholesterol levels increase the risk of cardiovascular diseases. Conversely the cardiovascular risk implication from higher hypertriglyceridaemia is less clear; hypertriglyceridaemia may increase the risk of pancreatitis. According to the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) guidelines, lifestyle modification is essential: smoking cessation, dietary modification and regular exercise should be promoted. Only after lifestyle modification has proved ineffective or when lipid levels are elevated severely are lipid-lowering agents necessary [30]. For elevated LDL cholesterol, hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors (statins) have produced favorable responses. Use of these drugs must be taken with caution, as elevated levels of statins resulting from the inhibitory effect of protease inhibitors on cytochrome P450 may result in myositis and rhabdomyolysis. The use of ezetimibe in combination with antiretroviral therapy and statin therapy is being studied [4]. For hypertriglyceridemia fibric acid analogues have produced favorable responses. The treatment of cardiovascular risk factors in HIV often involves polypharmacy, which increases the risk of suboptimal adherence and may compromise the continued benefit of antiretroviral drugs. The possibility of drug-drug interactions with antiretroviral drugs should be considered prior to introducing any treatment [4]. 7. Diagnosis and management of type 2 diabetes Criteria for the diagnosis of diabetes mellitus, impaired glucose tolerance and impaired fasting glucose of experts of World Health Organization: • Diabetes: fasting plasma glucose (FPG): > 126 mg/dl (7.0 mmol/l) or two-hour postprandial plasma glucose (2hrPPG) > 200 mg per dL (11.1 mmol/l) after a 75-g glucose load • Impaired fasting glucose: FPG from 110 to < 126 (6.1 to 7.0 mmol/ l) • Impaired glucose tolerance: 2hrPPG from 140 to < 200 (7.75 to < 11.1 mmol/l) [27]. A joint panel of American Diabetes Association and European Association for the Study of Diabetes experts updated the treatment recommendations for type 2 diabetes in a consensus statement which provides guidance to health care providers. The first step is comprised of lifestyle modifications and metformin. If glycemic parameters are not met or maintained, the algorithm proceeds to the second step which provides for either the addition of basal insulin or sulfonylurea, or the addition of pioglitazone or a glucagon-like peptide-1 (GLP-1) receptor agonists. If the second step paradigm does not meet or maintain glycemic goals, the third step is a transition to intensive insulin therapy [28]. Target levels for glycemic parameters are: HbA1c < 6.5-7% without hypoglycaemia, fasting plasma ISBN: 978-960-474-261-5 9 Conclusion Antiretroviral treatment reduces the mortality and the morbidity of HIV infection. The use of antiretroviral therapy is associated with increasing 149 Advances in Biology, Bioengineering and Environment reports of metabolic abnormalities such as body fat abnormalities, impaired glucose metabolism and insulin resistance, and dyslipidemia. The modification of cardiovascular risk factors has become an important aspect of HIV management. All treatment strategies should emphasize cardiovascular risk reduction, focusing particularly on hypertension control, smoking cessation, correction of glycemic parameters, and dyslipidemia. The treatment of cardiovascular risk factors in HIV often involves polypharmacy, which increases the risk of suboptimal adherence and may compromise on long term basis the benefit of antiretroviral drugs. This work was supported by CNCSIS –UEFISCSU, project number PNII – IDEI code 2177/2008 development of human immunodeficiency virusassociated lipodystrophy syndrome. Blood 95:31918, 2000. [9] Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleosideanalogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapyrelated lipodystrophy. Lancet 354:1112-5, 1999. [10] Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen UP, Schofer H, Setzer B, Venhoff N, Rickerts V, Staszewski S. Evidence of nucleoside analogue reverse transcriptase inhibitor--associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 29:117-21, 2002. [11] Mallon PW, Unemori P, Sedwell R, Morey A, Rafferty M, Williams K, Chisholm D, Samaras K, Emery S, Kelleher A, Cooper DA, Carr A; SAMA Investigators. In vivo, nucleoside reversetranscriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA. J Infect Dis.191(10):1686-96,2005. [12] Behrens GM, Boerner AR, Weber K, van den Hoff J, Ockenga J, Brabant G, Schmidt RE. Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1infected patients with lipodystrophy. J Clin Invest 110:1319-27, 2002. [13] Shao J, Yamashita H, Qiao L, Draznin B, Friedman JE. 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