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Antiretroviral Therapy-Associated Metabolic Complications: Review of the Recent Studies

Abstract The extensive utilization of antiretroviral therapy (ART) has successfully improved human immunodeficiency virus (HIV)-associated complications. The incidence of opportunistic infections is decreased by the viral load suppression and the CD4 count promotion. However, metabolic complications, commonly bone demineralization, lipodystrophy, and lactic acidosis, are arising following the adaptation of long-term ART. The events are not drug-specific, but the severity and incidence individually vary depending upon classes of drugs. Such concerning occurrences may lead to discontinuation of current therapy or switching to another regimen with fewer adverse effects. The purpose of this review is to demonstrate the common metabolic abnormalities associated with each class of widely used ART in people living with HIV (PLHIV). Electronic databases such as PubMed, ScienceDirect, Scopus, Google Scholar, SciFinder, and Web of Science were used for the literature search. A better understanding of ART-associated metabolic adverse effects is helpful in various clinical settings so that therapists may optimize treatments in this population.


Introduction
Since 10 years ago, acquired immune deficiency syndrome (AIDS)-related death has declined by 39% according to the global statistics of 2020. 1 The mortality related to human immunodeficiency virus (HIV) infection has been decreased with the discovery of effective antiretroviral therapy (ART). 2,3 Globally, of the 67% of patients receiving treatment, 59% had successfully viral suppression in 2019. 1 On the other hand, the increase in survival makes HIV infection a chronic illness which requires life-long treatment. Despite therapeutic effectiveness, ART regimens have long been accompanied with various metabolic complications. 4 Consequently, ART associated metabolic abnormalities become increasing concerns among people living with HIV (PLHIV). The severity and prevalence may be varied according to the individual or the type of regimen. Highly Active Antiretroviral Therapy (HAART) are combination regimens consisting of at least three ARTs from two different mechanism of actions. Commonly used regimens are two nucleoside reverse transcriptase inhibitors (NRTIs) plus one or two protease inhibitors (PIs) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI). NRTIs such as abacavir, lamivudine, zidovudine, tenofovir, and stavudine; PIs such as lopinavir, ritonavir, saquinavir, and nelfinavir; and NNRTIs such as nevirapine, efavirenz, and etravirine have long been widely used as first or second line ART. 5 Some metabolic side-effects of antiretroviral drugs include bone demineralization, increased cholesterol and triglyceride levels, and abnormalities in fat distribution. 4 Generally, the prevalence of reduced bone mineral density (BMD) was higher in PI-treated HIV-infected patients. They had three times higher prevalence of osteoporosis compared with uninfected people. 6 Lipodystrophy was a common metabolic adverse event which was associated with central adiposity, peripheral fat wasting, cushingoid feature, lipomas, and breast hypertrophy. 7 In particular, HIV-infected patients with abnormal fat distribution or lipoatrophy may experience dyslipidemia, which has become a significant issue. 8 In some HIV-infected individuals, serious metabolic events may lead to discontinuation of therapy or switching to another regimen with fewer side-effects. This review aims to better understand metabolic abnormalities associated with each class of ART, highlighting the HAART regimen. Therefore, advanced strategies for modification of therapy to mitigate complications in the HIV population can be more developed.

Methods
We performed a comprehensive literature search for the articles published between January 2000 and June 2020. Clinical trials, cross-sectional studies, and cohort studies which are available in English language were included. The articles which demonstrated metabolic abnormalities were mainly reviewed with a specific focus on lipodystrophy, abnormalities of lipid profiles, glucose levels, and bone. Other interesting side-effects related to ART were also thoroughly reviewed. Exclusion criteria were pilot studies, research protocols, conference proceedings, book chapters, review papers, and articles without full text. Terms such as human immunodeficiency virus/HIV/antiretroviral therapy/acquired immunodeficiency syndrome/metabolic/lipodystrophy/lipoatrophy/ lactic acidosis/bone demineralization/osteopenia/dyslipidemia/nucleoside reverse transcriptase inhibitor/abacavir/zidovudine/lamivudine/stavudine/tenofovir disoproxil fumarate (tenofovir DF)/tenofovir alafenamide (tenofovir AF)/didanosine/emtricitabine/non-nucleoside reverse transcriptase inhibitor/nevirapine/efavirenz/etravirine/rilpivirine/protease inhibitor/lopinavir/ritonavir/atazanavir/darunavir/indinavir/nelfinavir/saquinavir/integrase inhibitor/dolutegravir/raltegravir were used to search in the electronic databases: PubMed, ScienceDirect, Scopus, Google Scholar, SciFinder, and Web of Science.

Pathophysiology
Lipodystrophy refers to the abnormal distribution of adipose tissue. 9 It includes lipohypertrophy, which is fat accumulation in central areas: abdomen, breast, neck, and lipoatrophy, which is loss of fat in proximal areas: face, arms, legs, buttock. The exact etiology of lipodystrophy is still unknown. 9 The issue that should be emphasized is both ART and HIV cause changes in lipid distribution. The production of inflammatory cytokines such as interleukins are provoked, which results in adipose cell destruction. Moreover, insulin signaling function and glucose transport were impaired. As a consequence, ART associated lipodystrophy increases the risk for dyslipidemia, insulin resistance, diabetes mellitus, and heart disease. 10 Dyslipidemia is the condition in which total cholesterol levels above 5 mmol/L, triglycerides >1.7 mmol/L, and low-density lipoprotein cholesterol (LDL-C) levels of >3 mmol/L. 11 Lactic acidosis is also common, which referred to the level of uncuffed lactate >5 mmol/L and arterial pH <7.35 or a total venous carbon dioxide <20 mmol/L. 11 In some patients receiving ART, there was elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (>40 U/L) which were predictive factors of metabolic complications also in the general population. 12

Animal Studies
The safety and efficacy of antiretroviral drugs have been monitored, as has the metabolic alteration during the treatment period tested in preclinical trial studies. [13][14][15][16] Conradie et al 13 examined the effects of ART on bone metabolism and lipodystrophy in rats. Stavudine (6.2 mg/ kg), tenofovir DF (26.6 mg/kg), lopinavir/ritonavir (70.8 mg/kg), and water (1.5 mL) were subjected orally to 40 male rats for 9 weeks. Under examination by dual energy X-ray absorptiometry (DEXA), stavudine monotherapy was associated with a decrease in femoral BMD (0.247±0.02 g/cm 2 , P<0.05). Biomechanical testing showed that the load-bearing capacity and strength of femurs of stavudine-treated rats were significantly lower than those of other groups (P<0.05). Both NRTIs (stavudine and tenofovir) resulted in significant bone marrow adiposity. Another NRTI, zidovudine, also reduced BMD in mice. 14 Mice were orally treated with 0.25 mg zidovudine daily for 4 weeks while controls received water. Under examination by DEXA, zidovudine treated mice showed a significant decrease in BMD (P<0.04).

In vitro Studies
Lipin-1 is a gene necessary for the normal development of adipose tissues. 17 HIV-infected patients with lipodystrophy or metabolic abnormalities due to ART have decreased lipin-1 mRNA expression in subcutaneous adipose tissues. 18 In differentiated 3T3-L1 cells, treatments with PIs resulted in reduction in lipin-1 mRNA expression by promoting the miRNA-218 expression. Although the role of miRNA is still ambiguous, it was reported to have a relationship with glucose transporter type 4 (GLUT-4) gene expression which is the insulin-stimulated glucose transporter. During treatment with PIs, increased miRNA caused reduction in GLUT-4 which in turn resulted in insulin resistance and metabolic abnormalities. 3T3-L1 adipocytes on exposure to lopinavir: ritonavir combination showed a significant reduction in lipid (−13.2% in concentration of 12 μM:3 μM and −14.5% in 16 μM:4 μM, P<0.05). 18 Caron et al 19 examined the long-term effects of NRTIs on lipid accumulation and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3 adipocytes. Among the treated NRTIs, zidovudine (1 μM) and stavudine (10 μM) showed changes in lipid phenotype, content, and expression of metabolic markers. Thus, in vitro after 6-11 days of zidovudine and stavudine treatment at near C max concentrations, there were decreases in lipid content, survival of adipose cells, and mitochondrial activity. These results seemed to be relevant to the lipodystrophy of patients treated with low dose concentrations for months or years of treatment period. Nolan et al 20 explored the effect of cellular mitochondrial DNA (mtDNA) reduction in patients receiving NRTIs therapy. The amount of mtDNA was significantly decreased in NRTIs (zidovudine/stavudine) group compared to ART-naïve HIV-positive controls (P<0.001). There were also abnormalities of adipose tissue among patients receiving NRTIs.

Genetic and Ethnic Influence
The risk of metabolic abnormalities including dyslipidemia can be predicted by genetic factors. The effects of apolipoprotein C3 (APOC3), apolipoprotein E (APOE) on ART-associated lipid abnormalities have been explored. 21 The effects of alleles of APOC3 and APOE on plasma cholesterol and triglycerides in patients receiving ritonavir were prospectively monitored over 3-year study period.  23 highlighted the prevalence of metabolic bone abnormalities in a cohort of PLHIV under HAART. Non-African-Americans had higher risk of osteopenia (59%) than African-Americans (26%). Mean urinary N-telopeptide levels were also higher in non-African-Americans. Glucose levels were also varied among ethnicities. HIV-infected African-Americans and Hispanics had higher risk of diabetes than non-Hispanic whites. 24 HbA1c and 2 hour glucose levels were significantly higher in African-Americans than Hispanics or non-Hispanic whites. Ethnicity was also related to CD4 counts in patients on HAART which affect insulin sensitivity. In the occurrence of lipodystrophy due to NRTIs therapy, the increased risk was provoked in White patients (P=0.023). 25 This finding also suggested that there are differences in severity of metabolic variation among PLHIV based on ethnicity. In patients on PI regimens, the risk of dyslipidemia can be predicted by ethnicity. 26 African-Americans and Hispanics had higher levels of triglycerides than White HIV-infected patients on exposure to non-ritonavir PI regimens. However, on exposure to ritonavir regimens, all groups tended to increase in triglycerides.

Metabolic Complications Associated with ART in HIV-Infected Patients
The metabolic outcomes in HIV-infected patients receiving different classes of antiretroviral drugs in previous publications are summarized in Table 1. Questionnaires, abnormalities reports, physical measurements, and clinical assessments including evaluations of laboratory parameters such as CD4, HIV-1 RNA, lipid profiles, glucose, and serum lactate were applied in these studies.

NRTI-Associated Metabolic Complications
Several studies have reported the lipodystrophy occurrence in NRTI-treated HIV-infected patients. 11,28-32 Zidovudine and stavudine can cause lipodystrophy with different incidence. 28 Patients in the stavudine arm had more frequent symptoms of peripheral fat depletion compared to those in the zidovudine therapy. The fat depletion was presented by atrophy on the face, lower limb, buttock, and venomegaly (P=0.011, 0.006, 0.009, and 0.001, respectively). There were elevations in cholesterol, triglyceride, and glucose levels but they were not significantly different between the two groups. Univariate analysis showed that older patients and female genders had increased risk of central fat accumulation. Consistently, Menezes et al 11 reported the metabolic toxicity of stavudine during a median follow-up of 19 months in their prospective cohort study. The prevalence of abnormalities was 17.1% peripheral neuropathy, 5.7% symptomatic hyperlactatemia, 2.5% lactic acidosis, and 7.3% lipoatrophy in the study group on stavudine. They examined that patients with a body mass index (BMI) of 25-30 kg/m 2 or >30 kg/m 2 had higher risks of hyperlactatemia and lactic acidosis. Moreover, females had higher metabolic toxicities such as diabetes and dyslipidemia. The findings concur with the previous study. 28 In contrast, male gender was associated with lipodystrophy in the study by Alikhani et al. 29 The prevalence of lipodystrophy in this study was 47%, with a mean trunk/limb fat ratio of 1.87. Patients with lipodystrophy were at risk of development of diabetes and dyslipidemia following the elevations of blood glucose and triglyceride levels (P=0.002 and P<0.001, respectively). Additional factors such as duration of HIV infection, year of exposure to zidovudine or stavudine, and older age were also associated with lipodystrophy.
In a clinical trial of Gallant et al, 30 where the safety and efficacy of tenofovir DF versus stavudine in ART-naïve patients were assessed, the overall incidence of laboratory abnormalities were similar. Lower mean elevations in triglycerides (+0.01 mmol/L), total cholesterol levels (+0.78 mmol/L), LDL-C levels (+0.36 mmol/L), and higher increase in HDL-C levels (+0.23 mmol/L) were found in the tenofovir DF group. All the patients with lactic acidosis were from the stavudine group. In addition, patients with abnormal AST and ALT levels were more frequent in the stavudine group. Tenofovir DF receiving patients had higher loss of limb fat compared to the stavudine arm at week 96 (7.9 kg vs 5 kg), and at week 144 (8.6 kg vs 4.5 kg) (P<0.001). Surprisingly, the proportions of bone fractures showed no difference between two groups, whereas researcher-reported lipodystrophy was more common in stavudine receiving patients (P<0.001). This finding was supported by the study of Haubrich et al. 31 They reported that lipoatrophy was most frequent with stavudine-containing regimens. Median cholesterol levels were also elevated in the stavudine group (41 mg/dL, P=0.02). Regimens containing didanosine/stavudine were associated with greater limb fat loss. 33 In an openlabel randomized study by Gallant et al, 32 limb fat mass measured by DEXA showed that patients receiving tenofovir DF/emtricitabine had higher limb fat loss compared to the zidovudine/lamivudine group (P=0.03). The fasting lipid profile showed that the zidovudine/lamivudine group had a greater mean increase in total cholesterol (0.91 mmol/L vs 0.54 mmol/L, P<0.001) and LDL-C (0.52 mmol/L vs 0.34 mmol/L, P=0.01) compared to the tenofovir DF/emtricitabine group. Patients in the zidovudine/lamivudine group experienced more frequent adverse events which resulted in discontinuation of treatment. The study found that the most frequent cause of discontinuation of zidovudine/lamivudine containing regimen was anemia.
Sax et al 35

NNRTI-Associated Metabolic Complications
The use of NNRTIs showed alterations in metabolic parameters although the changes were not as much pronounced DovePress delavirdine also increased insulin resistance. 41 There was a significant elevation of mean insulin levels over the median study period of 5 years (P<0.01). This supported the close monitoring of risk of diabetes and glucose levels. Moreover, efavirenz in combination with NRTI (tenofovir DF) has been examined to reduce BMD in HIV-infected ART-naïve patients. 36

PI-Associated Metabolic Complications
The use of PIs was associated with a significant increase in lipid levels leading to hyperlipidemia. The lipid abnormalities due to PIs are severe and more common than other classes of drugs, 8 some of which resulted in discontinuation of the treatment. 42 In a clinical trial of Clumeck et al, 43 patients receiving PI-based therapy for at least 6 months were examined. The only recommended PI during randomization was ritonavir/saquinavir. Increased lipid profiles (triglyceride >2.3 mmol/L and cholesterol >5.2 mmol/L) were found in these patients. Some patients discontinued treatment because of lipodystrophy and significant elevation in triglyceride and cholesterol levels. Similarly, abnormally higher triglycerides and total cholesterol levels due to PIs were also observed in a study of Walmsley et al. 7 Patients on lopinavir/ritonavir regimens had higher abnormalities in laboratory profiles than those on nelfinavir regimens. During the 48-week period, the mean elevations in total cholesterol were 1.37 mmol/L vs 1.24 mmol/ L, and in triglycerides were 1.4 mmol/L vs 0.5 mmol/L in these groups. Lipodystrophy or lipoatrophy were reported but the prevalence was not much pronounced. The study suggested a longer follow-up time over 48 weeks to determine the clinical significance of elevations in lipids. When compared to efavirenz (NNRTI), nelfinavir was found with greater loss of limb fat in a randomized study by Dube et al 33 (P<0.003). Lipid profile measurements also showed high elevations in the nelfinavir group over 64 weeks. Ortiz et al 44 randomly subjected ART-naïve patients to receive either darunavir/ritonavir or lopinavir/ritonavir, in combination with tenofovir/emtricitabine. Grade 2-4 elevations in triglycerides and cholesterol were found more frequently in the lopinavir group than the darunavir group (11% vs 3%, and 23% vs 13%, respectively) at week 48. This finding was supported by the week 48 phase III trial of Madruga et al. 45 The grade 2-4 elevations of AST and ALT were also observed in addition to the same incidence of hyperglycemia in two groups. Hypertriglyceridemia and hypercholesterolemia were the adverse events leading to permanent treatment discontinuation found in the lopinavir/ritonavir group. In a randomized trial of Molina et al, 46 ART-naïve patients were subjected to receive atazanavir/ritonavir or lopinavir/ritonavir, each in combination with tenofovir/emtricitabine. Bilirubin-associated adverse events were higher in the atazanavir group. Some changes in lipid parameters (increased AST, ALT, cholesterol, and triglycerides) were significantly higher in the lopinavir group (P<0.0001) at week 96. Additionally, the patients in the lopinavir group had higher gastrointestinal intolerability rates, in which 1.6% of patients discontinued the treatment due to diarrhea. This study recommended atazanavir/ritonavir as the first-line treatment because it has a better lipid profile and high efficiency in treatment-naïve patients with high plasma HIV viral loads and low CD4 counts at baseline.
Arathoon et al 42 conducted a 192-week, randomized, Phase III, open-label trial to compare the efficacy and safety of darunavir/ritonavir and lopinavir/ritonavir, each in combination with fixed-dose tenofovir/emtricitabine in ART-naïve patients. Metabolic-related adverse effects were observed at week 96. Two patients on lopinavirbased regimens discontinued treatment due to hypercholesterolemia and hypertriglyceridemia. The occurrence of metabolic and nutritional disorders was higher in the lopinavir group. The most frequent lipid-related adverse events were hypertriglyceridemia (2% vs 5.8%), hypercholesterolemia (1.5% vs 4%), hyperlipidemia (0.6% vs 3.2%), and increased LDL-C (2.3% vs 1.2%) in the darunavir and lopinavir groups. Some anthropometric changes such as body weight or mid-waist/hip ratio were observed in week 96, but these were considered clinically irrelevant. PI containing regimens increased insulin resistance prevalence and glucose level in HIV-infected patients in previous randomized studies. 41,47 AIDS Clinical Trials Group (ACTG) A5260s, a trial study, examined the changes in insulin resistance after treatment with raltegravir, darunavir/ritonavir, or atazanavir/ritonavir in ART-naïve HIV-infected patients. 47 At the follow-up period of week 96, there were increases in homeostatic model assessment of insulin resistance (HOMA-IR) in all study groups. It was also observed that such an increase in insulin resistance was associated with changes in BMI, interleukin-6, and high-sensitivity C-reactive protein at week 48 and 96. Bone abnormalities were also pronounced in patients receiving PIs. In a randomized study of ARTnaïve patients, BMD changes were monitored at baseline and week 48 by DEXA. 48 The randomized regimens were PIs plus NNRTI and PIs plus NRTI or NNRTI plus NRTIs.

Other ART-Associated Metabolic Complications
Lipodystrophy was associated with the cumulative use of antiretroviral drugs such as raltegravir. 29 Patients with fat abnormalities were more likely to develop diabetes and dyslipidemia. However, raltegravir showed better safety and clinical profiles in a trial reported by Lennox et al. 49 ART-naïve patients were randomized to receive either 400 mg raltegravir twice daily or 600 mg efavirenz once daily, both in combination with tenofovir and emtricitabine. Fasting LDL-C >4.92 mmol/L and triglycerides >3.48 mmol/L were found more frequently in the efavirenz group. Mean LDL-C and triglyceride levels were higher in the efavirenz than the raltegravir group after week 48.

Switching Strategies
Several studies have recommended to switch or simplify the regimens in order to reverse the treatment-related abnormalities such as metabolic disorders, fat redistribution, or other manageable side-effects. 30  week trial in HIV-infected patients by switching from the existing NRTIs to either tenofovir/emtricitabine or abacavir/lamivudine. The baseline NRTIs included abacavir without tenofovir, tenofovir without abacavir, lamivudine, emtricitabine, zidovudine, didanosine, and stavudine. In the overall 357 patients, the abacavir group had more common lipid-related events compared to the tenofovir group (P=0.003). However, bone events such as osteopenia or osteoporosis were more common in the tenofovir group (P=0.032). In addition, the tenofovir regimen was not only associated with rapid decreases in body weight and lean body mass but also led to significant loss of hip and spine BMD. In a trial of Perez-Molina et al, 52 ARTexperienced patients were randomized into either dual therapy with atazanavir/ritonavir plus lamivudine or triple therapy with atazanavir/ritonavir plus two NRTIs (tenofovir/emtricitabine or abacavir/lamivudine or zidovudine/ lamivudine). From baseline to 96 weeks, analysis showed that two patients per group discontinued ART because of hyperbilirubinemia but there was no new discontinuation beyond 48-week duration. Increased total cholesterol and triglyceride levels were observed in the dual therapy arm. A decrease in BMD was also observed but there were no significant different changes between groups. Mills et al 27 conducted a multicenter, randomized, open-label, phase III clinical trial in treatment experienced HIV-infected adults. Participants were randomly assigned at a 2:1 ratio into either switching into single tablet tenofovir AF (n=959) 10 mg plus elvitegravir 150 mg, cobicistat 150 mg and emtricitabine 200 mg or continuing previous tenofovir DF regimens (n=477). At week 48, mean BMD at the hip and spine remained stable or decreased in the tenofovir DF group, whereas there were increases in the tenofovir AF group (P<0.0001). Patients on previous tenofovir DF regimens tended to improve BMD after switching to tenofovir AF regimens. Consistent with this finding, Maggiolo et al 55 observed the significant improvement in BMD after switching from tenofovir DF to tenofovir AF containing regimens in HIV-infected patients aged 60 years or older.
According to previous studies, PLHIV receiving to ART exhibited the changes in subcutaneous adipose tissues, commonly lipodystrophy and abnormal lipid profiles. Lists of antiretroviral drugs in each class associated with lipodystrophy are summarized in Table 2. Although lipodystrophy in patients receiving abacavir, nevirapine, or efavirenz had been decreased, newer cases were arising. Therefore, switching from PIs to these drugs in order to reduce tendency for discontinuation due to lipid abnormalities is still not an applicable strategy. 37 Individual drugs with their effects on changes in metabolic markers are summarized in Table 3. Types of ART with different metabolic profiles can be differentiated. Although some known drugs do not have optimal safety and tolerability profiles, their side-effects do not limit the efficacy in clinical settings. NRTIs (abacavir, lamivudine, zidovudine, emtricitabine, tenofovir), NNRTIs (nevirapine, efavirenz), and PIs (lopinavir, ritonavir, atazanavir) are commonly recommended in the first-line HAART regimens. 5 Each antiretroviral drug with their common metabolic complications examined in previous studies are summarized in Table 4.

Recommendations
The prevalence or severity of metabolic abnormalities are varied among individuals or classes of drugs; some of  Table 4 The Common Metabolic Effects of Antiretroviral Therapy 7,11,[27][28][29][30][31][32][33][34][35][37][38][39][40][42][43][44][45][46][48][49][50][51][52][53]56 which may be developed over time. Therefore, a longer study period is required to better recognize long-term abnormalities related to different classes of drugs. One more point to be noted is that the nutritional status of HIVinfected patients is affected by several metabolic complications due to both HIV infection and ART. Therefore, it is required to manage ART-associated metabolic abnormalities because HIV-infected patients require life-long therapy. Otherwise, patients with poor nutritional status will be exacerbated. Lifestyle management and pharmaceutical interventions are necessary for patients on long-term therapy. Nutritional counseling and intervention may be required especially in the patients who are at risk of malnutrition. In advance, dietary consideration should be provided to optimize treatment associated complications such as dyslipidemia, glucose abnormalities, and limb fat loss. 57 Individualization is also critical in relation to the treatment of metabolic abnormalities in combination with giving interventions according to each patient's needs.

Conclusion
Some drugs with high metabolic toxicity are still being used in resource-limited countries due to cost effectiveness. Thus, appropriate pharmacologic development and protocols are necessary to minimize toxicity. Nutritional counseling and management in PLHIV have been strongly recommended. The occurrence of ART-associated metabolic complication may be applied as predicting factors for either modification of therapy in PLHIV or finding new regimens with fewer side-effects. Active pharmacovigilance programs are recommended in HIV care programs to properly identify ART-related adverse events so that serious complications can be improved. 56 Moreover, strategies which differentiate PLHIV at high risk of metabolic complications may be helpful in exploring the appropriate regimens. At the beginning of ART in PLHIV, it has been highly recommended to perform genotyping. 21 Genetic polymorphism and ethnicities in some way may be related to the effects of ART. The better choice of ART regimen based on genetic analysis may help reducing the potential risk of metabolic abnormalities. Because of the multifactorial nature of metabolic complications, it is advisable to adjust the benefits and risks, including virologic success and potential toxicities of new regimens when switching or adding to the existing regimens. Prospective studies evolving the safety and efficacy of individual antiretroviral therapy or combination regimens in a large population are warranted. To get a sustained clinical benefit of therapy, pharmacologic improvements in administration of regimens have been recommended. The particular adverse effects of each drug or regimen should be clarified to achieve the effectiveness of therapy and improve the tolerability of treatment in HIV-infected patients.