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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 2  |  Page : 41-47

HIV and antiretroviral therapy-induced metabolic syndrome in people living with HIV and its implications for care: A critical review


Discipline of Public Health Medicine, College of Health Sciences, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, RSA

Date of Web Publication26-Apr-2019

Correspondence Address:
Ms. Sakhile Khetsiwe Salome Masuku
Discipline of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of Kwazulu-Natal, Private Bag, X54001, Durban 400
RSA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_21_18

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  Abstract 


HIV has remained a major global public health concern for more than three decades. While global efforts are coalesced in the fight against HIV, the number of people living with HIV (PLHIV) is continuously increasing due to the rollout of antiretroviral therapy (ART). This relates, in part, to the intensified efforts in HIV prevention and control strategies through extensive HIV testing. Consequently, more and new people have learnt their HIV-positive status, implying that more are at risk of suffering the negative effects of HIV and ART. HIV has been implicated in the development of many non-communicable diseases such as cardiovascular diseases and type 2 diabetes mellitus (T2DM). This study conducted a critical review of the literature on the mechanisms through which HIV and ART cause metabolic syndrome, and the implications such understanding has to the care provided to PLHIV. The findings of this review suggest that HIV induces metabolic syndrome through stimulation of immune cells which, in turn, trigger an inflammatory response. ART also triggers the inflammatory response. The inflammatory response suppresses adiponectin and causes impaired insulin action on skeletal muscles. Since the presence of metabolic syndrome greatly increases the risk of non-communicable diseases, particularly T2DM, there is a need for metabolic syndrome screening and prevention among PLHIV. Conducting routine body mass index and waist circumference measurement with periodical triglycerides measurement is necessary for the early detection of metabolic syndrome and the prevention of T2DM and cardiovascular conditions. There is also a need for a model of care for PLHIV that will provide guidance on the prevention of metabolic syndrome hence prevent the development of T2DM with its dire effects on the quality of life.

Keywords: Antiretroviral therapy, HIV, insulin resistance, metabolic syndrome, type 2 diabetes


How to cite this article:
Masuku SK, Tsoka-Gwegweni J, Sartorius B. HIV and antiretroviral therapy-induced metabolic syndrome in people living with HIV and its implications for care: A critical review. J Diabetol 2019;10:41-7

How to cite this URL:
Masuku SK, Tsoka-Gwegweni J, Sartorius B. HIV and antiretroviral therapy-induced metabolic syndrome in people living with HIV and its implications for care: A critical review. J Diabetol [serial online] 2019 [cited 2019 May 19];10:41-7. Available from: http://www.journalofdiabetology.org/text.asp?2019/10/2/41/257207




  Introduction Top


HIV has been a major global public health concern for almost three decades and has claimed an estimated cumulative 70 million cases and 35 million deaths.[1] In December 2015, approximately 36.7 million (34.0–39.8 million) people were estimated to be living with HIV globally.[1] The reproductive age group, 15–49 years, is the most affected group, with an estimated prevalence of 0.8% (0.7–0.9%).[1] In 2015 alone, on an average 350 children and adolescents (aged 0–19) died daily of AIDS-related deaths, and 86% of these deaths occurred in sub-Saharan Africa.[2]

While global efforts coalesce in the fight against HIV, the number of people living with HIV (PLHIV) is continuously increasing. [3,4] This relates, in part, to the intensified efforts in HIV prevention and control strategies through extensive HIV testing. Consequently, more and new people have learnt their HIV-positive status.[5] This also suggests that HIV prevalence has been under-reported, and may still be under-reported as an estimated 40% of all PLHIV do not know their HIV status.[2]

Globally, the sub-Saharan African (SSA) region is the most affected by HIV.[5] For instance, 4.4% of the adult population lives with HIV, and almost 70% of all PLHIV come from this region.[1] In 2015, the southern part of this region contributed 46% of all new HIV infections globally,[6] and 72% of all HIV-related deaths globally come from the SSA region.

HIV infection has been implicated in the development of many opportunistic and non-communicable diseases. Even though much effort has been focused on the control of opportunistic infections in HIV, there is still a need to control non-communicable diseases among HIV positive people. Metabolic syndrome was first described by Kylin back in the 1920s and described it as a cluster of metabolic dysfunctions that manifested through hypertension, hyperglycaemia.[7]


  Metabolic Syndrome Top


Metabolic syndrome is a combination of metabolic dysfunctions manifested through the presence of central obesity and insulin resistance or its surrogate, which is impaired glucose regulation manifested as impaired glucose tolerance (IGT).[8] IGT is commonly assessed using the oral glucose tolerance test.[9] Metabolic syndrome is diagnosed based on having at least three of five components, namely, central obesity, an elevated triglycerides level, a reduced high-density lipoprotein (HDL) cholesterol level, elevated blood pressure and an elevated fasting glucose concentration.[10] Metabolic dysfunction is triggered by a number of processes which involve the adipose tissue (free fatty acids), tumour necrotic factor-alpha (TNF-α), peroxisome proliferator-activated receptor gamma (PPARγ), interleukins, fuel oxidation and insulin secretion dysfunction.[11]

HIV and metabolic syndrome

HIV is implicated in the development of metabolic syndrome through two mechanisms, namely, the inflammatory response and cellular apoptosis. Inflammatory markers related to HIV infection have been implicated as causally associated to premature onset of chronic diseases,[12] and type 2 diabetes mellitus (T2DM) is one of the chronic diseases predicted by inflammatory markers in HIV infection.[13] As noted in the development of metabolic syndrome, the body's inflammatory state also suppresses the production of adiponectin with its anti-diabetic function, which impairs insulin sensitivity,[14] and leads to hyperglycaemia and subsequent T2DM.

Binding of HIV proteins to the host cells

Direct cell apoptosis involves the HIV proteins gp120 and gp 41. Gp 120 binds to CD4/CXC chemokine receptor 4.[15] Gp 41 mediates apoptosis through the fusion/hemifusion process.[15] In an in vitro study, using an in vitro model of co-culture of gp120-expressing cells as effectors and CD4+ T cells as targets, the study observed that apoptosis mediated by gp120 in bystander cells correlated with gp41-induced hemifusion.[16] This hemifusion signalling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. 15 This study showed that virion-induced apoptosis is gp41-dependent. This cell apoptosis triggers a pro-inflammatory state evident by elevated inflammatory cytokines, such as TNF-α, interleukins and C-reactive protein (CRP) levels.[17] Elevation in inflammatory cytokines is associated with impaired insulin action in skeletal muscles,[17] and suppression of the production of adiponectin, an adipose-specific collagen-like molecule[18] that has been observed to have antidiabetic, anti-atherosclerotic and anti-inflammatory functions,[19] leading to the eventual development of T2DM [Figure 1].
Figure 1: Summary of processes of metabolic syndrome development from HIV and antiretroviral therapy

Click here to view


Mitochondria dysfunction induced by cell apoptosis

Another link between HIV infection and metabolic syndrome relates to mitochondrial membrane dysfunction. HIV secretes cytotoxic proteases which cause apoptosis through a variety of host proteins including actin, Bcl2 and procaspase.[20] For instance, in an in-vitro study, the HIV accessory molecule, Vpr, caused mitochondrial permeability transition pore complex (PTPC) opening and loss of transmitochondrial potential when added directly to mitochondria.[21] Activation of the apoptotic protease cascade is dependent on cytochrome c, which is normally present exclusively in mitochondria.[22] Secondary to the apoptotic TNF and Fas signalling, there is disruption of the mitochondrial membrane potential.[23],[24],[25] When mitochondrial transmembrane potential occurs, there ions are distributed asymmetrically on both sides of the inner mitochondrial membrane.[21] After an apoptotic signal, the PTPC opens, disrupts the membrane potential and releases apoptogenic factors, including cytochrome c and procaspase-9.[21],[22]

In response to the release of the apoptogenic factors, regulatory proteins are released. These include bcl-2, a prototype of the family of protooncogenes and IAPs.[21],[22] Bcl2 family members have antioxidant behaviour[21],[24] and inhibit apoptosis by interference with the release of cytochrome c from mitochondria.[25],[26] However secondary to cytotoxic effects of HIV proteases, apoptosis to a variety of host proteins including Bcl2,[21] leads to uncontrolled release of cytochrome c and subsequent cell apoptosis. Mitochondrial dysfunction and the resultant cell apoptosis lead an inflammatory response and subsequent release of inflammatory cytokines, such as TNF-α, interleukins and CRP levels.[18] The inflammatory cytokines suppress the production of adiponectin[19] and induces impaired insulin action in muscles,[18] leading to the development of metabolic syndrome [Figure 1].


  Antiretroviral Therapy and Metabolic Syndrome Top


The introduction of antiretroviral therapy (ART) reverses the effects of HIV in the body. This offers a temporal relief. The long-term use of ART has been implicated in the development of metabolic syndrome. The main mechanism through which ART causes metabolic syndrome is side effects. ART causes dyslipidaemia, lipodystrophy and mitochondrial dysfunction. In general, the adverse effects of ART and long-term use of ART are implied to trigger body mechanisms that lead to the development of metabolic syndrome. ART implicated in the development of metabolic changes related to fat distribution and glucose homeostasis.[27] Introduction of ART to the body leads to increased levels of TNF-α, which, in turn, impairs metabolism of fatty acids and lipid oxidation, resulting in suppressed lipolysis.[28] This, in turn, results in altered fat distribution, and subsequent changes in lipid profile, evident in an observed increase in the levels of triglycerides (hypertriglyceridaemia) and low-density lipoprotein cholesterol, and a decrease in HDL cholesterol.[29],[30] Hypertriglyceridaemia is associated with insulin resistance.

ART also alters glucose homeostasis. In vitro studies demonstrated that the protease inhibitor (PI) indinavir inhibits the activity of GLUT-4, an insulin-sensitive glucose transporter responsible for glucose uptake into muscle and fat cells.[31],[32],[33] One PI, atazanavir, in one study did not inhibit GLUT-4,[32] which helps to explain some of the clinical data showing less insulin resistance in patients taking atazanavir compared to other PIs. In another study, healthy volunteers taking atazanavir had normal rates of glucose disposal, while those taking lopinavir/ritonavir had decreased glucose disposal.[34] Insulin sensitivity was unchanged in the healthy volunteers taking atazanavir/ritonavir 300/100 mg once daily but was significantly decreased in volunteers taking lopinavir/ritonavir 400/100 mg twice daily.[35] Increasing length of exposure to nuclear reverse transcriptase inhibitors (NRTIs) is associated with insulin resistance as well. In the Multicentre AIDS Cohort Study, cumulative exposure to NRTIs was associated with fasting hyperinsulinaemia.[36] Of all the ARVs, stavudine was associated with the highest risk of hyperinsulinaemia,[36] and in another study of healthy volunteers, stavudine administration for 1 month significantly reduced insulin sensitivity.[37]

There are two mechanisms implicated in the development of metabolic syndrome among PLHIV on ART:

Lipodystrophy and dyslipidaemia

Lipodystrophy is a clinical manifestation of metabolic syndrome. It is a complex syndrome thought to be a secondary effect of HIV infection, direct ART-induced toxicities, and the indirect changes of lipid metabolism[38] [Figure 1]. Dyslipidaemia, on the other hand, is a metabolic disorder characterised by hypertriglyceridaemia, hypercholesterolaemia and low levels of HDLs,[39] and results from erroneous metabolism of lipoproteins.[40]

Protein inhibitors (PIs) and NNRTI are the major implicated ARVs in causing lipodystrophy and dyslipidaemia.[41] PIs are effective ARVs in suppressing HIV replication. Realising their potency, the FDA approved the first PI in 1995. Currently, ten different PIs have been approved for clinical use in humans. These are darunavir, indinavir, nelfinavir, saquinavir, amprenavir lopinavir, atazanavir, fosamprenavir, ritonavir and tipranavir. PIs target the HIV aspartyl protease, an enzyme. They have a strong affinity for the active site of the aspartyl protease and irreversibly inhibit the catalytic activity of the enzyme. When the aspartyl protease is inhibited, viral particles are produced immature and fail to form proper infectious virions. Furthermore, PIs cause naturally occurring HIV protease mutations, which generally occur during suboptimal ART, to suffer impaired replication kinetics of progeny virions.

As PIs achieve this good work in the body, they trigger adipocytes differentiation inhibition. PIs alter the expression of sterol regulatory element-binding protein-1 and PPAR-γ, which are inevitably necessary for the differentiation of adipocytes.[42] Consequently, lipid metabolism becomes impaired, leading to lipodystrophy and dyslipidaemia. Secondary to dyslipidaemia, hyperglycaemia develops. Hypertriglyceridaemia has been found to be associated with acute pancreatitis,[43] a potential for altered function of the beta cells in the pancreas and subsequent development of T2DM. Dyslipidaemia and lipodystrophy have also been reported to be severe and prevalent with ART use.[41] PIs such as ritonavir have also been reported to cause a striking increase of triglycerides in <6 months post-ART initiation.[43]

Mitochondrial dysfunction

Therapy hinders polymerase-γ, with subsequent mitochondria dysfunction.[44],[45] Hindrance of polymerase-γ, coupled with the drain of mitochondrial deoxynucleic acid (DNA), termed mitochondrial toxicity, both caused by NRTIs, are also implicated in the development of metabolic syndrome among PLHIV on ART.[46] Mitochondria dysfunction results in insulin resistance, a component of metabolic syndrome and subsequent development of T2DM [Figure 1]. Different ARVs have been associated with metabolic dysfunction. These are nevirapine, stavudine, lamuvidine,[39],[46],[47] efavirenz,[48] indinavir, saquinavir, didanosine[49] and zidovudine;[50] yet some studies reported that both hypertriglyceridaemia and hypercholesterolaemia have been observed among HIV positive patients on ART regardless of regime.[39] This implies that all ART regimes may not completely spare HIV infected patients from metabolic syndrome and the subsequent risk of T2DM. In fact, Wohl (2007), concluded that the antiretroviral drug that causes the most severe visceral lipoaccumulation is unknown.[51] Therefore, even with reviewed ART regimes, the need to monitor patients on ART for development of metabolic syndrome and ultimately T2DM cannot be overemphasised, particularly in the era of universal ART access.

Evidence from population studies

Population studies have clearly shown that there is an increase in the risk of chronic non-communicable diseases associated with a progressive increase in total adiposity as measured through body mass index (BMI).[52] The prevalence of obesity is rising rapidly in many parts of the world.[53],[54],[55] The International Diabetes Federation considers the obesity epidemic as one of the main drivers of the high burden of metabolic syndrome; and there is a strong association between obesity and T2DM.[56],[57]

While the five components of metabolic syndrome have been observed as almost always present in cases of metabolic syndrome, there are other confounding factors involved. For instance, physical inactivity promotes the development of obesity and modifies muscle insulin sensitivity.[58] Another factor is ageing which is generally accompanied by a loss of muscle mass and an increase in body fat, especially in the abdomen.[59] Both of these factors can increase insulin resistance.[58] It has been suggested that the role of the components of metabolic syndrome may vary depending by ethnic group.[60],[61] Although the use of waist circumference to assess abdominal adiposity is superior to BMI, the influence of ethnicity should be considered. The cut-off value for waist circumference is likely to be population specific as there are clear differences across ethnic populations in the relationship between overall adiposity and visceral fat accumulation.[62],[63],[64] This depicts the need for each country to have population-based waist circumference reference points to enable accurate assessment of metabolic syndrome. Other studies have also observed other T2DM risk factors such as heredity and diet.[65],[66],[67]

Metabolic syndrome can be caused by many factors and predicted through the five components. There is growing evidence that there is link between HIV and metabolic syndrome and between metabolic syndrome and T2DM.[68],[69] ART and longer exposure to ART have been associated with T2DM.98 In fact, diabetes prevalence is 5–9-fold higher in PLHIV with metabolic syndrome compared to PLHIV without metabolic syndrome.[70],[71] Diabetes incidence and prevalence has been reported to be higher among PLHIV on ART compared to the HIV-negative population.[70],[71],[72],[73],[74] Studies conducted in Africa also reported an increase in the prevalence of diabetes among PLHIV on ART and as a function of longer duration on ART.[75],[76],[77]

Some studies have observed that non-diabetic people with the metabolic syndrome are at a very high risk for the development of T2DM[78] In fact, the risk for T2DM is up to fivefold higher in patients with metabolic syndrome,[79] and having impaired fasting glucose is associated with a 12-fold increased incidence risk of T2DM.[80] People with metabolic syndrome develop T2DM within 8 years, and the metabolic syndrome age-adjusted relative risk (RR) is RR6.92 (95% confidence interval 4.47–10.81) for T2DM.[81] Various studies have suggested that T2DM is also associated with HIV. T2DM had an incidence of 4.4 cases per 1000 person-years of follow-up in HIV infected patients in a Swiss HIV Cohort.[82] In the data collection on adverse events of Anti-HIV Drugs (D: A: D) study, T2DM incidence increased with cumulative exposure to ARVs and was significantly associated with exposure to stavudine, lamivudine and didanosine.[83] In a group of minority patients in Los Angeles taking PIs, the incidence of diabetes was 7.2% in 3 years of follow-up.[68] These studies show that there is a strong need to monitor PLHIV for metabolic syndrome and T2DM given their potentially increased risk compared to HIV uninfected populations. While these studies provide evidence on the link between HIV and T2DM, they did not compare the prevalence and incidence of T2DM between PLHIV and HIV negative population, which is a gap in research.


  Implications for HIV Care Top


Understanding metabolic syndrome, HIV infection and progression, and the link between HIV and T2DM has implications for care. From the perspective of clinicians and public health specialists, having a definition of a condition alone without it being put into practice, that is, having it guide the treatment or prevention of the condition, is not helpful. Looking through the same lens, understanding metabolic syndrome and its components is only useful if it is used to identify individuals at high risk of disease, and particularly if it is used to identify individuals who are eligible for a specific treatment that they would not otherwise receive.[56] Based on the current understanding of linkages between of HIV, ART and metabolic syndrome, there is value in screening PLHIV for metabolic syndrome, not simply for specific treatment of insulin resistance but to identify patients (even those having modestly elevated risk factors) with an extremely adverse metabolic state that warrants aggressive intervention for specific T2DM traits.[84] It is necessary to screen HIV-infected individuals for metabolic syndrome, given that HIV triggers metabolic syndrome through the inflammatory response and CD41 depletion through apoptosis.[85] Screening of metabolic syndrome can enhance early identification of individuals at risk for development of T2DM and other cardiovascular diseases among PLHIV and more timely implementation/initiation of preventive care measures.

While elevated BMI can give a general picture of body adiposity, use of waist circumference is preferred because it provides the most clinically useful indicator of central obesity and correlates well with insulin resistance.[86] Although epidemiological studies have shown that there is a greater prevalence and incidence of Type 2 diabetes, dyslipidaemia and other cardiovascular diseases as a function of increasing BMI values, there is often remarkable heterogeneity amongst individuals with similar BMI values.[87] It has been shown that among equally overweight or obese individuals, those characterised by an increase in abdominal fat have an increased risk of Type 2 diabetes.[88],[89] This emphasises the need to use central adiposity as a predictor of the metabolic syndrome rather than BMI when monitoring PLHIV longitudinally.

For effective care, it is important to use a standardised way of screening for metabolic syndrome.[90] The following risk factors can be a standard guide when assessing for metabolic syndrome: waist circumference >88 cm for women or >102 cm for men; blood pressure >130/85 mm Hg; triglycerides >150 mg/dL; fasting glucose >100 mg/dL and HDL cholesterol <50 mg/dL in women or <40 mg/dL in men.[91] It is also worth noting that if the waist circumference is high, fasting hypertriglyceridaemia may indicate the possibility that the increased girth is due to visceral fat accumulation.[92]


  Conclusion Top


The burden of HIV remains high and will shift to more chronic disease management as individuals on ART realise improved life expectancy and susceptibility. Besides the traditional risk factors such as physical activities, age and diet habits, HIV and related ART can cause metabolic syndrome. Metabolic syndrome increases the risk for development of T2DM and cardiovascular diseases. Screening PLHIV for metabolic syndrome can improve HIV care and can lead to early diagnosis and prevention of T2DM and cardiovascular conditions. This implies the need for a model of care for PLHIV that will provide comprehensive guidance on HIV care for prevention and screening of metabolic syndrome as a means of preventing T2DM and cardiovascular conditions among PLHIV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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