HIV, Antiretroviral Therapy and Metabolic Alterations: A Review

The introduction of antiretroviral therapy (ART) has caused some metabolic problems to people who suffer from HIV. ART probably is not the sole reason for these metabolic disorders. Most likely, HIV itself affects the metabolism as well. We conducted research to find the prevalence of the different types of metabolic disorders among HIV(+) patients. Female gender, high BMI, and older age are among the risk factors for the occurrence of metabolic disorders. Regarding dyslipidemia, hypertriglyceridemia and low high-density lipoproteins (HDLs) are the most common types of dyslipidemia in the studies we included. Protease inhibitors (PIs) are widely known as the most common class of antiretroviral drugs that cause metabolic disorders, and some studies in our review also demonstrated this knowledge. In our review, we concluded that HIV and ART concurrently alter the metabolism, but further research is required about this substantial topic.

risk while HIV was not a big risk factor itself [12][13][14][15][16][17][18]; another group of studies proposed that HIV and ART increase the risk together [19][20][21]. At the other end of the spectrum, some studies propose combined ART may have good effects on HIV(+) patients who also meet the criteria for MS [22]. Some studies also report that newer antiretroviral drugs decrease the prevalence of insulin resistance among HIV(+) patients compared to old therapies [23]. PIs are generally wellknown for these side effects [15,20,[24][25][26]; also, some NRTIs, especially stavudine, may cause long-term metabolic and cardiovascular complications [24]. Another study did not find PIs as an important contributor to CVD [12]. Some studies compared two NNRTIs for their metabolic effects [27]. A study from Korea has not found a correlation between the use of NNRTI and dyslipidemia [28]. There is also some evidence about the hepatitis C virus (HCV), boosting the risk of these abnormalities caused by HIV/ART [29]. Older age [6,12,14,15,19,20,30,31], high BMI [6,14,16,28] and female gender [6,9,15,19,20,30] are also among the factors, which independently increases the risk of MS in patients with HIV/on ART. Table 1 contains the baseline BMI values of ART-exposed and ART-naive patients in some of the articles.

Author
Treatment naive Treatment exposed  ART can also cause lipodystrophy syndrome [32]. It is defined by changes in adipose tissue and redistribution of fat from the periphery (face, buttocks, legs, arms) to the abdomen, neck, and breasts. Some studies have found that lipodystrophy is more common with dyslipidemia [29,[32][33][34], while some have not found a meaningful relation between dyslipidemia and lipodystrophy [35].
Our study group has reached a consensus about the lack of studies that compare the frequency of HIV/ART-related metabolic alterations and its consequence, CVD. Also, there are not enough studies that explain the pathophysiology of metabolic alterations among HIV(+) patients on ART.
In this review article, we tried to sum up the recent information about the mechanisms, epidemiology, and metabolic effects of different regimens of ART and other factors affecting HIV/ART-related MS and its consequence, CVD.

Review Methods
We conducted a comprehensive literature review via PubMed, PubMedCentral, Google Scholar, and ResearchGate. We used keywords antiretroviral, HIV, MS, hypertension, insulin resistance, dyslipidemia, both alone and in combination to look for the research papers. Our entire database included studies that only focused on the human population. Studies that were other than the English language were excluded. We have included all the full-text articles except one, in our review. Our whole data were collected ethically and legally.

Discussion
HIV infection is one of the most common diseases in the world; in 2018, there were about 37.9 million people who suffered from this condition, of whom 24.7 million were able to access ART according to UNAIDS [1]. ART has been a great improvement for the survival of these patients [2], but this therapy is also associated with some adverse metabolic effects as well [12][13][14]. HIV itself may be related to metabolic effects as well [6][7][8]. Besides, we already know that metabolic disorders can increase the risk of CVD, which is the most common cause of mortality worldwide, according to WHO [4,36].
The way HIV and ART alter the metabolism is not completely clear; these disorders are possibly from the coalescence of inflammation caused by the virus, altered intestinal flora, ART, and traditional risk factors such as old age ( Figure 1). Monaco [40]. Metabolic dysregulation was also common in this study; biogenic amine disturbances may have a role in the metabolic effects of HIV as well. According to Duro et al., HIV patients with MS had increased levels of C-reactive protein and interleukin-6 [21]. HIVrelated metabolic disturbances were more prevalent in female gender in our studies [6,9,15,19,20,30], old age was also an independent risk factor in some of the studies [6,12,14,15,19,20,30,31], and according to some studies, high BMI was a risk factor by itself [6,12,14,16,28].

HIV(+) patients
The pathogenesis of HIV/ART-related metabolic disturbances is not fully known. As we indicated, there are theories on this subject, such as the chronic inflammation of HIV or alterations in gut flora, but these theories are not proven. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to reduce chronic inflammation and may reduce metabolic alterations. Clinical trials using NSAIDs can be conducted to see the effect of chronic inflammation on metabolism better. Antibiotics may affect the gut flora, and clinical trials about the effect of antibiotics and gut flora dysbiosis on the subject can be performed as well.

Dysglycemia
According to WHO, there were about 422 million people who were suffering from diabetes mellitus (DM); there are more people who suffer from impaired plasma glucose when we add the prediabetic population into the equation [41]. Insulin resistance prevents insulindependent glucose entry. As per American Diabetes Association's new guidelines in 2020, criteria defining DM are fasting plasma glucose (FPG) level of >126 mg/dL after minimum eight hours of fasting, plasma glucose (PG) >200 mg/dL two hours after 75-gram oral glucose tolerance test (OGTT) and hemoglobin A1c (HbA1c) level of >6.5%; prediabetes criteria are FPG between 100 and 125 mg/dL, PG two hours after OGTT between 140 and 199 mg/dL and HbA1c level of 5.7% to 6.4% [42]. There is quite a bit of possibility that HIV or ART may affect the blood glucose levels and insulin resistance; most of the studies we collected have demonstrated this information.     Several studies suggested that HIV increases the risk of impaired glucose metabolism, even without the use of ART. Padmapriyadarsini et al. conducted a cross-sectional study of ARTnaive children in India to assess the associations between HIV and metabolic effects. In their study group, the prevalence of insulin resistance was high, 17%. According to this study, low height-for-age Z-score and weight-for-age Z-score were significantly associated with the development of insulin resistance (p = 0.01 and p = 0, respectively) [7].
Raposo et al. conducted a cross-sectional study in Brazil to find any association between HIV and MS in ART-naive adults. They suggest that HIV increases the risk of MS regardless of ART, and impaired plasma glucose is significantly associated with the presence of MS (p < 0.05) [8].
A cross-sectional study in Cameroon by Mbunkah et al. compared the prevalence of MS among ART-exposed, ART-naive, and HIV(-) control patients. MS was significantly more common in ART-exposed patients, 26.5% of the patients with MS had hyperglycemia. MS was significantly frequent in the ART-exposed group, especially in patients receiving first-line drugs (p = 0.022). The prevalence of MS was highest in patients on lamivudine/stavudine/nevirapine regimen (50%) [12].
Kingery et al. conducted a study in Tanzania, and they demonstrated that ART was associated with an increased risk of MS. MS was significantly more common in the ART-exposed group (11.3%) compared to the HIV-negative control group (3.3%) (p = 0.04). In this study, 11 of the 17 patients with MS had high fasting blood glucose [13].
A study in 2017 by Muhammad et al. compared the rates of MS between ART-naive and ART-exposed patients in Nigeria. The prevalence of MS in patients receiving ART was 19.3% compared to 5.3% in ART-naive patients. Insulin resistance identified by homeostatic model assessment for insulin resistance (HOMA-IR) was prevalent in 79.3% of the ART-exposed patients compared to the 25.0% ART-naive group (p = 0.008). A particular class of ART or more extended periods of ART-exposure was not significantly associated with insulin resistance [14].
Maganga et al. also concluded that glucose metabolism disorders were significantly more prevalent among ART-exposed patients (32.7%) compared to ART-naive (8.0%) and control groups (7.2%) (p < 0.001). DM and impaired glucose tolerance were also more common in patients receiving ART (p = 0.001 and p < 001, respectively). Longer duration of ART or exposure to PIs were not significantly associated with glucose metabolism disorders [18].
A cross-sectional study by Levitt et al. compared the dysglycemia prevalence in a South African patient group [20]. According to their findings, dysglycemia was more common in the patients receiving second-line ART (37.0%) compared to patients on first-line ART (26.0%), ART-naive patients (21.6%) and community-based survey (18.0%). The risk of dysglycemia was significantly increased in HIV(+) patients (p < 0.001) [20].
Araujo et al. conducted a study in 2017 to compare the prevalence of insulin resistance among different ART regimens and found that insulin resistance is less prevalent in patients using new antiretroviral regimens compared to old therapies. The prevalence of insulin resistance was 21%, significantly higher in patients on PIs (28%) compared to patients on NNRTIs (14%) (p < 0.01) [23].
According to Jain et al., HCV was significantly associated with the development of DM in HIVinfected patients (p < 0.01). In this study, initiation of PIs was not significantly associated with the occurrence of DM [29].

Dyslipidemia
Three types of lipoproteins are associated with atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein (LDL) cholesterol is the most atherogenic form in the blood. Very lowdensity lipoprotein (VLDL) is another atherogenic lipoprotein, while HDL is not known as an atherogenic type of cholesterol. Atherogenicity of chylomicron is not fully known. According to American Heart Association guidelines, LDL levels of <100 mg/dL and total cholesterol levels of <150 are ideal. The same guideline also suggests that a 1% decrease in LDL levels results in a 1% decrease in ASCVD risk. Table 3 contains the studies we have included about dyslipidemia [43].  In some studies, ART-naive individuals were at risk of having dyslipidemia before the ARTinitiation. Osoti et al. found that traditional factors were a more significant predictor for MS than ART in a study group with 164 ART-exposed and 136 ART-naive individuals. According to this study, MS was slightly more prevalent in patients receiving ART (16.9%) than ART-naive (15.2%), but this finding was not statistically significant (p > 0.05). Almost all patients were receiving NRTI (99%), while 92% and 6.7% were on NNRTI and PI, respectively. 56% of the patients were receiving nevirapine-based triple therapy (tenofovir/lamivudine/nevirapine) while efavirenz-based triple therapy (tenofovir/lamivudine/efavirenz) was the second most common regimen with a prevalence of 36%. Prevalence of high triglyceride levels was similar in both ART-exposed and ART-naive patients, but low HDL levels were significantly more common in ART-naive patients (p = 0.003) [6].
Anyabolu et al. concluded a cross-sectional study in South-East Nigeria with 393 patients to demonstrate the HIV effect on dyslipidemia in 2017. In their study, the prevalence of different types of dyslipidemias was 17.6% for high serum LDL, 11.4% for elevated total cholesterol, 9.9% for high serum triglycerides, and 34.4% for low serum HDL. Dyslipidemia and CD4 lymphocyte count were significantly associated (p = 0.027) [10].
Calza et al. also suggested that MS risk increased in ART-exposed patients. In this crosssectional study, MS was significantly higher in the ART-exposed group; high triglycerides and low HDL were the most common features of MS and levels of total cholesterol, triglycerides, and LDL was significantly higher while HDL levels were significantly lower in patients receiving ART. NNRTIs rilpivirine and efavirenz were not significantly associated with the development of MS while dual-PI therapies darunavir/ritonavir (OR: 1.89, p = 0.014) and atazanavir/ritonavir (OR:1.61, p = 0.039) had a significant positive association with MS. The decreased risk of having MS in integrase inhibitor receiving patients was not statistically significant [16].
Bune et al. conducted a cross-sectional study in Southern Ethiopia involving 422 ART-exposed and 211 ART-naive patients to compare the prevalence of MS in ART-exposed and ART-naive patients. MS was prevalent in 22.0% in the patients receiving ART while 20.9% in the ART-naive patients; the most common component of MS was dyslipidemia. Dyslipidemia was seen in 59.2% of the patients, and the prevalence was 60.4% and 56.9% in ART-exposed and ART-naive, respectively; high triglyceride levels (37%) and low HDL levels (34.3%) were the most frequent types of dyslipidemia [19].
Fontas et al. conducted a prospective cohort study with 7483 patients in 2004. In the study, triglyceride, total cholesterol, and LDL levels were lowest in the ART-naive group and highest in patients receiving two different PIs. Patients receiving NNRTIs had close triglyceride levels to ART-naive patients. There was no significant difference among groups for HDL levels, but it was highest in the group receiving NNRTI. In terms of risk of dyslipidemia, PI-exposed patients had a significantly higher risk of high triglycerides and total cholesterol/HDL levels. High total cholesterol risk was significantly higher in the double-PI group compared to the ART-naive group. Each ART-exposed groups were compared to each other about the risk of dyslipidemia as well; patients on double-PI therapy were at a significantly higher risk of dyslipidemias barring LDL and HDL levels. On the other hand, the risk of abnormalities in LDL, HDL, triglycerides, and total cholesterol/HDL levels were significantly lower in the NNRTI-exposed group compared to other drug-exposed groups. Within PIs, ritonavir (RTV)-exposed patients had a significantly higher risk of high total cholesterol levels than nelfinavir (NLF), and high total cholesterol/HDL levels than indinavir (IDV); patients receiving saquinavir (SQV) had the lowest risk of high total cholesterol/HDL. Concerning NNRTIs, patients on efavirenz (EFV) had a significantly higher risk of high triglyceride levels than patients on nevirapine (NVP) while both groups were at a similar degree of risk to have high total cholesterol levels [24].

Hypertension
According to WHO, hypertension is one of the most common disorders in the world; 1.13 billion people in the world have hypertension, even more, when prehypertensive patients are added to the equation [44]. Per American Heart Association and American College of Cardiology's latest guideline of high blood pressure, categories of blood pressure are: normal levels [systolic blood pressure (SBP): ≤120 mmHg and diastolic blood pressure (DBP): ≤80 mmHg], elevated (SBP: 120-129 mmHg, DBP: <80 mmHg), stage 1 hypertension (SBP between 130 and 139 mmHg, DBP between 80 and 89 mmHg), and stage 2 hypertension (SBP ≥140 mmHg and DBP ≥90 mmHg) [45]. High blood pressure may be a result of HIV or ART, according to some studies we collected.
Muhammad et al. conducted a cross-sectional study in northwestern Nigeria to assess the prevalence of MS among 150 ART-naive and 150 ART-exposed patients [14]. In the ART-exposed group, 135 of the patients were receiving first-line therapy, and 15 patients were receiving second-line therapy [12]; the prevalence of MS in the ART-exposed group was 29 (19.3%), while it was 8 (5.3%) in the ART-naive group [14]. High blood pressure was the most common feature of MS in both ART-exposed and ART-naive patients, 82.8% and 87.5%, respectively, but these findings were not statistically significant (p = 0.61) [14]. High blood pressure was considerably associated with the occurrence of MS (p < 0.001) [14].
The effect of ART was evaluated in a cross-sectional study by Dimala et al. in Cameroon, 100 first-line ART-exposed patients, and 100 ART-naive patients were involved in this study.
In a cross-sectional study that included 422 ART-exposed and 211 ART-naive patients by Bune et al., the prevalence of MS in ART-exposed was 22.5% while it was 20.9% in ART-naive. The prevalence of hypertension in ART-naive was 57.3% compared to 56.9% in ART-exposed patients, and hypertension was present in about 92% of the patients with MS. Hypertension was the only feature of MS that was more prevalent in ART-naive than ART-exposed [19].

Limitations
We could not find enough information about the impact of different drug classes on hypertension, some studies compare the effect of classes on dyslipidemia and insulin resistance, but similar studies are not available for hypertension. Another limitation of our review is most studies we included are cross-sectional studies; thus, there is not much information about the causality.

Conclusions
The effect of HIV or ART on MS is not entirely understood yet. Multiple factors probably play a role in the occurrence of those metabolic alterations. In our review, we came to the following conclusions: both HIV and ART may have a role in the development of metabolic disorders; these adverse effects are more common in women, people in high BMI, and older people. Also that PIs are the most dangerous class of drugs concerning metabolic disorders. There are not many studies that explain the pathophysiology of HIV/ART-related metabolic alterations; further information about their mechanism is mandatory to prevent or treat these conditions. A detailed comparison of frequencies of ART-related metabolic alterations among different races is also another valuable information we do not have. Further research about genes or proteins in various races that affect the rate or severity of MS in patients on ART can be conducted after this review. A study that enlightens the reasons for the higher prevalence of metabolic alterations in women can be undertaken as well.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.