Cell targeting is the process of delivering a therapeutic substance to a particular cell organelle or compartment. In endocytosis gene therapy, especially in cellular absorption of non-viral gene delivery methods, it is the most often employed technique. Viral gene delivery systems are made up of viruses that have undergone engineering to become replication-deficient. These viruses are able to carry the genes to the cells for expression. For the delivery of viral genes, lentiviruses, retroviruses, and adenoviruses are used. The continual expression and expression of therapeutic genes are benefits of viral systems. The utilization of these systems is however constrained by certain drawbacks, including the creation of viruses, immunogenicity, toxicity, and lack of optimization in large-scale manufacturing [32–34].

As an alternative to systems based on viruses, non-viral gene delivery methods were created. These systems' ability to develop transfection is one of their key benefits. Physical and chemical delivery methods for non-viral genes are separated into these two groups. The most popular physical techniques include microinjection, electroporation, gene guns, ultrasound-mediated techniques, and hydrodynamic systems. Physical techniques entail applying physical pressure to make the cell membrane more permeable so that the gene may enter the cell. Physical approaches' main benefits are that they are dependable and simple to utilize. They can also injure tissue in particular situations, which is a drawback.

For gene transport into the cell, chemical approaches employ carriers made from synthetic or natural chemicals, such as synthetic and natural polymers, liposomes, dendrimers, synthetic proteins, and cationic lipids. The fact that these systems are non-immunogenic and often have minimal toxicity is one of their main benefits [35].

## **Table 1.**

*Difference between in vivo and ex vivo gene therapy.*

The difference between in vivo and ex vivo gene therapy as given in **Table 1**.

## **3.2 Viral vectors and their role in delivering therapeutic genes**

According to whether their genomes integrate into the host cellular chromatin (oncoretroviruses and Lentivirus) or remain in the cell nucleus mostly as extra chromosomal episomes (Adeno-Associated Virus, Adenovirus, and herpes viruses), the five main classes of viral vectors may be divided into two categories. The effectiveness of transgenic expression, simplicity of manufacture, safety, toxicity, and stability all factor into the selection of viral vectors for clinical usage.

Additionally, RNA and DNA viruses with either single-stranded (ss) or doublestranded (ds) genomes serve as examples of the various vector types. Eight Infectious agents are categorized into risk groups for laboratory research (Risk Groups 1–4) in the World Health Organization (WHO) Laboratory Biosafety Manual and the National Institutes of Health (NIH) Recombinant DNA Guidelines. The risk group provides information on the biosafety degree of containment required to reduce risk while handling certain infectious pathogens.

## *3.2.1 Adenovirus vector*

Adenoviruses are a group of non-enveloped DNA viruses with double-stranded genomes that range in size from 34 to 43 kb. These viruses use alternative splicing to encode genes in both sense and antisense directions. The AV genome has eight transcription units and two ITRs on either side of it. The first viral sections to be transcriptionally transcribed are known as the early regions (E1A, E1B, E2, E3, and E4), which also include the proteins that activate transcription of additional viral regions and modify the cellular environment to enhance viral production [36]. From an alternatively spliced transcript, the late sections (L1-L5) are translated. After infection, the AV genome persists in an additional chromosomal form. Humans have 51 different serotypes of AV; 45–80% of the population harbors neutralizing antibodies against Ad5, the most prevalent, due to natural infections, which typically date back to infancy [37]. They are capable of high titer production and high infection multiplicity gene delivery. These characteristics have made them one of the viral vectors most often utilized in in vivo research and clinical trials for gene therapy. Adenoviral vectors can, however, cause a large amount of inflammation, which severely restricts

## *Gene Therapy Approaches in HIV Treatment DOI: http://dx.doi.org/10.5772/intechopen.112138*

their practical application. Additionally, because adenoviral vectors cannot integrate into the host's genome, the transgene's expression is episomal and hence transitory. Due to this drawback, adenoviral vectors are more frequently utilized to create short-term gene expression than they are for illnesses that call for continuous gene expression. Adenoviral vectors, for instance, are used in cancer research to transmit a suicide gene that kills tumor cells [38].

## *3.2.2 Retrovirus vector*

Retroviruses have a diploid ssRNA genome, an enveloped RNA structure, and at least 4 genes: gag, pro, pol, and env. The major structural polyprotein, which is encoded by the gag gene, is required for the formation of immature and noninfectious viral-like particles [39]. The viral protease, which is encoded by the pro gene, aids in the development of viral particles. Reverse transcriptase, RNase H, and integrase are made by the pol gene, whereas the env gene makes the viral surface glycoproteins and transmembrane proteins that facilitate binding to cellular receptors and membrane fusion. The capacity of RV and retroviral vectors to incorporate into host DNA is a common characteristic. In addition, complex RV like HIV-1 encode auxiliary proteins that improve replication and contagiousness. Reversible transcription of viral RNA results in integration of the transcript into a provirus. The host cell's enzymes are extremely successfully used by the RV for both long-term production of viral proteins and replication. Like the majority of viruses, the RV requires a receptor to enter the host cell. Many oncogenic RVs are replication-defective variants that include oncogene sequence in place of a portion of their normal viral gene complement. Malignant illness and a number of other pathogenic states are also brought on by replication-competent retroviruses in a wide range of animals. The acquired immunodeficiency syndrome (AIDS) is caused by the retrovirus's HIV-1 and HIV-2 [40].

Retroviruses display a number of properties/characteristics that influences their potential asvectors in gene therapy protocols. These may be summarized as follows:

The use of retroviruses as gene therapy vectors is nonetheless restricted by several of the other traits described. Their capacity to infect only dividing cells obviously limits their usage in the majority of cases.

Another drawback is that they are not selective about the kinds of proliferating cells that they infect. The entrance of each particular retrovirus is contingent upon the presence of an adequate viral receptor on the surface of a target cell, and they will not infect all types of proliferating cells. It is still challenging to forecast the full spectrum of cell types that any retrovirus is likely to infect during a gene therapy regimen since the identities of the majority of retroviral receptors are yet unknown. Physiological issues might arise if the foreign gene is integrated and expressed in cells other than the target cells as depicted in **Figure 7**.

In the context of gene therapy, clinical applications for monogenic disorders, cancer, and infectious illnesses, retroviral vectors have been widely utilized to transport therapeutic genes, ensuring a stable and effective expression of the transgene in patients [41].

**Figure 7.** *Ex vivo gene therapy.*

## **3.3 Modification of hematopoietic stem cells for enhanced antiviral properties**

The treatment of an increasing variety of human illnesses with hematopoietic stem cell gene therapy (HSC GT) is proving to be an effective and adaptable method. After receiving a conditioning therapy that encourages their engraftment in the bone marrow, hematopoietic stem/progenitor cells (HSPC) are removed from the body, genetically modified ex vivo, and then reinjected back into the same person. The engrafted HSPC guarantee a consistent flow of genetically modified offspring, maybe throughout the recipient's whole life.

Then, mature cells from many lineages may treat diseases including cancer, infections, genetic immune weaknesses, and problems with blood and storage.

Treatment of numerous hematologic illnesses has shown effective when hematopoietic stem cells (HSCs) are genetically modified using lentiviral or anti-retroviral vectors (LVs). The degree of alteration of real repopulating HSCs continues to be a key determinant of therapy success. Gene delivery has been demonstrated to be improved by transduction-enhancing methods such as HSC-enhancing cytokine culture, high multiplicity of infection (MOI), repeated LV injection, alternative LV envelope pseudotyping, or the inclusion of transduction-enhancing small molecules [42].

Hematopoietic stem and progenitor cells (HSPCs) are resistant to infection by a variety of viruses and intracellular bacteria in addition to LV transduction. The significance of constitutive interferon-stimulated gene expression in pluripotent and multipotent cell types has recently come to light. The interferon-induced transmembrane (IFITM) family of proteins in particular, which are interferon-regulated innate effectors, offer an inherent defense against pathogens that depend on cellular endosomes for entrance and transport [43].

The IFITM proteins were initially discovered to be antiviral effectors against the vesicular stomatitis virus (VSV). They have the ability to limit the transduction of VSV-G protein pseudotyped (LV) LV and to control cellular growth, adhesion, and development. We recently shown that the mammalian target of rapamycin (mTOR) inhibitor rapamycin pharmacologically overcomes the IFITM limitation, which restricts the effectiveness of gene delivery using VSV-G pseudotyped LVs in HPSCs. Rapamycin, a substance that suppresses the immune system and has a variety of undesirable consequences, can cause cell growth to be delayed. Although they can have unfavorable cytotoxic effects, staurosporine and the IFITM3-modulating cyclosporines also exhibit LV transduction enhancer activity. The various restriction factors from HIV-1 trafficking that the VSV-G pseudotyped LVs experience as a result of their different subcellular trafficking approach might impact integration and change delay [44].

## **3.4 Genetic engineering of T cells for improved immune response**

The gene transfer could be used to improve the effectiveness of T lymphocytes was apparent from the beginning of clinical studies in the field. T cells were the very first targets for genetic modification in human gene transfer experiments. An advantage of T cell-based immunotherapy compared to conventional chemotherapy, small molecules, and monoclonal antibodies is endurance because of continual generation of antigen-specific effector and memory T cells. In the presence of chronic infections or cancer, this hallmark allows both responses to pathogens and hiking for recurrence and minimal residual disease. However, persistence of genetically modified lymphocytes has been variable and often suboptimal in clinical trials. This variability may be

a result of differences in the composition of infused cells, with some studies infusing a mixture of CD4+ and CD8+ cells, and other pure populations of CD8+ cytotoxic cells [45]. In addition, T cells may differ in their expansion potential, homing, and persistence, based on their differentiation status. When T lymphocytes encounter antigen, they undergo a developmental program from naïve (TNA), to central memory (TCM) and effector memory (TEM) cells. Gene-modified lymphocytes currently infused to patients are usually generated starting from unselected circulating T cells and will thus contain an unpredictable mixture of cellular subsets. Investigators are now trying to identify the optimal T cell target for gene transfer [46].

## **4. Safety and ethical considerations**

The following elements should be considered in order to ensure the security of gene therapy for HIV: international cooperation between researchers from the public and private sectors, as well as participation from communities affected by the virus, social value, scientific validity, fair participant and study site selection, a favorable and acceptable risk-benefit balance, independent scientific and ethical review, informed and voluntary consent, and respect for enrolled patients. Participants should receive appropriate medical care and compensation if they suffer unpleasant study-related occurrences.

Genome editing technologies are regarded as the most challenging yet effective tools for gene therapy procedures [47]. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) are the most widely used methods for editing the genome. The biggest moral problem with gene therapy is called "off-target mutation," which can lead to insertional mutagenesis and gene mutation. Because genome editing is a new and unpredictable technique and because the mechanisms regulating gene regulation and embryonic development are still poorly understood, bioethicists and scientists fear that the effects of germline therapy could be fatal [48]. Despite having demonstrated its value in therapeutic somatic applications, CRISPR/Cas has not yet advanced to the point where it may be utilized to alter the human genome for clinical reproductive purposes. As a result, the apparent long-term effects cannot be ignored. Genome editing on human embryos carries a very high risk of causing pathological diseases and disabilities, which may have long-term consequences for both the patient and their offspring. Off-target cleavage activity in DNA sequences has been demonstrated to occasionally occur in the past, despite stringent constraints on Cas9 targeting specificity [49].

Since the first gene therapy death in a clinical trial was announced in September 1999, the informed decision to participate in a clinical study has become more and more contentious. It is encouraged that patients in gene therapy clinical trials receive in-depth information about the potential dangers and benefits of the therapy in order to provide them the knowledge to make an informed decision about whether or not to participate without being forced [50]. The National Human Genome Research Institute (NHGRI) highlighted the requirement and significance of informed permission in CRISPR somatic genome editing after interviewing individuals with sickle cell disease for a study [51]. Though gene therapies may one day treat a wide range of terminal illnesses, the perceived benefits of the technology should not overshadow the difficulties patients may face in comprehending long-term hazards. While somatic gene therapy complies with the requirement for informed consent, the regulation

*Gene Therapy Approaches in HIV Treatment DOI: http://dx.doi.org/10.5772/intechopen.112138*

of germline embryo editing raises more difficult issues, such as whether or not a future generation's consent is required and, if so, who should provide that consent given that embryos are unable to give their consent for germline intervention [51]. Regarding the extent of parental authority over the embryo, there is ethical discussion about whether parents will be the only autonomous entity to make decisions for their unborn children or if this will be seen as displacing the interests of future generations who are unable to consent at the time of the decision [52].

## **5. Conclusions**

Gene therapy approaches in HIV treatment hold immense promise in addressing the challenges associated with the management and potential cure of human immunodeficiency virus (HIV) infection. This chapter has provided a comprehensive overview of the principles, techniques, and potential applications of gene therapy in the context of HIV.

The exploration of various gene therapy strategies, including gene editing technologies such as CRISPR/Cas9 and gene transfer methods utilizing viral and non-viral vectors, has shed light on the potential advantages and limitations of each approach. These advancements have opened up new avenues for targeted intervention, modification of viral reservoirs, and enhancement of the immune response against HIV.

Critical considerations surrounding the safety, efficacy, and ethical implications of gene therapy have been addressed. It is crucial to conduct rigorous preclinical and clinical evaluations to ensure the safety of these approaches and to monitor longterm effects. Additionally, ethical discussions must accompany the development and implementation of gene therapies to ensure responsible and equitable use.

Looking ahead, the future of gene therapy in HIV treatment holds significant potential. Continued interdisciplinary collaboration between researchers, clinicians, and policymakers is essential to advance the field and translate scientific discoveries into practical applications. Ongoing research, clinical trials, and technological advancements will further refine gene therapy approaches and increase their efficacy and accessibility. While challenges remain, including the need for efficient delivery systems, cost-effectiveness, and scalability, the progress made in gene therapy for HIV treatment offers hope for a potential cure. By harnessing the transformative power of gene therapy and building upon the knowledge gained, researchers and practitioners can strive toward improved outcomes for individuals living with HIV.

## **Acknowledgements**

The authors would like to express their sincere gratitude to the Management of RSM's N. N. Sattha College of Pharmacy, Ahmednagar, for providing the necessary resources and support for the completion of this work. We would also like to acknowledge the valuable contributions of our colleagues who provided insightful discussions and suggestions throughout the research process.

## **Conflict of interest**

The authors declare no conflict of interest.

*HIV Treatment – New Developments*

## **Author details**

Sachin Kothawade1 \*, Vaibhav Wagh1 , Vishal Pande1 and Amit Lunkad2

1 RSM's N.N. Sattha College of Pharmacy, Ahmednagar, MH, India

2 SCSSS's Sitabai Thite College of Pharmacy, Shirur, MH, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Gene Therapy Approaches in HIV Treatment DOI: http://dx.doi.org/10.5772/intechopen.112138*

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## **Chapter 4**

## HIV Treatment and Obesity: What's New?

*Paula Freitas and Sara Ribeiro*

## **Abstract**

Obesity among people living with human immunodeficiency virus (people living with human immunodeficiency virus (HIV) (PLWH)) is an emerging public health issue. In recent years, new drugs have been approved for the treatment of HIV infection, which have greatly extended the lives of patients, but they may also play a role in rising obesity rates. In addition to HIV-specific factors, traditional risk factors shared with the general population (aging, diet, inactivity, and genetics) are credible culprits for this pandemic. Importantly, the compounded presence of obesity and HIV infection seems to magnify the risk of metabolic disease. To date, several questions remain to be fully elucidated including the mechanisms by which antiretroviral drugs may lead to excessive weight gain, the influence of the interplay with environmental and genetic factors, and the long-term clinical effect of obesity in PLWH. Recently, new drugs for the treatment of obesity and new metabolic surgeries have emerged, shading new hope on obesity management. The aim of this chapter is to take a journey into the world of obesity, showing the most recent evidence in HIV patients.

**Keywords:** obesity, human immunodeficiency virus (HIV), antiretroviral therapy, anti-obesity treatments, metabolic surgery

## **1. Introduction**

Infection with the human immunodeficiency virus (HIV) was once a debilitating and ultimately fatal condition. With the advent of highly active antiretroviral therapy (HAART), posteriorly renamed combined antiretroviral therapy (cART), the course of the disease has rapidly changed. HIV is now considered a chronic and manageable condition with a significant improvement in life expectancy, meaning that individuals infected with HIV are at risk of the same comorbidities as an aging population without HIV may suffer, including obesity and its related metabolic dysfunction and cardiovascular disorders [1, 2]. Furthermore, people living with HIV (PLWH) face additional problems as HIV itself is an independent risk factor for metabolic and cardiac disorders, and modern cART regimens may promote excessive weight gain in some HIV-infected patients [3].

Obesity is one of the greatest pandemics of the twenty-first century, and since 1980, its prevalence has doubled in more than 70 countries. Over 600 million adults were obese in 2015, with a high body mass index (BMI) accounting for approximately 4 million deaths worldwide and several years of lost lifespan [4, 5].

Obesity is a chronic, complex, heterogeneous, and relapsing disease that remains a global health concern, associated with an increased risk of multiple conditions [6].

In HIV-infected patients, the presence of obesity may potentially increase the risk of morbidity and mortality. Hence, it is crucial to promptly act to prevent and/or treat obesity in PLWH, paying special attention to the potential impact of antiretroviral therapy on weight gain [7].

The treatment of obesity is challenging and frequently requires a multidisciplinary approach including lifestyle modifications, behavioral therapy, pharmacotherapy, and/or bariatric surgery. In recent years, new drugs have been approved (with others underway) that are revolutionizing the way obesity is treated and will be treated in the near future [8].

Much of the knowledge about pharmacological obesity treatment is extrapolated from studies in people without HIV, but a growing body of research has come to light in recent years regarding nonpharmacological and pharmacological treatment and bariatric surgery in HIV-infected patients [9, 10].

The aim of this chapter is to provide an overview of the pathophysiology, impact, and management of obesity in the context of HIV infection, highlighting the most recent advances on the field.

## **2. Pathophysiology of obesity in people living with HIV**

Following the widespread trend of rising obesity rates and thanks to the undisputable success of cART in prolonging the life expectancy of PLWH, obesity in PLWH is also becoming an emerging public health challenge. In recent years, the prevalence of obesity among PLWH in high-income countries has risen and is now estimated to be 12.5–34% [7, 11, 12]; the same trend is found in low-middle-income countries [13, 14].

Obesity is associated with increased adipose tissue, a special connective tissue containing adipocytes and several other types of cells, surrounded by capillary and innervation networks that function together as an integrated unit. In addition to the classical functions attributed to adipose tissue such as lipid storage, thermal activity, and mechanical insulation, this tissue is also now recognized as a multifunctional and metabolically active immune and endocrine organ, directly modulating many processes including energy balance and metabolism [15].

In obesity, dysfunctional adipocytes and resident-immune cells, particularly T cells and macrophages, display distinct biochemical properties with a pro-inflammatory profile and altered secretion of adipokines and lipokines, thereby creating and perpetuating a state of chronic inflammation, which contributes to the development of comorbidities such as insulin resistance and type 2 diabetes mellitus (T2DM), atherosclerosis, and nonalcoholic fatty liver disease (nonalcoholic steatohepatitis NASH) [16]. Among PLWH, a high BMI has also been shown to magnify the risk of metabolic disease and neurocognitive impairment [17–19]. In fact, HIV-infected patients are a particularly high-risk group, as HIV infection per se, even when treated, induces a state of chronic inflammation and immune activation that contributes to the development of metabolic disease [20]. Accordingly, HIV and obesity seem to act synergistically enhancing the risk of T2DM, as demonstrated in a study that included 7177 HIV-positive American veterans in which a 5-pound gain was associated with a 14% increased risk for diabetes in HIV-infected compared with only 8% in the general population [21].

The anatomical distribution of fat also influences its pro-inflammatory properties. Depending on where it is localized, adipose tissue can be classified as subcutaneous,

## *HIV Treatment and Obesity: What's New? DOI: http://dx.doi.org/10.5772/intechopen.112667*

with peripheral distribution, or visceral adipose tissue, mainly present in the mesentery and omentum. Clinically, visceral adipose tissue may be evaluated by measures such as increased waist circumference or waist-to-hip ratio, as well as elevated intra-abdominal fat area in cross-sectional abdominal imaging. Visceral adipose tissue has distinct physiological and prognostic differences in comparison with subcutaneous fat, being more cellular, vascular, innervated, and containing a higher number of inflammatory and immune cells [22]. In accordance with these features, visceral adipose tissue is strongly associated with increased cardiometabolic risk and carries a greater prediction of mortality than subcutaneous adipose tissue.

In fact, evidence suggests that the quantity of visceral fat may dictate whether an individual has a "metabolically healthy obesity" (obesity without overt metabolic disease) or a metabolically unhealthy obesity (with metabolic syndrome) [15]. This also seems to hold true in PLWH. In a study that included 580 HIV-infected patients, the proportion of "metabolically unhealthy" patients (patients with metabolic syndrome) was higher among patients with excessive weight and central obesity, with those patients presenting a higher cardiovascular risk [23]. This highlights the importance of addressing obesity and its phenotype (visceral adipose tissue vs. subcutaneous adipose tissue) in patients with HIV, when evaluating cardiometabolic risk [23].

Despite many years of research, the etiopathogenesis of obesity remains to be completely elucidated. Although simple in its most basic principle—it results from an energetic imbalance in which the caloric intake exceeds ongoing energy expenditure—growing evidence indicates that obesity pathogenesis involves processes far more complex than the passive accumulation of excess calories [24]. Many elements influence this equation including genetic, behavioral, and environmental factors, the sleep-wake cycle, hormonal changes, intestinal microbiota, stress, endocrine diseases, and drugs [25]. Besides the antiretroviral agents, many other drugs are also associated with weight gain including antidiabetic agents (insulin, meglitinides, sulfonylureas, and thiazolidinediones), neurologic agents (anticonvulsants, lithium), psychiatric agents [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antipsychotics, monoamine oxidase inhibitors (MAOIs), and phenothiazines], and other agents (α-adrenergic blockers, antihistamines, β-adrenergic blockers, centrally acting agents, corticosteroids, and hormonal contraceptives) [26].

Sedentary lifestyle, influences of cultural dietary practices, and lack of education or resources regarding proper nutrition are primary drivers for significant weight gain [10]. In addition to quantity, diet quality also determines the obesogenic effects of foods and affects metabolic health through diverse biological pathways [27]. In this regard, increasing attention is being paid to food insecurity and its role in obesity.

## **3. Food insecurity in PLWH**

Food insecurity is defined as having limited or uncertain access to nutritionally adequate and safe foods to maintain a healthy life [28].

Likely a consequence of the socioeconomic challenges that many HIV-infected patients experience, PLWH are disproportionately affected by food insecurity with studies suggesting that up to half of PLWH in urban areas of North America experience food insecurity [29].

Food insecurity is a known risk factor for obesity in both PLWH and HIVuninfected people [30] and is a major determinant of poor nutrition; PLWH with food insecurity can have a similar caloric intake as people with food security, but of poorer quality based on nutrient-poor, energy-dense food [31–33]. Very low food security has been associated with more frequent frailty among women, independently of HIV serostatus and has been implicated in worse clinical outcomes in PLWH, the reason why it should be part of the assessment in PLWH and obesity [33].

In conclusion, obesity is an emerging comorbidity in PLWH with important metabolic consequences. Several factors are implicated, many of which are shared with HIVuninfected patients, such as diet and sedentarism. However, PLWH face the additional burden of obesity-promoting HIV-specific factors, notably the overlapping immune activation arising from chronic HIV infection and exposure to antiretroviral therapy (ART).

## **4. The new era of antiretroviral therapy: integrase inhibitors**

In the early days of the HIV epidemic and cART, weight gain in PLWH, particularly in those with low CD4 count and high HIV RNA, was attributed to the reversal of the catabolic state of HIV infection and was associated with improved survival and immunologic recovery, and therefore was considered a "return to health" [34].  Lipodystrophy was a frequent condition among PLWH receiving combination antiretroviral therapy containing older-generation thymidine analog nucleoside reverse transcriptase inhibitors (NRTIs) and early protease inhibitors (PIs) [35]. In the last 20 years, however, the scenario has changed. Greatly thanks to an earlier diagnosis and highly effective newer generation cART, wasting syndrome and lipodystrophy have become much rarer. Instead, weight gain and obesity are becoming the greatest concern as evidence coming from a multitude of studies show that the median BMI and prevalence of baseline obesity among PLWH initiating cART have been steadily increasing, with most of the patients having normal or high BMI [36]. Moreover, following cART initiation many individuals gain an excessive amount of weight, leading to posttreatment obesity. In a study by Tate and colleagues in 2012, 20% of PLWH had moved to a more deleterious BMI category (from normal to overweight/obese or overweight to obese BMI categories) after 24 months on cART, with greater BMI increases observed for those on a boosted protease inhibitor (PI) regimen [37].

In line with these results, the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study that included over 14,000 individuals showed that after 3 years on cART, 22% of individuals with a normal BMI at baseline had become overweight (BMI 25–29.9 kg/m2 ) and 18% of those overweight at baseline had become obese (BMI >30 kg/m2 ). The weight gain was largest for women and, for White women greater than age-matched population control [36].

The same phenomenon seems to be replicated and aggravated with newer ART regimens as accumulating evidence suggests that therapies including new generation integrase strand transfer inhibitors (INSTIs) cause more weight gain and treatmentemergent obesity than other ART regimens [38–41].

The first INSTI approved by the U.S. Food and Drug Administration (FDA) was raltegravir in 2007, followed by approval of five other drugs: raltegravir, elvitegravir, cabotegravir, dolutegravir, and bictegravir. Since 2017, acknowledging the good tolerability profile and (for the latter two), a substantial genetic barrier to drug resistance, the INSTI integrate the preferred combination of antiretroviral drugs for initial therapy (consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and an INSTI) [42].

## *HIV Treatment and Obesity: What's New? DOI: http://dx.doi.org/10.5772/intechopen.112667*

From 2006 to 2019, the Women's Interagency HIV Study enrolled a geographically and racially diverse sample of 1458 women living HIV and on ART. In this relevant sample, the switch from non-INSTI regimens to INSTIs and/or tenofovir alafenamide (TAF) was associated with significant short-term body weight and BMI gains [43]. Additionally, results from five randomized studies support the association between the use of INSTIs and increases in weight (two studies evaluated raltegravir and three evaluated dolutegravir) [44].

The statistically significant increases in body weight and clinical obesity with INSTIs appear to be most pronounced in Black individuals and women, suggesting the presence of vulnerable subgroups. The effect of cART drugs on weight gain is heterogeneous and differences clearly exist among various INSTIs and NRTI backbones; in particular, evidence suggests that tenofovir alafenamide (TAF) potentially enhances the weight gain effect and that the use of tenofovir disoproxil fumarate (TDF) seems to lessen these effects [44]. In what respects INSTIs and dolutegravir appear to have the greatest effect, while elvitegravir may have minimal effect. Evidence on cabotegravir, the newest integrase inhibitor, is limited [45]. Novel treatments such as the next-generation NNRTI doravirine could offer a suitable alternative therapy, with current evidence showing efficacy and limited effect on weight gain [39].

Still, data on this topic are inconsistent, and more randomized studies accounting for diet and lifestyle factors, such as smoking, are needed. It remains unclear whether INSTI-based regimens also contribute to visceral adiposity or intensification of the cardiometabolic risk [46].

The mechanisms driving weight gain following cART remain largely unknown and certainly override the traditional concept of "return to health." Proposed mechanisms include improved tolerability, direct impact on adipogenesis, and gut microbiome disturbance [39, 45]. Alterations in the composition and function of the intestinal microbiome seem to precede weight gain and may promote obesity through increased bowel permeability, increased fermentation and absorption of dietary polysaccharides, and even through modulation of genes regulating lipogenesis and insulin resistance [47].

Furthermore, *in vitro* studies have shown that dolutegravir inhibits the binding of radiolabeled α-melanocyte-stimulating hormone (MSH) to the human recombinant melanocortin 4 (MC4R) [48]. Since MC4R is involved in the regulation of energy homeostasis and food intake, and deficiency in MC4R is associated with monogenic obesity, increased appetite caused by dolutegravir could contribute to the observed changes [49].

## **5. Treatment of obesity**

Many strategies can be effective in inducing weight loss in people with obesity, including low-calorie diets, exercise-based interventions, pharmacological treatments, and surgery, either separately or in combination [50]. Besides the beneficial impact on weight, these interventions also lead to enhanced quality of life in addition to improvement in glycemic and lipid control, particularly for those who lose more than 10% of their baseline weight [50, 51]. However, how weight loss exactly affects adipose tissue physiology and obesity-related systemic inflammation as well as its long-term implications in terms of mortality and life expectancy remain to be fully clarified [52].

In PLWH specifically, obesity treatment remains largely unaddressed and little research has yet tested the efficacy of these weight loss programs and whether the benefits translate to this population.

Understanding the multifactorial nature of obesity is essential for better informing its management [38].

## **6. Nonpharmacological treatment**

When determining the optimal weight-loss strategy for individuals living with HIV (PLWH), several factors should be considered.

Lifestyle interventions are crucial in addressing obesity and typically encompass a combination of dietary modifications, physical activity, and behavioral strategies. Caloric restriction should be contemplated as the primary element in weight-loss interventions. Additionally, aerobic exercise and resistance training are recommended for all individuals [53]. Behavioral interventions also play a pivotal role in obesity management; strategies, such as self-monitoring, goal-setting, stress management, and social support systems, can enhance adherence to lifestyle changes and improve long-term outcomes [54].

The optimal lifestyle approach for weight loss in PLWH has not yet been defined. For example, multiple interventions, such as low-fat, Mediterranean, or micronutrient-supplemented nutrition, combined with behavioral interventions, have shown modest improvements in blood pressure, metabolic parameters, immune activation, and favorable gut microbiota changes [55–59]. However, these studies were mainly designed to target cardiovascular factors and/or lipodystrophy rather than on weight loss and its long-term maintenance.

In general, when studied in those without HIV, the effect of different dietary macronutrient patterns (carbohydrate reduction, fat reduction, and moderate macronutrients) and popular named diet programs on weight loss has found small differences of limited clinical significance [60]. Although a recent meta-analysis showed that most macronutrient diets lead to modest weight reductions and substantial improvements in blood pressure and lipids over 6 months, the effects were not sustained [61]. On the other hand, higher intakes of protein and fiber, as well as lower glycemic load diets, seem to contribute to weight maintenance by increasing satiety [62]. The Mediterranean diet has been shown to improve metabolic parameters, immune activation, regulatory T-cell (Treg) function, and the composition of the gut microbiota in HIV-1-infected individuals. Furthermore, the Mediterranean diet has been associated with increased abundances of *Bifidobacterium* after the intervention, which is linked to a beneficial profile [58]. Data are still lacking regarding the effects of intermittent fasting regimens in PLWH with obesity and directed clinical trials are warranted [63].

When addressing obesity, it is crucial to set a realistic and meaningful weight goal. People can lose weight on any dietary plan as long as a total caloric deficit is achieved. The choice of a dietary approach should be individualized, but typically, a deficit of at least 500 kcal per day can lead to a loss of 0.5–1.0 kg per week. Sustained weight loss of as little as 3–5% of body weight can result in clinically meaningful reductions in specific risk factors associated with cardiovascular disease (CVD) [64]. Moreover, moderate diet-induced weight loss (6–8%) has been shown to improve metabolic function in people with HIV, obesity, and insulin resistance [65].

## **7. Physical activity and exercise training**

Compared to adults without HIV but with other chronic diseases, PLWH generally tend to be less physically active [66], which may contribute to weight gain. Studies

*HIV Treatment and Obesity: What's New? DOI: http://dx.doi.org/10.5772/intechopen.112667*

investigating the benefits of combined aerobic and resistance exercise training in PLWH have consistently shown (despite the relatively small sample sizes and short intervention duration) physiological improvements, including lower BMI, waist circumference, improved lipid profile, and enhanced cardiorespiratory fitness [67]. Additionally, exercise has been associated with reduced distress, lower levels of depression, and improved neurocognitive function [68–71].

As a principle, PLHW should follow the general guidelines that recommend engaging in 30 min or more of moderate-intensity physical activity most days of the week for weight loss and maintenance, with the goal of achieving a minimum of 150 min per week [64, 67]. Resistance training should also be incorporated into the regimen, preferably performed 2 to 3 times per week [53]. Furthermore, periodization of exercise, which involves manipulating the volume, intensity, and recovery between exercises, has also demonstrated better results than nonperiodized training in PLWH [72] and can be considered.

In conclusion, exercise training is considered safe and beneficial for medically stable adults living with HIV and should be part of the recommendations [68].

## **8. Metabolic adaptation**

Why do people who follow a diet plan not continue to lose weight? And why is weight regain so common? The answer lies in metabolic adaptation.

Metabolic adaptation occurs during weight loss and involves an increase in hunger as a result of elevated levels of the orexigenic hormone ghrelin and decreased levels of anorexigenic hormones. Simultaneously, energy requirements decrease, thereby creating what is known as the "energy gap" [62]. The decrease in total daily energy expenditure that occurs during weight loss results from many contributors such as a decrease in circulating leptin levels, a reduction in resting metabolic rate, a diminished thermic effect of food, and increased energy efficiency during daily activities [62]. Further investigation is required to identify effective strategies for narrowing the energy gap and reducing weight regain. Nevertheless, factors related to long-term weight loss maintenance have been recognized and include increased protein and dietary fiber intake, consuming diets with lower glycemic loads, and high levels of physical activity. Maintaining a high-energy flux state, characterized by a significant daily energy expenditure that matches energy intake, may help mitigate reductions in resting metabolic rate and may facilitate a more precise regulation of energy intake to align with daily energy expenditure [62].

## **9. Pharmacological treatment of obesity**

Limited information is available regarding the safety and effectiveness of weightloss medications in PLWH since they are often excluded from clinical trials and not adequately reported. However, the efficacy of treatment is likely to be similar to that in the general population, although potential interactions with antiretroviral therapy need to be considered. Notably, there are theoretical and documented drug-drug interactions between anti-obesity pharmacotherapy and antiretroviral therapy [10]. Therefore, healthcare providers must acknowledge the potential hazard of impaired control over HIV viremia when specific weight-loss medications are administered concurrently with antiretroviral therapy [10].

Glucagon-like peptide 1 (GLP-1) receptor agonists have demonstrated promising results in managing obesity in individuals without HIV, and studies investigating their effectiveness in PLWH are currently underway.

Further research is needed to optimize the selection of ART and the combined use of weight loss medications, when indicated [38].

## **10. Orlistat**

Orlistat is the sole anti-obesity drug approved by the FDA and European Medicines Agency (EMA) available both as a prescription medication and an overthe-counter (OTC) product. This accessibility allows widespread public use without close medical supervision [10].

Orlistat induces weight loss by reversibly inhibiting the activity of the enzyme lipase and consequently blocking the hydrolysis of triglycerides into absorbable fatty acids and monoglycerides. Hence, orlistat acts mainly via its local effect, directly reducing the absorption of dietary fat by around 30% [10]. Systemic exposure is minimal as it is primarily metabolized within the gastrointestinal wall and mostly undergoes fecal elimination. While orlistat does not interfere with the activity or elimination of other drugs through conventional mechanisms, it can potentially interact with other medications due to its impact on absorption [10, 73].

The impact of orlistat on weight loss, weight maintenance, cardiovascular disease risk, and glycemic control has undergone thorough investigation among overweight individuals, including those with and without T2DM. In the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study, participants who received orlistat, in addition to lifestyle changes, experienced an average weight change of 5.8 kg throughout the study duration, compared to a mean weight change of 3 kg in the lifestyle plus placebo group (p < 0.001). Furthermore, orlistat therapy reduced the incidence of T2DM beyond the result obtained with lifestyle changes only, an effect particularly evident in patients with impaired glucose tolerance at baseline [74]. Notably, while clinical trials have not explicitly excluded individuals with HIV infection, there is a lack of data specifically documenting outcomes in this particular population [10].

Regarding the safety of orlistat use in PLWH, multiple case reports have linked the initiation of this weight-loss agent to loss of HIV viremia control [10].

In general, drugs classified as Class II according to the Biopharmaceutics Drug Disposition Classification System (BDDCS), characterized by extensive metabolism, low water solubility, and high lipid permeability, are prone to significant alterations when-coadministered with orlistat, potentially resulting in unfavorable outcomes [10].

Significantly, non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (INSTIs) are classified as BDDCS Class II drugs, which imply that coadministration with orlistat is likely to result in reduced drug absorption [10]. Furthermore, NRTis, such as zidovudine, abacavir, and TDF, although belonging to different BDDCS classes, are generally acknowledged to possess lipophilic properties [75–77], hence enhancing the probability of potential interferences. Considering the significant risk associated with compromised control of HIV viremia, the absence of efficacy data in HIV patients, and the availability of alternative weight-loss agents suitable for PLWH, orlistat is generally not recommended in all HIV patients currently taking cART. Given the over-the-counter (OTC) availability of orlistat, it is critical that PLWH on cART are properly advised to consult their healthcare provider before independently initiating any weight-loss medication [10].

## **11. Naltrexone-bupropion**

Naltrexone-bupropion is a combination regimen that consists of an opioid antagonist (naltrexone) and an aminoketone antidepressant (bupropion). The use of bupropion in combination with naltrexone is believed to help regulate food intake by leveraging their individual effects on the mesolimbic dopamine circuit and hypothalamus, respectively.

In phase 3 trials, such as Contrave Obesity Research-I (COR-I), Contrave Obesity Research-II (COR-II), Contrave Obesity Research-Intensive Behavior Modification (COR-BMOD), and Contrave Obesity Research-Diabetes study (COR-Diabetes), the administration of naltrexone-bupropion demonstrated significant weight reduction compared to placebo [78–81]. Using a modified intent-to-treat analysis, these trials reported average weight losses of approximately 4.7, 5.9, 4.2, and 3.4 kg, respectively, surpassing the outcomes observed with placebo [82]. However, it is important to note that these trials did not include individuals with HIV [10].

Naltrexone and its major active metabolite, 6-β-naltrexol, undergo minimal metabolism by cytochrome P450 (CYP) enzymes and do not exhibit significant inhibition or induction capabilities. Both the parent compound and metabolite are primarily eliminated through renal excretion, with average elimination half-lives of 4 and 13 h, respectively [83].

In contrast, bupropion undergoes extensive hepatic metabolism via cytochrome P450 2B6 (CYP 2B6) to hydroxybupropion, while non-CYP-mediated pathways contribute to the production of erythrohydrobupropion and threohydrobupropion. Bupropion has an average half-life of 21 h, whereas its metabolites exhibit extended half-life in comparison with the parent compound [10].

Based on the pharmacokinetics of bupropion, multiple drug-drug interactions can be recognized or anticipated. Importantly, antiretroviral agents, such as ritonavir and certain NNRTIs, are known inducers of CYP2B6, which may potentially interfere with bupropion concentration. However, at present, no dose adjustments are recommended based on the current understanding of this interaction.

Still, for healthcare providers considering the initiation of naltrexone-bupropion in PLWH, increased monitoring of bupropion is recommended when coadministration with ritonavir-boosted PIs, efavirenz, nevirapine, or any regimen containing cobicistat is planned. Periodic monitorization should include evaluating the efficacy of weight loss, assessing the occurrence of neuropsychiatric events and suicidal behavior and ideation, and evaluating blood pressure, heart rate, and renal and hepatic function. In the event of negative changes in mood or behavior, irrespective of the HIV status or antiretroviral regimen, it is recommended to promptly initiate a tapering process and discontinue the use of naltrexone-buproprion for all patients [10].

## **12. Liraglutide**

Liraglutide is a GLP-1 receptor analog primarily designed for treating T2DM. It is administered via subcutaneous injection and is highly bound to human serum albumin, with more than 99% binding *in vitro*. Liraglutide promotes weight loss by slowing gastric emptying and inducing early satiety [84, 85].

The efficacy of liraglutide for weight loss in patients without T2DM was evaluated in the Satiety and Clinical Adiposity–Liraglutide Evidence (SCALE) randomized controlled clinical trial. In this study, 3.0 mg of liraglutide in addition to diet and

exercise was associated with a significant reduction in body weight (mean weight change of 8.4 kg compared to a mean weight change of 2.8 kg with placebo, at week 56 of treatment) [86]. However, individuals living with HIV were not eligible for enrollment in this trial. Other studies, primarily conducted to address liraglutide efficacy in treating T2DM although not explicitly excluding PLWH, have not conducted specific subgroup analysis on this patient population [10]. Nevertheless, based on what it is currently known, there is no reason to expect the benefits of liraglutide therapy in PLWH to differ from the general population.

Liraglutide undergoes rapid clearance by the kidneys through metabolism by endogenous dipeptidyl peptidase IV (DPP-IV) and endopeptidases [87]. As it undergoes a metabolism pathway independent of CYP, the potential for drug-drug interactions is greatly reduced, simplifying its use in individuals receiving cART. Nonetheless, concerns have been raised regarding interactions between liraglutide and antiretroviral agents that necessitate an acidic gastric environment for proper absorption, due to the known inhibitory effect of the natural GLP-1 hormone on gastric secretion. However, an evaluation of individuals at steady state using liraglutide 1.8 mg compared to placebo reported no statistically or clinically significant differences in gastric pH [88]. Liraglutide was also found to have minimal impact on the gastric absorption of concomitant medications from various Biopharmaceutics Drug Disposition Classification System (BDDCS) classes [88].

Overall, liraglutide is regarded as a viable choice for promoting weight loss in PLWH [10].

## **13. Semaglutide and tirzepatide**

Semaglutide, also a GLP-1 receptor agonist, and tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) agonist, are both promising options for weight management.

In the STEP 1 trial, individuals treated with semaglutide achieved an average weight loss of almost 15% from baseline (compared to 2.4% with placebo), and nearly 70% of participants experienced more than a 10% reduction in weight (compared to 10% with placebo) [89]. Recent evidence suggests that tirzepatide demonstrates similar or possibly even superior efficacy compared to semaglutide for weight management [90, 91]. Currently, there are two ongoing clinical trials assessing the safety and efficacy of semaglutide in individuals living with HIV (PWH) who also have obesity, with a focus on weight loss achieved through a combination of semaglutide treatment and diet and exercise interventions. These trials aim to evaluate the effectiveness of semaglutide specifically in PWH and its potential impact on weight reduction compared to diet and exercise alone [92], and its effects on ectopic fat, insulin resistance, inflammation markers, and cardiovascular risk [93].

Importantly, despite the lack of substantial data regarding the impact of GLP-1 receptor analogs on weight-loss in PLWH, initial observational studies indicate that treatment of patients with both HIV infection and T2DM using GLP-1 receptor analogs may provide a protective effect against major adverse cardiovascular events such as myocardial infarction and acute heart failure [94].

Regarding weight-loss drugs currently available in Europe, the majority of drugs are generally considered safe for PLWH undergoing cART, except for orlistat. When planning to start pharmacological treatment for obesity, clinicians should contemplate each agent's specific characteristics, counseling points, and monitoring parameters that necessitate assessment when used in conjunction with cART.

In conclusion, obesity in PLWH should be addressed using a similar approach employed to the general population. Healthcare providers should consider incorporating most of the currently approved weight-loss agents as adjuncts to adequate lifestyle modifications [10].

## **14. New hopes in the treatment of obesity**

Several upcoming drugs promise to revolutionize the treatment of obesity by combining different incretin pathways. Retatrutide (LY3437943), a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, seems of special interest due to the substantial reduction in body weight observed in its Phase 2 trial [95].

Similarly, the coadministration of cagrilintide—a long-acting amylin analogue and semaglutide (CagriSema), resulted in clinically relevant improvements in glycemic control and significantly greater weight loss versus semaglutide in people with T2DM [96, 97].

Finally, orforglipron, a nonpeptide GLP-1 receptor agonist given as an once-daily oral therapy, has also shown to lead to substantial weight reduction in adults with obesity without T2M [98]. Phase 3 trials are currently underway for all these new promising drugs. Their role in obesity treatment in PLWH remains to be clarified.

## **15. Bariatric or metabolic surgery**

Bariatric surgery is gaining popularity as an effective surgical intervention for addressing severe obesity and metabolic dysregulation in cases where lifestyle modifications are insufficient to attaining weight-related objectives [99]. Bariatric surgery may be a suitable option for patients with a BMI of 40 kg/m2 or greater, or a BMI of 35 kg/m2 or greater with one or more severe obesity-related comorbidities [53]. Given the rising prevalence of obesity in PLWH, bariatric surgery is increasingly being used among PLWH [45].

The American Society for Metabolic and Bariatric Surgery recommends laparoscopic approaches, such as Roux-en-Y gastric bypass, sleeve gastrectomy, adjustable gastric banding, and biliopancreatic diversion/duodenal switch, as preferred methods compared to over open bariatric procedures [99].

There is limited literature available on the efficacy of bariatric surgery in HIVinfected individuals and no large-scale or randomized clinical trials have been conducted in this patient population. However, existing literature suggest that patients with HIV are likely to share the same benefits in terms of weight loss and resolution of obesity-associated comorbidities to those without HIV. Also, data concerning HIVrelated outcomes and pharmacokinetics of cART following bariatric surgery remain scarce and, as a result, there are no specific guidelines for managing HIV-infected individuals after bariatric surgery.

Understandably, factors specific to these patients, such as viral load, CD4 cell counts, absorption of antiretroviral therapy, and other medications, are important outcomes to consider [9].

Patients who undergo bariatric surgery experience significant anatomical and physiological alterations, including changes in gastric volume, acidity, gastrointestinal emptying time, enterohepatic circulation, and delayed entry of bile acids [45]. Additionally, they will have to undertake a specific diet plan, may receive instructions to crush oral medications, and may be prescribed postoperative acid-suppressing agents and vitamin supplements. These alterations can affect different aspects of antiretroviral absorption and pharmacokinetics. Some antiretrovirals with specific characteristics, such as requiring an acidic environment, administration with fatty meals, longer intestinal exposure, and enterohepatic recirculation for absorption, may be more impacted by bariatric surgery interventions [45]. Additionally, certain antiretrovirals can interact with polyvalent cations in supplements or drugs that inhibit gastric acid.

In this context, healthcare providers need to carefully evaluate the patient's antiretroviral medications taking into consideration factors such as the absorption site of the antiretrovirals, their compatibility with being crushed, the need for administration with food, and any contraindications or drug interactions with acid-suppressing agents or supplements [99].

Predicting pharmacokinetics based solely on drug characteristics has proven to be challenging, underscoring the importance of pharmacokinetic studies in this specific population [45]. Still, dolutegravir, darunavir, and most NRTIs seem appropriate drug options postbariatric surgery [45] and despite these concerns regarding drug absorption after bariatric surgery, so far, there is no evidence suggesting a significant impact on markers of HIV disease progression, such as CD4 count and viral load, for both sleeve gastrectomy and Roux-en-Y gastric bypass [9, 100, 101].

Finally, recent research has demonstrated that bariatric surgery induces an immediate and enduring modification of the gut microbiota, which is independent of the surgical procedure itself [102]. It has been suggested that changes in the gut microbiome can influence the pharmacokinetics of certain antiretrovirals, such as abacavir and dolutegravir [103]. Gut microbiota alterations can lead to increased levels of s-glucuronidase enzymes in the gut environment, potently increasing the regeneration of active forms of these drugs and resulting in higher exposure concentrations [104]. However, it is important to interpret these data with caution, as the gut microbiome is influenced by multiple interfering factors such as diet, antibiotic use, and demographic parameters, possibly introducing different biases.

In conclusion, bariatric surgery is a viable option for selected patients with obesity, considering its success in driving weight loss without significantly interfering with cART-induced viral suppression. Nevertheless, the potential impact of perioperative changes in diet, supplements, and medications on antiretroviral regimens must always be carefully considered and close surveillance should be maintained [99].

## **16. Conclusions**

Obesity in individuals with HIV is an emergent and complex issue with various contributing factors, many of which are still not fully understood. While research on weight gain and obesity in people living with HIV has increased in recent years, much of the knowledge is based on studies conducted in individuals without HIV.

The increasing rates of obesity among PLWH are most likely multifactorial, resulting from the compounded effect of exposure to the obesogenic environment we currently live in and its associated traditional risk factors (e.g., inactivity, diet, and genetics) and HIV-specific factors including HIV-associated systemic inflammation/ immune dysregulation and direct cART effects, most particularly with the use of integrase strand transfer inhibitors.

## *HIV Treatment and Obesity: What's New? DOI: http://dx.doi.org/10.5772/intechopen.112667*

Importantly, weight gain in PLWH confers a greater risk of metabolic disease compared with HIV-negative individuals, highlighting the need to properly prevent and/or manage obesity in this population.

To improve the care of the growing population of people aging with HIV, it is crucial to better understand the mechanisms and clinical implications of cART-mediated weight gain and obesity.

Prospective clinical trials and further research are needed to optimize ART selection, explore the use of weight loss medications, and determine the efficacy and safety of metabolic surgeries. A multidisciplinary approach involving a team of surgeons, endocrinologists, nutritionists, psychologists, HIV providers, and clinical pharmacists is necessary to effectively prevent and treat obesity in people living with HIV.

The coordination and collaboration of interdisciplinary healthcare professionals are essential to ensure optimal outcomes for this unique patient population.

## **Author details**

Paula Freitas1,2,3\* and Sara Ribeiro1,2,3

1 Department of Endocrinology Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal

2 Faculty of Medicine, Universidade do Porto, Porto, Portugal

3 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3 IRIS

## **Chapter 5**

## Immune Reconstitution Inflammatory Syndrome and Hodgkin's Lymphoma

*Alexander Pivnik and Arsen Vukovich*

## **Abstract**

Immune reconstitution inflammatory syndrome (IRIS) is defined as a clinically significant exacerbation of known low-symptomatic serious, more often infectious diseases, in conditions of a significant increase in the level of initially low levels of CD4+ T-lymphocytes in response to highly active antiretroviral therapy (HAART) for HIV infection. Without prior etiotropic therapy for an opportunistic infection, its exacerbation with a pronounced clinical picture during HAART can be fatal for the patient. Lymphomas, including Hodgkin's lymphoma (HL), are considered within the framework of this problem. Unlike other malignant lymphoid tumors that occur with low levels of CD4+ T-lymphocytes, HL develops with elevated levels of CD4+ lymphocytes in response to HAART in HIV-infected patients in the first months of starting antiretroviral treatment. HL was diagnosed in 8% of HIV-infected individuals without HAART. After the appointment of HAART, the frequency of HL increases to 17%. These data allow the problem of IRIS to be considered as the main one in the study of the etiology and pathogenesis of HL in HIV-infected patients.

**Keywords:** IRIS, Hodgkin lymphoma, HAART, aggressive lymphoma, hematology

## **1. Introduction**

Classical HL is a monoclonal tumor, the substrate of which is Reed-Sternberg cells (R-SH) and Hodgkin cells, which originate from the germinal center of the follicles. After, it was introduced into the clinical practice of HAART the incidence of aggressive lymphomas and Kaposi's angiosarcoma decreased many times, and the incidence of HL, on the contrary, increased to 17% [1]. We are going to introduce our study of HL and IRIS.

## **2. Hodgkin's lymphoma: definition, history, and diagnostics**

Hodgkin's lymphoma (HL; Hodgkin's disease, lymphogranulomatosis) is a disease that includes classical HL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Classical HL is a monoclonal tumor, the substrate of which is Reed-Sternberg cells (R-SH) and Hodgkin cells, which originate from the B cells of the germinal center of the follicles. They make up about 1% of the total mass of tumor tissue, which consists of reactive, non-tumor T- and B- lymphocytes with an admixture of granulocytes and macrophages. Histological variants of HL were determined: lymphoid predominance, mixed-cell variant, nodular sclerosis, and lymphoid depletion. Later, the nodular variant is divided into two: the first type and the second type. In the first type, a small number of R-SH cells are distributed and scattered in the histological specimen. The prognosis of the disease is favorable. In the second type of variant with nodular sclerosis, tumor cells form syncytium. The prognosis is unfavorable. Hypereosinophilia in the specimen also indicates an unfavorable prognosis.

Hodgkin's lymphoma was first described in six patients in 1832 by Thomas Hodgkin as "a disease in which the lymph nodes and spleen are affected." After 23 years, S. Wilkes called this condition "Hodgkin's disease", having studied the observations described by T. Hodgkin and added 11 of his own to them [2]. The term "lymphogranulomatosis" was introduced in 1904, at the VII Congress of German Pathologists in Vienna, and for a long time, the process was differentiated with tuberculosis. In 1971, at the Ann Arbor conference, a classification was adopted for the staging of lymphomas from I to IV with the presence of clinical symptoms of intoxication (B) and without them (A). In 1988, Costwolds adopted additions: a massive tumor (bulky) X and a letter representation of the affected organs (S – spleen, H – hepar, etc.) [3]. In the classification of tumors of hematopoietic and lymphoid tissues, WHO 2001 approved the name "Hodgkin's lymphoma". Later, a nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) was isolated in which the addition of rituximab to the regimens of chemotherapy is required, which may differ from those developed for HL [4]. During immunohistochemical examination, the basic markers of HL were identified: CD30, CD25, and CD15. Up to 70% of patients are carriers of the Epstein-Barr virus (EBV). The problem of EBV oncogenesis in lymphomas is being intensively studied, but it has not yet been solved [5]. The generally accepted treatment regimens for HL are ABVD AVD, BEACOP-14, BEACOPPescalated, DHAP, and ESHAP. In some patients, autologous hematopoietic stem cell transplantation is used at the stage of consolidation after high-dose chemotherapy, more often with relapses/refractory course of the tumor.

Before starting chemotherapy, young men are offered cryopreservation of sperm, and women are offered cryopreservation of follicles.

According to the staging system adopted in Ann Arbor [6], bone marrow involvement qualifies as stage IV of tumor spread. However, the bone marrow naturally belongs to the hematopoiesis system, and the stage should be designated as III (personal point of view of the authors). Bone marrow damage is not a risk factor. Trepanobiopsy is not performed during the initial diagnosis of HL, but in case of relapse, this procedure is mandatory. Bone marrow involvement in primary HL patients according to bilateral trepanobiopsy is confirmed only in 12–14% of cases [1, 7]. According to the results of PET-CT, bone marrow involvement is registered much more often in 54% of patients [8].

## **3. Immune reconstitution inflammatory syndrome**

The first reports on the side effects of HAART appeared in 1997. As the viral load decreased and the CD4+ T-lymphocyte count in the blood increased, reflecting the effectiveness of antiretroviral treatment for HIV. In the past few years, the

## *Immune Reconstitution Inflammatory Syndrome and Hodgkin's Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.112193*

effectiveness of antiretroviral treatment for HIV infection has led to a resurgence of known, previously asymptomatic diseases. For example, these include pulmonary and extrapulmonary forms of tuberculosis, including atypical nontuberculous mycobacterioses: paratuberculosis, leprosy, fungal infections, parasitosis, contagious mollusks, cryptococcal infection, toxoplasmosis, shingles, leishmaniasis, and exacerbation of syphilis with a return of the initial clinical picture [9–19]. In addition, Guillain-Barré syndrome has been described in patients with HIV infection on HAART [20]. A. Weetman reports thyroiditis occurring 15 months after starting HAART [21].

In 2000, the Annals of Internal Medicine journal J.A. DeSimone et al. first described a new syndrome [22]. It is based on the phenomenon called IRIS (Immune Reconstitution Inflammatory Syndrome). In Russian literature, IRIS is recognized to be an inflammatory immune reaction.

The most frequent description of IRIS is tuberculosis-associated. There are several criteria and three categories of coinfection [23–30].

IRIS and tuberculosis occur in almost 1/3 of all HIV-infected patients on HAART [31, 32]. There is an urgent need of tuberculosis therapy prior to the administration of HAART [32, 33].

C.C. Chang et al. concluded that low levels of CD4+ T- lymphocytes and protein in the spinal fluid increase the risk of death in cryptococcal meningitis [34]. I. Sereti points out that HAART should be administered only after microbiological confirmation of cerebrospinal fluid sterility [35]. Cryptococcal meningitis is detected within 2 weeks to 4 months from the start of HAART [36–38].

Uveitis after initiating HAART is recognized as IRU (Immune Reconstitution Uveitis) and is found in 37.5% of cases [39]. HAART reduced the number of cases of CMV retinitis by 90%. Without HAART, uveitis occurred at CD4+ T-lymphocyte levels of 50 cells/μL or lower, and with HAART, it occurred at 200 cells/μL or higher [40–44].

Literature in the Russian language provides the first mention of IRIS in work of N.V. Matievskaya in 2012. The author described 73 patients with HIV infection, indicating the occurrence of severe IRIS in eight of them. The patients were diagnosed with purulent meningitis, toxoplasmosis, tuberculosis, and lymphomas, including HL in one patient. Manifestations of IRIS were noted after 1 week and up to 1 year from the start of HAART. HL was diagnosed 1 year after the start of antiretroviral therapy. Lethal outcomes occurred in five patients [45].

Panteleev A.M. reports on corticosteroid treatment in IRIS and tuberculosis [46]. A.M. Bitneva et al. reports the results of data analysis of 179 patients observed in a phthisiology department, 21 of which with IRIS [47]. The Belarusian authors Tyushchenko T.V. and Tsyrkunov V.M. reported that 47 patients with HIV infection died of opportunistic infections 3 months after the initiation of HAART [48]. I.M. Ulyukin notes the importance of careful monitoring in patients taking HAART with previous tuberculosis background [49].

IRIS also occurs in patients without HIV infection after treatment of tumor and autoimmune diseases with immunosuppressants and corticosteroid hormones [50].

IRIS has been described by P. Vishnu et al. in three patients with Burkitt's lymphoma (BL) diagnosed 20–24 weeks after HAART initiation, with CD4+ T-lymphocytes at 323, 553 and 293 cells/μL, respectively. In two patients, the viral load was not determined. Of the patients examined, one patient died, and two others achieved complete remission. The authors in their literature review of 2000–2013 found descriptions of only three patients with LB diagnosed 8–28 weeks after initiation of HAART. Lymphoma was diagnosed at an average CD4+ T- lymphocyte count of 277 cells/μL. Two patients died from the progression of LB, and one achieved complete remission [51].

Although HL is not an HIV-indicating malignancy, the incidence of this particular malignant lymphoid tumor is about 10 times higher in HIV-positive populations than in HIV-negative ones [52]. Despite the fact that the incidence of many opportunistic infections is decreasing in the "HAART era" [53, 54] incidence of HL in HIV-infected patients is increasing [55–60].

The largest number of patients with HIV infection and HL were described by R.J. Biggar et al. in 2006. Authors analyzed 317,428 cases of HIV infection of which classical HL was diagnosed in 173 cases. The mixed-cell variant was predominant (54%). It was shown that the risk of LC in HIV-infected patients with a CD4+ T-lymphocyte count of 225–249 cells/μL increases 10-fold compared to the general population. The authors also confirmed that the mixed-cell variant of HL with frequent detection of Epstein-Barr virus prevailed [56].

A multicenter study in which the authors linked the development of HL in HIV-infected patients with IRIS analyzed data of 64,368 HIV-infected patients from 1992 to 2009 in France, of whom 187 developed HL. This study did not specify what level of CD4+ T- lymphocytes prior to the development of HL. More than half of these patients were diagnosed with HL within the first 3 months of HAART initiation. An important conclusion is that the risk of HL diagnosis in patients who received HAART is generally low. However, it is shown that patients with a CD4+ T-lymphocyte level of at least 500 cells/μL have an almost 10-fold increased risk of HL compared to patients with a CD4+ T-lymphocyte level of 50–99 cells/μL [59].

J. Bohlius et al. indicate that a decreased level of CD4+ T-lymphocytes in patients receiving HAART correlates with an increased risk of developing HL [61]. A. Kowalkowski et al. reported the results of a multicenter analysis of 31,056 patients with HIV infection from 1985 to 2010 in Houston, of whom 196 had HL. It was shown that in patients with HL, CD4+ T-lymphocyte levels continued to decline 3–6 months after initiation of HAART. After 3 years of follow-up, it was found that the risk of developing HL in patients who received HAART doubled during the first year. It is noted that patients with CD4+ T-lymphocytes level of 200–350 cells/μL are in the group with the highest risk of HL [62]. Long-term HAART has been shown to reduce the risk of developing HL. Thus, HL was diagnosed in 211 of 31,576 patients with HIV infection who received HAART [63]. D. Gotti et al. report on 5087 HIV-infected patients followed up for 10 years, of whom 30 patients developed HL. It was shown that the risk of HL increases within 6 months of starting HAART [64]. Increased incidence of HL in HIV-infected patients receiving HAART has also been reported in other studies [65, 66].

Thus, in the literature, there are reports of better results of antitumor therapy in combination with HAART in patients with multiple myeloma and concomitant HIV infection than in the group without HIV infection [67].

## **4. Our study**

## **4.1 Materials and methods**

From 2002 to 2019, we observed 85 patients with HIV infection, HL, and concomitant hepatitis C and/or B. For technical reasons, data for 2008–2011 were excluded from the analysis. Thus, the study included 85 patients aged 20–74 years (median 35 years), 67% male.

*Immune Reconstitution Inflammatory Syndrome and Hodgkin's Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.112193*

## **4.2 Results**

Immunohistochemical study of tumor biopsy specimens revealed that 60 (70%) patients were EBV-positive. Coinfection with hepatitis C and B viruses was detected in 81 (95%) patients with HL. The level of CD4+ lymphocytes before the start of anticancer treatment for HL was about 400/mcL, and the viral load was above 100,000 copies/mcL. Before the start of chemotherapy, seven patients died. These patients presented with stage IVB HL, massive tumor lesions, and B-symptoms and died from tumor progression and opportunistic infections.

The treatment was carried out according to internationally accepted chemotherapy regimens: 6 courses of ABVD, 6 courses of BEACOPP-14, and 6 courses of BEACOPP-escalated with or without subsequent radiation therapy. Without exception, all patients underwent HAART simultaneously with anticancer treatment. In cases of a combination of HL, HIV infection and hepatitis B and/or C, simultaneous treatment of all three diseases is carried out. In the case of hepatitis C, direct-acting drugs orally are used for 12 weeks, with complete eradication of the virus achieved in 96% of cases. After the end of chemotherapy treatment of HL, the level of CD4+ lymphocytes increased to 700/μl, and the viral load decreased significantly to undetectable at the sensitivity threshold of the method of 25 copies/μl and below. It should be emphasized that over the entire historical period of observation under conditions of strict monitoring from 2002 to 2019, we did not observe relapses of HL. And as a consequence, we have not had to refer patients for transplantation of autologous hematopoietic stem cells. At the time of writing the article, 70 patients remained in complete remission of HL, confirmed by CT or PET-CT. See **Table 1**.

### **Table 1.**

*Clinical characteristics of patients.*

## **5. Conclusions**

The pathogenesis of IRIS is unclear. Obviously, an increased number of CD4+ T-lymphocytes plays an important role in the pathogenesis of IRIS. In addition, elevated levels of cytokines such as interferon-γ, interleukin-6, and tumor necrosis factor α can be detected, simultaneously [68–77]. Risk factors for the development of IRIS include increased levels of T- lymphocytes, CD4+, CD4+ to CD8+ T-lymphocyte ratio, the drop

## *Immune Reconstitution Inflammatory Syndrome and Hodgkin's Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.112193*

in the viral load after 90 days of HAART, and its early administration in case of opportunistic infections. When risk factors were taken into account, the decrease in viral load was significant, and the baseline CD4+ T-lymphocyte level was about 200 cl/μL [78, 79].

The incidence of HL in the "HAART era" has increased markedly [80, 81]. An essential feature of HL is the microenvironment of reactive cells in the tumor mass. Neoplastic-Reed-Sternberg cells and Hodgkin's cells usually make up 0.1–1% among the tumor microenvironment cells [82, 83]. However, tumor cells actively produce cytokines and chemokines, providing influx of activated CD4+ T- lymphocytes, as well as cells expressing CD40, CD26, histiocytes, and other cellular elements.

Thus, the experience of foreign and domestic researchers allows us to consider IRIS as one of the main problems in the study of the etiology and pathogenesis of HL in HIV-infected patients. The specificity of the directed action of T cells to the tumor antigens, which have not yet been elucidated, remains open. In this connection, it is strongly recommended to continue research in this direction.

Generalization of our own data allows us to conclude that HL in patients with HIV infection with standard chemotherapy regimens with simultaneous HAART gives better results in comparison with the HL group without HIV infection. These results are consistent with the reports available for another malignant lymphatic tumor. Thus, there are reports in the literature about better results of antitumor therapy in combination with HAART in patients with multiple myeloma and concomitant HIV infection than in the group without HIV infection [84].

Based on our own 17-year clinical experience in treating patients with HIV and HIV infection (antitumor treatment and HAART), we allowed ourselves to express a seditious idea about the possible use of HAART in hematological malignant tumors without concomitant HIV infection, although this requires serious research and evidence.

Deciphering the etiology and pathogenesis of HL is most likely possible when solving the IRIS problem and clarifying the issues of EBV oncogenesis.

Bone marrow involvement in primary patients with HL does not serve as an unfavorable prognostic sign and does not require histological confirmation based on the results of a trepanobiopsy study. At the same time, with relapses of HL, trepanobiopsy is a mandatory diagnostic procedure since the involvement of bone marrow in relapses is regarded as an extremely unfavorable prognostic factor. Cryopreservation of sperm and storage of follicles in persons of reproductive age is desirable.

A clear knowledge of the specificity and sensitivity of the T-cell reaction in the formation of granulomas is needed. The unraveling of this phenomenon may shed light on the possible deciphering of the pathogenetic mechanisms of the occurrence and development of HL in the general population without HIV infection.

*HIV Treatment – New Developments*

## **Author details**

Alexander Pivnik and Arsen Vukovich\* Peoples' Friendship University of Russia, Russia, Moscow

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Immune Reconstitution Inflammatory Syndrome and Hodgkin's Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.112193*

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