**4.1 HIV infection per se and HIV wasting syndrome**

HIV wasting was included as an AIDS-defining criterion (ADC) in 1987 by the Centers for Disease Control and Prevention (CDC). HIV wasting is defined as an involuntary weight loss of >10% from the baseline and associated with diarrhoea, fever or weakness of ≥30 days duration in the absence of a concurrent illness. HIV wasting is associated with disease progression and death even when patient is on effective ART [18]. Wasting is associated with low serum albumin levels and deficiency of important micronutrients like zinc and selenium [13].

The primary cause for weight loss in PLHA is inadequate calorie intake. One of the key factors leading to this is anorexia secondary to elevated levels of proinflammatory cytokines like interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). These cytokines also cause a rise in total daily energy expenditure (TEE) due to an increase in resting metabolic rate (RMR) or resting energy expenditure (REE) [19, 20]. RMR may increase by 10–30%, more so in the presence of concurrent infections or high viraemia and increased catabolism of proteins [14, 21–25]. Macallan et al. evaluated patients with HIV/AIDS for TEE, REE and energy intake. The REE was 9.6% higher in HIV-infected men than in HIVnegative men (25.0 vs. 22.8 kcal/kg/d; p = 0.002). But the mean TEE in HIV-infected men was lower than that of the population standard for HIV-negative men between

30 and 39 years of age (2750 kcal/d versus 3420 kcal/d) The authors concluded that this was due to reduced physical activity. However, there is a net negative energy balance because reduced TEE does not offset decreased energy intake due to anorexia and malabsorption [19]. Roubenoff and colleagues showed that cytokines released from activated PBMCs like TNF-α and IL-1β independently predicted loss of lean body mass and changes in REE [26]. And, nutritional and metabolic abnormalities correlated better with cytokines from PBMCs than plasma cytokines. Levels of TNF-α and IL-1β and IL-6 from PBMCs were better than plasma cytokines in distinguishing between participants with or without HIV wasting [27].

#### **4.2 Anorexia**

Various causes of anorexia leading to HIV wasting include oral candidiasis, oesophageal candidiasis, CMV oesophagitis, fever and tuberculosis. ART is also associated with significant adverse effects that include anorexia. Many NRTIs cause mitochondrial toxicity. Lactic acidosis and pancreatitis are two of the most serious effects of mitochondrial toxicity due to NRTIs, especially didanosine, stavudine and zidovudine. Frank lactic acidosis is not common, but hyperlacticacidaemia is fairly common and is seen in about 15% of patients on these NRTIs. It manifests with anorexia, nausea, weight loss, peripheral lipoatrophy and mildly deranged transaminitis. Zidovudine causes anorexia, nausea and fatigue in 5–10% patients during the early stages of therapy. Other drugs associated with anorexia and nausea include ritonavir and elvitegravir-cobicistat combination [28, 29]. Anorexia may also be secondary to jaundice secondary to HBV/HCV coinfection. Many ART drugs can cause hepatitis by different mechanisms. NRTIs cause steatohepatitis by mitochondrial toxicity. This usually develops after 6 months of treatment. NNRTIs cause hepatitis by hypersensitivity reaction. This usually occurs within the first 2–4 months of therapy. Protease inhibitors may cause hepatitis especially with HBV or HCV confection by an unknown mechanism. Anti-tubercular therapy is also another significant cause of iatrogenic hepatitis. Alcoholism, drug abuse and depression may all be associated with anorexia.

#### **4.3 Chronic diarrhoea**

Diarrhoea remains a common complaint among PLHA and adversely affects quality of life. In the early years of the HIV epidemic, HIV wasting syndrome was a common presentation, especially in sub-Saharan Africa. It would often be associated with prolonged diarrhoea (>30 days duration). Causes for diarrhoea can be infectious and non-infectious. In most of the low-income countries, the aetiology continues to be infectious, and etiologic agents differ according to geographical region [30, 31]. The aetiological agents can be broadly grouped as protozoa, bacteria, fungi and viruses.

#### *4.3.1 Infectious diarrhoea*

*Cryptosporidium parvum* is the most frequently identified protozoan causing chronic diarrhoea in PLHA universally [32]. In developing countries, prevalence rates of cryptosporidium infection can be as high as 20% [33]. The high prevalence is due to sewage/faecal contamination of water sources [34]. Although cryptosporidium is commonly associated with chronic diarrhoea in HIV-positive persons, it can also cause cholera-like explosive diarrhoea and intermittent acute and relapsing illnesses. Microsporidia (*Enterocytozoon bieneusi* and *Encephalitozoon intestinalis*) are other important protozoa causing diarrhoea in AIDS patients [35–38]. In a study from New York, microsporidia were found in 39% of AIDS patients undergoing

**33**

mm3

*Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

compromised patients (CD4+ T-cell count <50/ mm3

and diarrhoea; and may require hospitalisation [46].

pression (i.e. CD4+ T-cell count <50 cells/mm3

gastrointestinal evaluation for diarrhoea [39]. But this high prevalence is uncommon in other parts of the USA and the rest of the world [36]. *Isospora belli* is an endemic gastrointestinal pathogen among PLHA in Haiti, but it is uncommon in the USA [36, 37]. The widespread use of trimethoprim-co-trimoxazole prophylaxis for *Pneumocystis carinii* may be the reason for this low prevalence: *Isospora* being very susceptible to trimethoprim-sulphamethoxazole. Cyclospora have also been identified in HIV-infected patients with chronic diarrhoea in low- to middle-income countries (LMIC) [35–37]. Amoebic dysentery or invasive amoebic disease like liver abscess or amoeboma is not more common in PLHA than in the general population even in developing countries. A high frequency of stool carriage in asymptomatic homosexual men is however common [30]. Stool carriage of amoebae in PLHA includes *E. dispar*, *E. hartmanni*, *E. coli* and also non-pathogenic *E. histolytica* [40]. There is no difference in the prevalence or severity of giardiasis among PLHA and HIV-negative populations. The spectrum of bacterial pathogens causing diarrhoea in HIV-infected patients is similar to that in the general population. *Salmonella*, *Shigella*, *Campylobacter* and *E. coli* remain the commonest causes of diarrhoea in PLHA also. The immunocompromised state can lead to a symptomatic carriage of *Shigella* and *Campylobacter* [30]. *Clostridium difficile* should be actively excluded in patients with recent history of antibiotic therapy [41]. Clostridial infection is more common in severely immuno-

(MAC) typically causes diarrhoea in patients with AIDS with profound immunosup-

*Cytomegalovirus* (CMV) was identified in as many as 45% of GI biopsies in AIDS patients with diarrhoea in a study from France [47]. CMV infection usually presents late in the natural history of HIV/AIDS, occurring when CD4 count is <100 cells/

. In contrast, CMV was not detected in any of the rectal biopsies from 29 African

ment in the form of fever and weight loss often accompany diarrhoea [43]. MAC usually involves the small intestine; however, it can affect the entire GI tract [44, 45]. Fungi are rare etiologic agents for diarrhoea in HIV-infected. The only exception is histoplasmosis which can infect all parts of the GIT; can cause fever, weight loss

patients with chronic diarrhoea and abnormally appearing rectal mucosa [48]. Other viruses that have been identified in stools of PLHA with chronic diarrhoea include adenovirus, rotavirus, astrovirus, picornavirus and coronavirus [49, 50]. An Italian study followed up a cohort of 50 HIV-negative and 10 HIV-positive children for 1 year and collected stool samples from the children every alternate week. The samples were tested for rotavirus (RV), and they found that while HIV-positive children shed more RV in stools, these rotaviral infections were not more often associated with diarrhoea than in HIV-negative children [51]. Similar prevalence was

also reported from Lusaka in Zambia and Baltimore in the USA [52, 53]. Chronic *Strongyloides* infection may be present as chronic diarrhoea.

which can trigger systemic inflammation and sepsis [54].

*4.3.2 Non-infectious diarrhoea*

*4.3.2.1 ART-induced diarrhoea*

*Strongyloides* hyper-infection can occur in the immunocompromised. Disseminated *Strongyloides* infection leads to migration of larvae into various tissues outside the gut. The migrating larvae carry gut bacteria along, leading to bacterial translocation

With early diagnosis and institution of antiretroviral therapy, the incidence of infective diarrhoea has declined, and non-infectious causes are being increasingly identified. The common causes now are ART-associated diarrhoea, HIV enteropathy

). *Mycobacterium avium* complex

) [42]. Features of systemic involve-

#### *Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

*Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

30 and 39 years of age (2750 kcal/d versus 3420 kcal/d) The authors concluded that this was due to reduced physical activity. However, there is a net negative energy balance because reduced TEE does not offset decreased energy intake due to anorexia and malabsorption [19]. Roubenoff and colleagues showed that cytokines released from activated PBMCs like TNF-α and IL-1β independently predicted loss of lean body mass and changes in REE [26]. And, nutritional and metabolic abnormalities correlated better with cytokines from PBMCs than plasma cytokines. Levels of TNF-α and IL-1β and IL-6 from PBMCs were better than plasma cytokines in

distinguishing between participants with or without HIV wasting [27].

depression may all be associated with anorexia.

**4.3 Chronic diarrhoea**

*4.3.1 Infectious diarrhoea*

Various causes of anorexia leading to HIV wasting include oral candidiasis, oesophageal candidiasis, CMV oesophagitis, fever and tuberculosis. ART is also associated with significant adverse effects that include anorexia. Many NRTIs cause mitochondrial toxicity. Lactic acidosis and pancreatitis are two of the most serious effects of mitochondrial toxicity due to NRTIs, especially didanosine, stavudine and zidovudine. Frank lactic acidosis is not common, but hyperlacticacidaemia is fairly common and is seen in about 15% of patients on these NRTIs. It manifests with anorexia, nausea, weight loss, peripheral lipoatrophy and mildly deranged transaminitis. Zidovudine causes anorexia, nausea and fatigue in 5–10% patients during the early stages of therapy. Other drugs associated with anorexia and nausea include ritonavir and elvitegravir-cobicistat combination [28, 29]. Anorexia may also be secondary to jaundice secondary to HBV/HCV coinfection. Many ART drugs can cause hepatitis by different mechanisms. NRTIs cause steatohepatitis by mitochondrial toxicity. This usually develops after 6 months of treatment. NNRTIs cause hepatitis by hypersensitivity reaction. This usually occurs within the first 2–4 months of therapy. Protease inhibitors may cause hepatitis especially with HBV or HCV confection by an unknown mechanism. Anti-tubercular therapy is also another significant cause of iatrogenic hepatitis. Alcoholism, drug abuse and

Diarrhoea remains a common complaint among PLHA and adversely affects quality of life. In the early years of the HIV epidemic, HIV wasting syndrome was a common presentation, especially in sub-Saharan Africa. It would often be associated with prolonged diarrhoea (>30 days duration). Causes for diarrhoea can be infectious and non-infectious. In most of the low-income countries, the aetiology continues to be infectious, and etiologic agents differ according to geographical region [30, 31]. The aetiological agents can be broadly grouped as protozoa, bacteria, fungi and viruses.

*Cryptosporidium parvum* is the most frequently identified protozoan causing chronic diarrhoea in PLHA universally [32]. In developing countries, prevalence rates of cryptosporidium infection can be as high as 20% [33]. The high prevalence is due to sewage/faecal contamination of water sources [34]. Although cryptosporidium is commonly associated with chronic diarrhoea in HIV-positive persons, it can also cause cholera-like explosive diarrhoea and intermittent acute and relapsing illnesses. Microsporidia (*Enterocytozoon bieneusi* and *Encephalitozoon intestinalis*) are other important protozoa causing diarrhoea in AIDS patients [35–38]. In a study from New York, microsporidia were found in 39% of AIDS patients undergoing

**4.2 Anorexia**

**32**

gastrointestinal evaluation for diarrhoea [39]. But this high prevalence is uncommon in other parts of the USA and the rest of the world [36]. *Isospora belli* is an endemic gastrointestinal pathogen among PLHA in Haiti, but it is uncommon in the USA [36, 37]. The widespread use of trimethoprim-co-trimoxazole prophylaxis for *Pneumocystis carinii* may be the reason for this low prevalence: *Isospora* being very susceptible to trimethoprim-sulphamethoxazole. Cyclospora have also been identified in HIV-infected patients with chronic diarrhoea in low- to middle-income countries (LMIC) [35–37]. Amoebic dysentery or invasive amoebic disease like liver abscess or amoeboma is not more common in PLHA than in the general population even in developing countries. A high frequency of stool carriage in asymptomatic homosexual men is however common [30]. Stool carriage of amoebae in PLHA includes *E. dispar*, *E. hartmanni*, *E. coli* and also non-pathogenic *E. histolytica* [40]. There is no difference in the prevalence or severity of giardiasis among PLHA and HIV-negative populations.

The spectrum of bacterial pathogens causing diarrhoea in HIV-infected patients is similar to that in the general population. *Salmonella*, *Shigella*, *Campylobacter* and *E. coli* remain the commonest causes of diarrhoea in PLHA also. The immunocompromised state can lead to a symptomatic carriage of *Shigella* and *Campylobacter* [30]. *Clostridium difficile* should be actively excluded in patients with recent history of antibiotic therapy [41]. Clostridial infection is more common in severely immunocompromised patients (CD4+ T-cell count <50/ mm3 ). *Mycobacterium avium* complex (MAC) typically causes diarrhoea in patients with AIDS with profound immunosuppression (i.e. CD4+ T-cell count <50 cells/mm3 ) [42]. Features of systemic involvement in the form of fever and weight loss often accompany diarrhoea [43]. MAC usually involves the small intestine; however, it can affect the entire GI tract [44, 45].

Fungi are rare etiologic agents for diarrhoea in HIV-infected. The only exception is histoplasmosis which can infect all parts of the GIT; can cause fever, weight loss and diarrhoea; and may require hospitalisation [46].

*Cytomegalovirus* (CMV) was identified in as many as 45% of GI biopsies in AIDS patients with diarrhoea in a study from France [47]. CMV infection usually presents late in the natural history of HIV/AIDS, occurring when CD4 count is <100 cells/ mm3 . In contrast, CMV was not detected in any of the rectal biopsies from 29 African patients with chronic diarrhoea and abnormally appearing rectal mucosa [48]. Other viruses that have been identified in stools of PLHA with chronic diarrhoea include adenovirus, rotavirus, astrovirus, picornavirus and coronavirus [49, 50]. An Italian study followed up a cohort of 50 HIV-negative and 10 HIV-positive children for 1 year and collected stool samples from the children every alternate week. The samples were tested for rotavirus (RV), and they found that while HIV-positive children shed more RV in stools, these rotaviral infections were not more often associated with diarrhoea than in HIV-negative children [51]. Similar prevalence was also reported from Lusaka in Zambia and Baltimore in the USA [52, 53].

Chronic *Strongyloides* infection may be present as chronic diarrhoea. *Strongyloides* hyper-infection can occur in the immunocompromised. Disseminated *Strongyloides* infection leads to migration of larvae into various tissues outside the gut. The migrating larvae carry gut bacteria along, leading to bacterial translocation which can trigger systemic inflammation and sepsis [54].

#### *4.3.2 Non-infectious diarrhoea*

#### *4.3.2.1 ART-induced diarrhoea*

With early diagnosis and institution of antiretroviral therapy, the incidence of infective diarrhoea has declined, and non-infectious causes are being increasingly identified. The common causes now are ART-associated diarrhoea, HIV enteropathy and causes seen in the general population. About 60% of patients receiving ART gave history of diarrhoea in the previous month [55]. Data from clinical trials suggest that up to 19% of these events may have been due to the adverse effects of ART [56]. Among the ART drugs, protease inhibitors (PIs) seem to be most strongly associated with diarrhoea. In mouse models, PIs and reverse transcriptase inhibitors significantly increased water and electrolyte secretion into intestinal lumen *in vivo* [57]. Rufo and colleagues demonstrated that protease inhibitors in general, and nelfinavir in particular, potentiate signalling through muscarinic and calciumdependent receptors of intestinal cells leading to increased chloride secretion into the lumen [58]. Stool samples of these patients also had increased concentrations of sodium and chloride consistent with secretory diarrhoea. In an *in vitro* study, Bode and colleagues showed that PIs induced apoptosis of human intestinal epithelium, thereby compromising barrier function and increasing water secretion in gut lumen. Decreased alkaline phosphatase activity in cells exposed to PIs led to accumulation of unfolded proteins in the cytosol. A failure of the cell's 'unfolded protein response', a specific signalling pathway aimed at returning the cell's protein folding function back to normal, triggered cellular apoptosis [59]. Wu and colleagues found that lopinavir and ritonavir induced endoplasmic reticulum dysfunction in intestinal epithelial cells that led to diarrhoea [60].

#### *4.3.2.2 HIV enteropathy*

HIV enteropathy is an idiopathic form of diarrhoea observed in all stages of HIV disease in the absence of an infectious source and with characteristic histologic features [61–63]. Changes include crypt epithelial proliferation leading to increased crypt height, later crypt cell encroachment onto villi and relative decreased villous height. The consequence of these changes are diarrhoea and malabsorption [64, 65]. While the exact mechanisms by which these changes occur in the GI tract are unclear, HIV has been postulated to alter signalling and cellular structure, which may lead to architectural distortion [61]. Keating and colleagues investigated monosaccharide absorption in patients with HIV and AIDS. They demonstrated that patients with diarrhoea had significant malabsorption of all monosaccharides tested [66]. Malabsorption occurred irrespective of pathogen-positive or pathogennegative diarrhoea, indicating that HIV had an independent direct role. This may be due to the ability of HIV to infect mucosal epithelial cells [67]. Increased mucosal infiltration by activated CD8+ T cells results in high levels of pro-inflammatory cytokines which can directly damage the mucosal barrier [61, 63]. Other hypotheses for the mechanism of HIV enteropathy include decreased transepithelial electrical resistance, decreased sodium-dependent glucose absorption and increased intercellular permeability in HIV-infected cells [68]. HIV enteropathy can also lead to malabsorption of vitamin B12, bile acid and monosaccharides [61, 64, 68].

#### **4.4 Environmental enteric dysfunction**

Chronic diarrhoea, water, sanitation and hygiene (WASH) have been implicated as causative factors for severe stunting in low- and middle-income countries for a long time. Efficacy of WASH interventions in reducing diarrhoea and malnutrition has been lower than expected. This led to the search for another cause. Today, there is sufficient evidence that the cause is environmental enteric dysfunction (EED). It is 'an apparently seasonal and reversible disorder characterised by gut mucosal cell villous atrophy, crypt hyperplasia, increased permeability and increased inflammatory cell infiltrate'. The principal driver of EED is the high

**35**

*Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

leads to stunting [69].

response to oral vaccines.

**4.5 Oral ulcers**

burden of intestinal infectious disease which is not enough to cause diarrhoea but enough to induce a state of chronic immune activation in the gut mucosa, thereby leading to epithelial damage. Dysbiosis of gut microbiota is also now considered to have an important role. The pathogenesis is probably chronic exposure to pathogens leading to a T cell-mediated immune response in the gut which continues to remain in an inflammatory hyperimmune state. This exaggerated immune response leads to structural changes in the gut mucosa, increased inflammation and permeability of the intestines, resulting in disrupted gut immune response; reduced absorption, delivery and utilisation of nutrients; and finally nutritional deficiency. There are also features of systemic inflammation, microbial translocation (MT) across the permeable gut mucosa and changes in the gut microbiome. Malnutrition further impairs the renewal of gut mucosal cells, maturation and proliferation of intestinal cells and pancreatic islet cells. The chronic low-grade inflammation inhibits endochondral ossification, thus inhibiting bone growth and

The pathological hallmark of EED is villus blunting, which means that in histological sections villus height is reduced and villus width increased. Increased intestinal permeability can be detected using disaccharide probes. This is considered a diagnostic hallmark of EED. In adults confocal laser endomicroscopy (CLE) can be used to detect leakage of fluorescein dye from systemic circulation into the gut lumen. In adults with EED, CLE shows extensive leakage into the gut lumen occurring especially at the villous tips. This suggests that micro-erosions secondary to disordered epithelial cell shedding may be an important cause for the increased permeability [70]. The increased permeability leads to malabsorption of nutrients and also microbial translocation (MT) from the lumen into systemic circulation via gut mucosa. This MT is also important in perpetuating a chronic inflammatory state. Due to MT, some important biomarkers of MT are now being used to detect EED. These include bacterial cell wall lipopolysaccharide (LPS), soluble lipopolysaccharide co-receptor (sCD14) and antibodies to the LPS core antigen (EndoCAb) [71]. The clinical impact of EE, apart from stunting, is decreased immunological

Does EED fuel HIV replication and disease progression? It is attractive to think it does so. Aggregation of intraepithelial lymphocytes and lamina propria T-cell populations has been described in children with EED. The T cells expressed CD69 and HLA-DR. Children with EED had 4–5 times more CD3+ T cells and 15–30-fold higher number of CD25+ T cells in the lamina propria than the UK controls. They also had a higher proportion of T cells than TCRαδ+ [72]. Activated lymphocytes in a milieu rich in inflammatory cytokines would be the perfect ground for HIV attachment and replication. However there have been no studies to prove or disprove this. But Jacob and his colleagues have demonstrated that the dominant effect of HIV on enteric mucosa is to increase villous crypt depth [73]. Hence HIV and

Recurrent and severe oral ulcers make eating uncomfortable and painful. Decreased food intake over a period of time can precipitate malnutrition. Oral candidiasis is the most frequent oral disease associated AIDS, with a prevalence of 70–90% [74–76]. It often occurs early in the course of the disease. With decline in immune status, its frequency and severity worsens, and it may occur along with oesophageal candidiasis. Recurrent major aphthous ulcers and herpetiform aphthous ulcers are painful and adversely affect food intake. Other conditions like

EED may work synergistically to aggravate malnutrition.

Kaposi sarcoma are becoming uncommon now.

#### *Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

*Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

that led to diarrhoea [60].

*4.3.2.2 HIV enteropathy*

and causes seen in the general population. About 60% of patients receiving ART gave history of diarrhoea in the previous month [55]. Data from clinical trials suggest that up to 19% of these events may have been due to the adverse effects of ART [56]. Among the ART drugs, protease inhibitors (PIs) seem to be most strongly associated with diarrhoea. In mouse models, PIs and reverse transcriptase inhibitors significantly increased water and electrolyte secretion into intestinal lumen *in vivo* [57]. Rufo and colleagues demonstrated that protease inhibitors in general, and nelfinavir in particular, potentiate signalling through muscarinic and calciumdependent receptors of intestinal cells leading to increased chloride secretion into the lumen [58]. Stool samples of these patients also had increased concentrations of sodium and chloride consistent with secretory diarrhoea. In an *in vitro* study, Bode and colleagues showed that PIs induced apoptosis of human intestinal epithelium, thereby compromising barrier function and increasing water secretion in gut lumen. Decreased alkaline phosphatase activity in cells exposed to PIs led to accumulation of unfolded proteins in the cytosol. A failure of the cell's 'unfolded protein response', a specific signalling pathway aimed at returning the cell's protein folding function back to normal, triggered cellular apoptosis [59]. Wu and colleagues found that lopinavir and ritonavir induced endoplasmic reticulum dysfunction in intestinal epithelial cells

HIV enteropathy is an idiopathic form of diarrhoea observed in all stages of HIV

disease in the absence of an infectious source and with characteristic histologic features [61–63]. Changes include crypt epithelial proliferation leading to increased crypt height, later crypt cell encroachment onto villi and relative decreased villous height. The consequence of these changes are diarrhoea and malabsorption [64, 65]. While the exact mechanisms by which these changes occur in the GI tract are unclear, HIV has been postulated to alter signalling and cellular structure, which may lead to architectural distortion [61]. Keating and colleagues investigated monosaccharide absorption in patients with HIV and AIDS. They demonstrated that patients with diarrhoea had significant malabsorption of all monosaccharides tested [66]. Malabsorption occurred irrespective of pathogen-positive or pathogennegative diarrhoea, indicating that HIV had an independent direct role. This may be due to the ability of HIV to infect mucosal epithelial cells [67]. Increased mucosal infiltration by activated CD8+ T cells results in high levels of pro-inflammatory cytokines which can directly damage the mucosal barrier [61, 63]. Other hypotheses for the mechanism of HIV enteropathy include decreased transepithelial electrical resistance, decreased sodium-dependent glucose absorption and increased intercellular permeability in HIV-infected cells [68]. HIV enteropathy can also lead to

malabsorption of vitamin B12, bile acid and monosaccharides [61, 64, 68].

Chronic diarrhoea, water, sanitation and hygiene (WASH) have been implicated as causative factors for severe stunting in low- and middle-income countries for a long time. Efficacy of WASH interventions in reducing diarrhoea and malnutrition has been lower than expected. This led to the search for another cause. Today, there is sufficient evidence that the cause is environmental enteric dysfunction (EED). It is 'an apparently seasonal and reversible disorder characterised by gut mucosal cell villous atrophy, crypt hyperplasia, increased permeability and increased inflammatory cell infiltrate'. The principal driver of EED is the high

**4.4 Environmental enteric dysfunction**

**34**

burden of intestinal infectious disease which is not enough to cause diarrhoea but enough to induce a state of chronic immune activation in the gut mucosa, thereby leading to epithelial damage. Dysbiosis of gut microbiota is also now considered to have an important role. The pathogenesis is probably chronic exposure to pathogens leading to a T cell-mediated immune response in the gut which continues to remain in an inflammatory hyperimmune state. This exaggerated immune response leads to structural changes in the gut mucosa, increased inflammation and permeability of the intestines, resulting in disrupted gut immune response; reduced absorption, delivery and utilisation of nutrients; and finally nutritional deficiency. There are also features of systemic inflammation, microbial translocation (MT) across the permeable gut mucosa and changes in the gut microbiome. Malnutrition further impairs the renewal of gut mucosal cells, maturation and proliferation of intestinal cells and pancreatic islet cells. The chronic low-grade inflammation inhibits endochondral ossification, thus inhibiting bone growth and leads to stunting [69].

The pathological hallmark of EED is villus blunting, which means that in histological sections villus height is reduced and villus width increased. Increased intestinal permeability can be detected using disaccharide probes. This is considered a diagnostic hallmark of EED. In adults confocal laser endomicroscopy (CLE) can be used to detect leakage of fluorescein dye from systemic circulation into the gut lumen. In adults with EED, CLE shows extensive leakage into the gut lumen occurring especially at the villous tips. This suggests that micro-erosions secondary to disordered epithelial cell shedding may be an important cause for the increased permeability [70]. The increased permeability leads to malabsorption of nutrients and also microbial translocation (MT) from the lumen into systemic circulation via gut mucosa. This MT is also important in perpetuating a chronic inflammatory state. Due to MT, some important biomarkers of MT are now being used to detect EED. These include bacterial cell wall lipopolysaccharide (LPS), soluble lipopolysaccharide co-receptor (sCD14) and antibodies to the LPS core antigen (EndoCAb) [71]. The clinical impact of EE, apart from stunting, is decreased immunological response to oral vaccines.

Does EED fuel HIV replication and disease progression? It is attractive to think it does so. Aggregation of intraepithelial lymphocytes and lamina propria T-cell populations has been described in children with EED. The T cells expressed CD69 and HLA-DR. Children with EED had 4–5 times more CD3+ T cells and 15–30-fold higher number of CD25+ T cells in the lamina propria than the UK controls. They also had a higher proportion of T cells than TCRαδ+ [72]. Activated lymphocytes in a milieu rich in inflammatory cytokines would be the perfect ground for HIV attachment and replication. However there have been no studies to prove or disprove this. But Jacob and his colleagues have demonstrated that the dominant effect of HIV on enteric mucosa is to increase villous crypt depth [73]. Hence HIV and EED may work synergistically to aggravate malnutrition.

### **4.5 Oral ulcers**

Recurrent and severe oral ulcers make eating uncomfortable and painful. Decreased food intake over a period of time can precipitate malnutrition. Oral candidiasis is the most frequent oral disease associated AIDS, with a prevalence of 70–90% [74–76]. It often occurs early in the course of the disease. With decline in immune status, its frequency and severity worsens, and it may occur along with oesophageal candidiasis. Recurrent major aphthous ulcers and herpetiform aphthous ulcers are painful and adversely affect food intake. Other conditions like Kaposi sarcoma are becoming uncommon now.

#### **4.6 Tuberculosis**

Coinfection with HIV and *Mycobacterium tuberculosis* (TB) is an extremely common problem. TB is the largest single cause of death in HIV-positive individuals, and, in areas of high prevalence, it is the most common coinfection in HIV-positive children. HIV and TB pathogens interact, resulting in an accelerated clinical course and premature death. TB infection results in secondary wasting. Indeed, weight loss is the presenting feature in almost 50% of cases of TB, and persistent anorexia is a feature in approximately one-quarter. Swaminathan, Padmapriyadarsini and colleagues studied the nutritional status of HIV-positive subjects with TB (n = 174) and HIV-positive ones without TB (n = 488). They compared their nutritional status to that of HIV-negative people of the same socioeconomic status (n = 160). They found that 50% of HIV-positive subjects with TB and one-third of HIV-positive subjects without TB had a BMI of <18.5 kg/m2 . Moreover, HIV-positive subjects both with and without TB had lower mid-arm circumference, hip circumference and waist circumference than HIV-negative individuals. HIV-positive people with TB remained underweight even after adequate treatment for TB underscoring the negative impact of TB on the nutritional status of these people and also the synergistic effect of HIV-TB confection in aggravating malnutrition [77]. Furthermore, malnutrition is a risk factor for the acquisition of primary TB infection, as well as progression to active disease [78–80]. Other infections—particularly pneumonias, which are very common in HIV-positive children—have also been found to contribute to the increased risk of malnutrition in children in several lower-income countries.

#### **4.7 HIV endocrinopathies**

Adrenal insufficiency is the commonest endocrinopathy in the HIV-infected. The mechanism of primary adrenal insufficiency in the HIV-infected is twofold: HIV adrenalitis and adrenal gland destruction secondary to tuberculosis, CMV or other opportunistic infections [81]. Sepsis may also precipitate acute adrenal insufficiency. Adrenal insufficiency can also be iatrogenic, triggered by drugs like ketoconazole and rifampicin [82]. Secondary adrenal insufficiency can be due to the direct effect of HIV on the hypothalamic-pituitary-adrenal (HPA) axis also. Cytokines like interleukin-1 (IL-1), IL-6 (in a synergistic manner) and TNF-α can suppress the HPA [83]. HIV-positive patients who develop adrenal insufficiency may present either acutely or chronically. Acute insufficiency manifests in the critically ill as Addisonian crisis characterised by profound hypotension. In our study on hypoadrenalism in the HIV-infected with current or past tuberculosis, it was found that certain clinical features occurred consistently. They included history of fatigue, lethargy, muscle weakness, low mood/irritability, significant weight loss and need to micturate frequently and findings of hypotension, both resting and postural and pale skin (under publication). The prevalence of hypoadrenalism in HIV and HIV-TB varies from 20 to 70%. This is mainly because many studies were only done on critically ill patients in the hospital. The use of standard and low-dose ACTH stimulation test also made a difference in pickup. Nevertheless, wasting in an HIV-positive patient should trigger a search for adrenal insufficiency. On the other hand, in one study it was seen that testosterone deficiency does not lead to significant wasting [26].

#### **4.8 Co-trimoxazole prophylaxis (CPT)**

Severe acute malnutrition (SAM) contributes to 1 million childhood deaths annually worldwide, and its treatment is a key strategy for reducing childhood mortality [84]. Infectious disease is thought to be the main mediator of mortality

**37**

anced meals [97].

*4.10.1 Food insecurity*

shame over food' [99].

**4.10 Socioeconomic factors**

*Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

enteropathy and perturbations of gut flora [93].

**4.9 Substance abuse and psychiatric disorders**

cefdinir arms [85].

in children with SAM. Trehan and colleagues studied the efficacy of empirical antimicrobial therapy in children with severe acute malnutrition but without clinical features of infection. Two thousand seven hundred sixty-seven children in the age group of 6–59 months were randomised into three arms. One received oral amoxycillin, the other cefdinir and the last group a placebo for 7 days. Twelve-week mortality rates for the three groups were 4.8, 4.1 and 7.2%, respectively. The relative risk for death for placebo compared with amoxycillin was 1.55 (95% CI 0.7–2.24) and for placebo compared with cefdinir was 1.80 (95% CI 1.22–2.64). Differences in mortality and recovery were not statistically different between the amoxycillin and

Daily co-trimoxazole prophylaxis reduced all-cause mortality and hospital admissions in children with HIV/AIDS. This was despite high levels of antimicrobial resistance being identified in vitro among invasive isolates at study sites [86, 87]. Co-trimoxazole protected HIV-infected children against malaria, pneumonia and sepsis [88]. Other studies have shown its role in preventing recurrent urinary tract infections, pneumonia in children with measles and infections in children with specific immunodeficiencies [89–91]. Prendergast and colleagues reported that co-trimoxazole prophylaxis retards decline in weight and height for age in HIVinfected children, not on ART [92]. Boettiger and colleagues also found that CPT may enhance weight recovery in children with malnutrition on ART [10]. In both HIV-infected and malnourished children, the beneficial effect of antimicrobial therapy is primarily due to prevention and treatment of infections. Other collateral benefits could be reduction of inflammation which would reduce diversion of nutrients and decreased cytokine-mediated growth retardation and also reduced

HIV infection and chronic drug abuse both compromise nutritional status. There is a synergistic effect in HIV-positive drug users that leads to wasting and significantly impacts mortality. Illicit drug use may interfere with nutrient absorption, mute appetite and alter metabolism. Lifestyle of chronic drug users may compromise their access to food, food selection, housing, family and social support [94]. Use of injection drugs correlated with lower protein intake in the NFHL cohort study [14]. IV drug can be associated with HIV-HBV or HIV-HCV coinfections. Patients with hepatitis frequently lose weight and develop anaemia and neutropenia. As liver disease advances, anorexia, dietary intolerance and limitation of nutrient intake occur [95, 96]. AIDS-related dementia and neuropsychiatric disorders can cause malnutrition as the ability of patients to care for themselves is compromised. Many may forget to eat and others may be unable to prepare bal-

Wasting and malnutrition in HIV-positive children is not only due to the HIV disease or opportunistic infections. It is also due to breakdown of family structure and the failure of social and healthcare systems. Food insecurity is defined as a lack of access to sufficient, safe and nutritious food to meet dietary needs and maintain a healthy and active life [98]. Another way of defining it is 'insufficient quantity or quality of food, reductions of food intake, and feelings of uncertainty, anxiety, or

#### *Malnutrition in HIV/AIDS: Aetiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.90477*

*Nutrition and HIV/AIDS - Implication for Treatment, Prevention and Cure*

subjects without TB had a BMI of <18.5 kg/m2

**4.7 HIV endocrinopathies**

Coinfection with HIV and *Mycobacterium tuberculosis* (TB) is an extremely common problem. TB is the largest single cause of death in HIV-positive individuals, and, in areas of high prevalence, it is the most common coinfection in HIV-positive children. HIV and TB pathogens interact, resulting in an accelerated clinical course and premature death. TB infection results in secondary wasting. Indeed, weight loss is the presenting feature in almost 50% of cases of TB, and persistent anorexia is a feature in approximately one-quarter. Swaminathan, Padmapriyadarsini and colleagues studied the nutritional status of HIV-positive subjects with TB (n = 174) and HIV-positive ones without TB (n = 488). They compared their nutritional status to that of HIV-negative people of the same socioeconomic status (n = 160). They found that 50% of HIV-positive subjects with TB and one-third of HIV-positive

with and without TB had lower mid-arm circumference, hip circumference and waist circumference than HIV-negative individuals. HIV-positive people with TB remained underweight even after adequate treatment for TB underscoring the negative impact of TB on the nutritional status of these people and also the synergistic effect of HIV-TB confection in aggravating malnutrition [77]. Furthermore, malnutrition is a risk factor for the acquisition of primary TB infection, as well as progression to active disease [78–80]. Other infections—particularly pneumonias, which are very common in HIV-positive children—have also been found to contribute to the increased risk of malnutrition in children in several lower-income countries.

Adrenal insufficiency is the commonest endocrinopathy in the HIV-infected. The mechanism of primary adrenal insufficiency in the HIV-infected is twofold: HIV adrenalitis and adrenal gland destruction secondary to tuberculosis, CMV or other opportunistic infections [81]. Sepsis may also precipitate acute adrenal insufficiency. Adrenal insufficiency can also be iatrogenic, triggered by drugs like ketoconazole and rifampicin [82]. Secondary adrenal insufficiency can be due to the direct effect of HIV on the hypothalamic-pituitary-adrenal (HPA) axis also. Cytokines like interleukin-1 (IL-1), IL-6 (in a synergistic manner) and TNF-α can suppress the HPA [83]. HIV-positive patients who develop adrenal insufficiency may present either acutely or chronically. Acute insufficiency manifests in the critically ill as Addisonian crisis characterised by profound hypotension. In our study on hypoadrenalism in the HIV-infected with current or past tuberculosis, it was found that certain clinical features occurred consistently. They included history of fatigue, lethargy, muscle weakness, low mood/irritability, significant weight loss and need to micturate frequently and findings of hypotension, both resting and postural and pale skin (under publication). The prevalence of hypoadrenalism in HIV and HIV-TB varies from 20 to 70%. This is mainly because many studies were only done on critically ill patients in the hospital. The use of standard and low-dose ACTH stimulation test also made a difference in pickup. Nevertheless, wasting in an HIV-positive patient should trigger a search for adrenal insufficiency. On the other hand, in one study it was seen that

testosterone deficiency does not lead to significant wasting [26].

Severe acute malnutrition (SAM) contributes to 1 million childhood deaths annually worldwide, and its treatment is a key strategy for reducing childhood mortality [84]. Infectious disease is thought to be the main mediator of mortality

**4.8 Co-trimoxazole prophylaxis (CPT)**

. Moreover, HIV-positive subjects both

**4.6 Tuberculosis**

**36**

in children with SAM. Trehan and colleagues studied the efficacy of empirical antimicrobial therapy in children with severe acute malnutrition but without clinical features of infection. Two thousand seven hundred sixty-seven children in the age group of 6–59 months were randomised into three arms. One received oral amoxycillin, the other cefdinir and the last group a placebo for 7 days. Twelve-week mortality rates for the three groups were 4.8, 4.1 and 7.2%, respectively. The relative risk for death for placebo compared with amoxycillin was 1.55 (95% CI 0.7–2.24) and for placebo compared with cefdinir was 1.80 (95% CI 1.22–2.64). Differences in mortality and recovery were not statistically different between the amoxycillin and cefdinir arms [85].

Daily co-trimoxazole prophylaxis reduced all-cause mortality and hospital admissions in children with HIV/AIDS. This was despite high levels of antimicrobial resistance being identified in vitro among invasive isolates at study sites [86, 87]. Co-trimoxazole protected HIV-infected children against malaria, pneumonia and sepsis [88]. Other studies have shown its role in preventing recurrent urinary tract infections, pneumonia in children with measles and infections in children with specific immunodeficiencies [89–91]. Prendergast and colleagues reported that co-trimoxazole prophylaxis retards decline in weight and height for age in HIVinfected children, not on ART [92]. Boettiger and colleagues also found that CPT may enhance weight recovery in children with malnutrition on ART [10]. In both HIV-infected and malnourished children, the beneficial effect of antimicrobial therapy is primarily due to prevention and treatment of infections. Other collateral benefits could be reduction of inflammation which would reduce diversion of nutrients and decreased cytokine-mediated growth retardation and also reduced enteropathy and perturbations of gut flora [93].
