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Inflammation in Persons Living with HIV (18HH03)

Jihad Slim, MD, and Christopher F. Saling, MD

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DIABETES MELLITUS

The incidence of DM may be increased in PLWH.4 The pathophysiology can be divided into the same 3 features:

Inflammation and HIV lipodystrophy; this involves adipose tissue redistribution, mitochondrial dysfunction, altered differentiation of adipocytes, and increased adipocyte lipolysis.48,57 This leads to altered adipokine secretion, as well as the release of pro-inflammatory cytokines and free fatty acids.48,57 This, in turn, exacerbates chronic inflammation, dyslipidemia and insulin resistance.48,57

Traditional risk factors; some DM risk factors are becoming more prevalent in PLWH, namely aging and obesity.50 Family history is also an important risk factor. Finally, co-infection with HCV plays a significant role in the risk of DM in PLWH, and its prevalence depends on the same risk factors for the acquisition of HIV58,59; it is estimated that 25% of PLWH in the US are co-infected with HCV.58,59

Specific ART regimens as a risk factor for DM; the D:A:D study implicated zidovudine and stavudine as two NRTIs that are significantly associated with a higher incidence of DM, even after adjustment for risk factors for DM and lipids.60

An illustration of the interaction of these risk factors can be found in the paper by Betene et al.,61 whereby they assessed inflammatory markers in a cohort of 3,695 PLWH with an average CD4+ count of 523 cells/mm³.61 These patients did not have DM and were on ART. 137 patients developed DM over an average follow up period of 4.6 years.The median levels of IL-6 and hs-CRP were significantly higher among those who had developed DM compared with those who did not.61 Body mass index, age, co-infection with hepatitis B or C, and smoking status were all associated with an increased risk of DM.

NON-AIDS RELATED MALIGNANCIES

Malignancies that are considered AIDS-related such as Kaposi’s sarcoma, primary central nervous system (CNS) lymphoma, and cervical cancer have dramatically declined since the advent of suppressive ART.62 Furthermore, the incidence of non-AIDS related malignancies (NARM) including anal cancer, hepatocellular carcinoma, head and neck cancers, lung cancers, non-Hodgkin’s lymphoma, and melanoma have increased so significantly that they now represent one of the most common causes of death in PLWH in the US.37 Risk factors are multiple and can be divided into the 3 previously mentioned categories63:

Immune dysregulation and chronic inflammation; these processes can promote increased cell proliferation and generate potentially damaging reactive oxygen species.64 The immune dysfunction associated with HIV infection may also lead to impaired immune surveillance with an impaired ability to both detect and eliminate early tumor cells.65 Powles et al. reported from their large prospective cohort that a nadir CD4+ count <200 cells/μL had a significant association with NARM.66

Traditional risk factors for NARM; some are more prevalent in PLWH such as smoking, with its subsequent increase in lung cancer, as well as hepatitis B and C viruses, with their associated risk for hepatocellular carcinoma.67,68 Hodgkin’s lymphoma in PLWH is seen at a higher incidence than that of the general population and is often associated with EBV co-infection.69 Probably the highest increase in cancer types in PLWH compared to those that are HIV-uninfected are related to HPV.70 Associated cancer types to this co-infection include anal cancer, head and neck cancer, and cervical cancer (which is an AIDS-related malignancy).70

ART regimens that increase NARM incidence, most-notably hepatocellular carcinoma (HCC); Ryom et al. reviewed the association of antiretroviral drugs and their association with HCC from a large D:A:D cohort.71 In this study, the cumulative use of stavudine, didanosine, tenofovir disoproxil fumarate (TDF), and amprenavir were independently associated with increased end stage liver disease and HCC rates.71 Conversely, cumulative exposure to emtricitabine, and nevirapine were actually shown to be protective against HCC.71

An example of the interaction between these risk factors towards NARM is HCV predisposing an individual to DM, which in itself is an independent risk factor for HCC.72

RENAL DISEASE

HIV infection is a well-established risk factor for chronic kidney disease (CKD) and subsequent end stage kidney disease (ESKD) in the US.73 The risk factors can be divided as were the previous co-morbidities:

Immune dysregulation and chronic inflammation; HIV-associated nephropathy (HIVAN) is most commonly seen in those of African descent in the setting of untreated HIV infection with advanced immunosuppression.75 It is characterized clinically by heavy proteinuria without hematuria on urinalysis, as well as rapid glomerular filtration rate (GFR) decline to ESKD within a few months.74 Nonetheless, the chronic inflammatory state that persists after viral control may play a role in CKD, but it seems minimal at this point.75

Traditional risk factors for ESKD; DM, HTN, HCV co-infection, African American race, and aging seem to play the major role for predicting ESKD once HIV is well controlled.75 Also, the use of potentially nephrotoxic agents like NSAIDs, diuretics, and ACE inhibitors contribute towards renal disease in PLWH.76

ART causing renal disease; nephrotoxicity has been mainly linked to TDF, which can cause several patterns of kidney injury. The most common of these injury forms is proximal tubular dysfunction, but TDF, although rarely, may lead to acute kidney injury, CKD, and nephrogenic diabetes insipidus.77

Again, here is an example to show the various interactions involved between the risk factors of a specific comorbidity, in this case renal disease, and HIV. HCV is a co-infection that increases the chronic inflammatory state present in PLWH, which could then increase the incidence of DM, and, subsequently, both cofactors could contribute towards renal damage.78

LIVER FIBROSIS

The effect of HIV on liver disease was well characterized by Towner et al. in a case-control study which concluded that HIV-infected individuals have a higher risk of hepatic dysfunction and hepatic-related death compared to those without HIV infection, even with adjustment for known hepatic risk factors.79 Co-morbidities contributing towards liver disease and fibrosis can be divided into the same three categories:

Immune dysregulation and chronic inflammation; Marchetti et al. revealed that HIV co-infected patients (mainly HCV) with higher Tumor necrosis factor alpha (TNF-α) plasma levels had a 13-fold increase in the risk of progression to a fibrosis-4 (Fib-4) >1.45.80 However, these patients were not receiving ART.80 A more recent study suggests that ART with good immune reconstitution can slow down liver fibrosis in HIV/HCV co-infected patients.81

Traditional risk factors for liver fibrosis; alcohol abuse, steatosis, rare genetic diseases (Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency), drug-induced liver injury, or co-infection with HCV or HBV can all lead to liver injury and, ultimately, liver fibrosis.81

ART causing liver disease; most ART can cause drug induced liver injury and this side effect is more commonly reported in patients with underlying chronic liver disease.82 Although this could lead to permanent liver failure, most of these hepatotoxic side effects resolve after removal of the offending agent.82,83 A different mechanism of liver injury that is associated with progressive fibrosis has been linked to ART when lipodystrophy occurs with subsequent nonalcoholic steatohepatitis.83

 
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