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Inflammation in Persons Living with HIV (18HH03)

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

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PATHOPHYSIOLOGY OF INFLAMMATION IN PLWH (continued)

A third factor relating to inflammation in PLWH is T-cell function. It is unclear if immune dysregulation leads to inflammation or vice versa. Nonetheless, they are usually present together and both contribute to the burden of comorbid illnesses.24 Hunter et al. studied the relationship of immune activation and increased CD4+ count when HIV was suppressed with ART and found that increased T-cell activation was associated with shorter duration of viral suppression, HCV co-infection, frequent low-level viremia, lower nadir CD4+ T-cell counts, and a lower gain in CD4+ T-cells.25 In an elegant study of impaired gut junctional complexes by Tincati et al., a relationship was established between gut damage, HIV viral reservoir, and CD4+ response to ART.26 These researchers concluded that the more damage to the gut and the larger the reservoir, the less of an increase in CD4+ cells while on suppressive ART.26

It has been well established that a high proportion of PLWH who delay ART until the CD4+ count drops below 200 cells/ mm3 do not achieve a normal CD4+ count, even after a decade of effective therapy.27 Engsig et al. shed more light on this concept by examining data on PLWH whose VL was suppressed on ART for >three years with a CD4+ count <200 cells/mm3.28 They were able to identify that increasing age, lower initial CD4+ count, and injection drug use were among the risk factors contributing towards a continued low CD4+ count, as well as clearly show a higher all-cause mortality in this subgroup compared to those who achieved a CD4+>200 cells/mm3 after three years of suppressive therapy.28 Furthermore, in a prospective, observational cohort study in persons with acute or early HIV infection, Le et al. concluded that early suppressive therapy led to better immune recovery.29 Additionally, INSIGHT START study group found that patients with CD4+ >500 cells/mm3 benefit from ART when started early compared to patients who waited until CD4+ reached 350 to initiate ART.30 Those who started treatment when CD4+>500 had significantly less morbidity and mortality.30 Negredo et al. in a cross-sectional, case-control study established that CD4+ nadir was the best predictor of a discordant immune response (defined as CD4+<350 after >2 years of VL<50 copies/ml) and also suggested early initiation of ART.31 Lastly, in the ICONA study, Lapadula et al. were able to define immune non-responders as <120% increase in CD4+ cell count by the time VL is undetectable.32 This subgroup of PLWH had higher risk of severe clinical events than immune responders.32

Finally, ART must always be considered a potential cause of adverse events, and therefore, a possible contributor towards inflammation and aging in those with controlled HIV infection.33 Leeansyah et al. studied telomerase activity and length in vitro by looking at peripheral blood mononuclear cells (PBMCs) from PLWH receiving a nucleoside reverse transcriptase inhibitor (NRTI)- containing regimen, and found that they had significantly lower telomerase activity than both HIV-uninfected persons and PLWH receiving a non- NRTI-containing regimen.34 Telomerase length was inversely associated with age, as well as the total duration of NRTI-containing therapy.34 This study concluded that NRTIs at therapeutic concentrations, specifically tenofovir, inhibit telomerase activity and leads to its accelerated shortening in activated PBMCs, which could play a role in the enhanced aging of PLWH.34

In summary, indicators of poor prognosis in PLWH are increased markers of inflammation and immune activation. These often correlate with low current and/or nadir CD4+ T-cell counts, co-infections, and gut immune damage with microbial translocation.35,36 What makes this subject so difficult to study are the diversity of the comorbidities involved and the variability of the markers that seem to be important to measure.37 However, it is probably safe to assume that the better the immune system, the less the degree of chronic inflammation, and, thus, the closer the incidence of comorbidities and life expectancy of a PLWH with undetectable VL to that of the general population.37,38

CARDIOVASCULAR DISORDER

Multiple studies have identified HIV as an independent risk factor for acute myocardial infarction (AMI). Freiberg et al. reviewed data from participants in the Veterans Aging Cohort Study that included both HIV-infected and HIV-uninfected individuals. This study concluded that infection with HIV was associated with a 50% increased risk of AMI beyond which was explained by recognized risk factors.39 In two cohorts from the Partners HealthCare System in Boston, Triant et al. compared the rate of AMI in HIV-infected and HIV-uninfected patients while adjusting for age, gender, race, hypertension, DM, and dyslipidemia. They, too, concluded that there was an increased risk of AMI in PLWH, especially in women.40

When attempting to analyze the reasoning for the higher risk of AMI in PLWH, three factors are confronted:

Inflammation or dysregulation of the immune system; this is related to HIV viremia, low CD4+ cell count (nadir or current), microbial translocation, and co-infections.41-46

Traditional risk factors for CVD; especially smoking, DM, and dyslipidemia.47-50 These risk factors are more prevalent in PLWH then in the general population.47-50 Also, obesity prevalence is increasing in PLWH, and as the HIV population ages, the prevalence of hypertension within this group will increase as well.47-50

ART; namely abacavir and certain protease inhibitors such as ritonavir + lopinavir. 51,52

There exist interactions between HIV infection and these risk factors for AMI. Valiathan et al. compared HIV-infected smokers and non-smokers that had documented viral suppression on ART to HIV-uninfected smokers and non-smokers.53 They found that smoking and HIV infection both independently influence T-cell immune activation and function, and together they present the worst immune profile.53 Another example that highlights this interaction between HIV and AMI risk factors is the use of ritonavir + lopinavir and a higher incidence of hyperlipidemia and potential insulin resistance.54 Lastly, Okeke et al. reviewed the hospital discharge data from the Nationwide Inpatient Sample from 2002 to 2012 looking specifically for patients with AMI or stroke.55 They used multivariable logistic regression to evaluate the association between HIV and in-hospital death.55 They found that patients with a history of AIDS were significantly more likely to die in-hospital after AMI and stroke than HIV-uninfected patients.55 This disparity was not observed when PLWH without a history of AIDS were compared to HIV-uninfected patients.55

Based off the above findings, the best chances of reducing the risk of PLWH for CVD include the following: completely suppressing the HIV VL as early as possible with an ART regimen that has not been implicated in increasing CVD risk factors; advising patients to stop smoking and increase their physical activity; and controlling any dyslipidemia, hyperglycemia, or hypertension.56

 
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