There is a complex interaction between HIV infection, inflammation, and the immune system. Antiretroviral therapy (ART) has evolved to a point where most persons living with HIV (PLWH) can achieve an undetectable viral load within 12 weeks of starting treatment. However, chronic inflammatory processes still occur even in well-controlled HIV infection. Therefore, in an effort to further improve disease outcome, methods to decrease chronic inflammation have become a new focus of research.
Inflammatory markers appear to directly correlate with morbidity and mortality in PLWH. This connection has been studied most in those with cardiovascular complications, but also fits well in other models of comorbid conditions that inflict PLWH. Some of these comorbidities include diabetes mellitus (DM), non-AIDS related cancers, HIV-associated neurocognitive disorders, osteoporosis, liver fibrosis, and renal insufficiency. For the sake of completeness, when studying any of those conditions in PLWH, one must take into consideration a variety of factors. These include: (1) the degree that HIV infection is currently controlled, (2) the duration that HIV has been controlled, (3) the extent of immune damage prior to the initiation of ART, (4) the amount of immune system recovery with ART, (5) the presence of other co-infections, (6) the role of environmental factors, and (7) the effect of ART on the co-morbidity itself.
Over the past two decades, ART has dramatically reduced the incidence of morbidity and mortality related to both HIV and opportunistic infections. However, even with this advancement in HIV treatment, the life expectancy of an HIV-infected individual is still slightly less than that of the general population. The highest estimated life expectancy for a newly diagnosed HIV-infected 20 year old on ART in the United States (US) or Canada is just above 70 years1; and, inflammation is theorized to be the driving factor for this gap.
The new challenges facing PLWH are non-AIDS related conditions. The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) prospective HIV cohort study found that the most common comorbidities leading to death in PLWH were non-AIDS cancers, cardiovascular disease (CVD), and liver disease.2 Morlat et al. expressed these same findings in a study in France in 2010.3 The Swiss HIV cohort study by Hasse et al. revealed that stroke, myocardial infarction, DM, fragility bone fractures, and non-AIDS-defining malignancies were significantly elevated for persons aged ≥65 years.4 Guaraldi et al. performed a case-control study in ART-experienced patients treated at Modena University, Italy, from 2002 through 2009. They were compared with age-, sex-, and racematched adults from the general population. They specifically looked at noninfectious comorbidities (NICMs), which included CVD, hypertension, DM, bone fractures, and renal failure. The study defined polypathology (Pp) as the concurrent presence of ≥2 NICMs and concluded that the prevalence of Pp among PLWH aged 41-50 years was similar to that among controls aged 51-60 years. Logistic regression models showed that independent predictors of Pp in the overall cohort were age (odds ratio [OR], 1.11), male sex (OR, 1.77), nadir CD4+ count <200 cells/μL (OR, 4.46), and ART exposure (OR, 1.01).5
The pivotal SMART trial provided evidence of the association of inflammatory biomarkers and coagulation with increased risk of all-cause mortality.6 They also showed that interleukin-6 (IL-6) and D-dimer were significantly associated with increased risk of CVD and other causes of death, even in patients on ART.7 Tenorio et al. conducted a case-control study that concurred with these findings, concluding that soluble inflammatory markers correlated with non-AIDS defining events in PLWH virally suppressed on therapy.8
This paper will review the most common comorbidities encountered in PLWH and discuss their relationship to environmental and genetic risk factors, HIV-related inflammatory state, and ART. Since the inflammatory component, which is a correlate of T-cell activation, is much more pronounced when the virus is not suppressed, we will limit the discussion towards PLWH receiving effective treatment for HIV.9 Although successful ART does not suppress all inflammatory mechanisms associated with HIV, it has been shown to decrease some immune activation markers to the level of HIV-uninfected individuals, particularly monocyte-macrophage activation.10
It is relatively well established that a chronic inflammatory state in PLWH receiving appropriate ART is primarily related to the extent of damaged gut-associated lymphoid tissue and its subsequent microbial translocation, as well as the presence of other active viral infections like cytomegalovirus (CMV) and hepatitis C virus (HCV).11,12 Furthermore, in clinical practice HIV viral load (VL) is measured intermittently and there are different cut offs for detection. Thus, it is conceivable that low-grade or intermittent viremia is actually occurring in PLWH that are classified as undetectable. This phenomenon could also play a role in persistent inflammation.
PATHOPHYSIOLOGY OF INFLAMMATION IN PLWH
Acute HIV infection is associated with immune activation and severe inflammatory reaction, as evidenced by the intense surge of cytokines such as interferon-α, interferon-ϒ, tumor necrosis factor, and IL-6.13 There is a profound depletion of CD4+ cells from the gut during acute infection, which only partially improves with effective ART.14,15 This explains the reasoning behind intestinal microbial translocation and subsequent immune activation.16
One method for studying microbial translocation is through the measurement of serum lipopolysaccharide (LPS). The Strategies for Management of Anti-Retroviral Therapy (SMART) study revealed that soluble CD14, a marker of monocyte response to LPS, was an independent predictor of mortality in PLWH.17 This was corroborated by another case-control study by Hunt et al., which concluded that gut epithelial barrier dysfunction independently predicts mortality in individuals with virally suppressed HIV infection who also have a history of AIDS.18 Microbial translocation is currently one of the most accepted elements defining the pathophysiology of a chronic inflammatory state present in PLWH on ART with well-controlled viremia.
Another important determinant of this inflammation is coinfection. Modjarrad et al. reviewed the literature up to April 2010 and found that treatment of Mycobacterium tuberculosis, syphilis, and other infections significantly decreased HIV VL, even when no ART was used.19 In another prospective study using CMV polymerase chain reaction (PCR), Deayton et al. established a direct correlation of positive PCR findings with new AIDS-defining disorders and mortality in PLWH in the highly active ART era.20 Furthermore, in review of CMV in PLWH, Barrett et al. summarize the evidence that CMV could be an important cofactor in the development of age-related morbidities in PLWH.21
Since HCV is another prevalent virus found in 20-25% of PLWH, it is relevant to study its impact on immune recovery after HIV is effectively suppressed. Zaegel-Faucher et al. retrospectively reviewed this data in patients with undetectable HIV VL for at least 3 years and concluded that CD4+ percentage and CD4/CD8 ratio were lower in patients co-infected with HCV compared to those with mono-infection, despite having similar ART regimens and CD4+ and CD8+ counts at first undetectable HIV VL.22 The association between co-infection and chronic inflammation in PLWH was further established by Masia et al., who prospectively studied multiple blood biomarkers of inflammation in mono-infected PLWH compared to those co-infected with human herpesvirus 8 (HHV-8).23 Both groups had a suppressed HIV VL, but inflammation and immune activation were significantly higher in those with HHV-8 co-infection.23 This further highlights that co-infection is a key component of the residual immune dysregulation present in PLWH receiving suppressive ART.