Chapter 35

Human immunodeficiency virus (HIV) infection is associated with non-specific polyclonal activation of B-cells and, consequently, elevations in polyclonal IgG and sFLCs have been observed [787][788]. Bibas et al. [787] measured ΣFLCs in 182 patients with HIV infection but without co-morbidities known to raise FLC levels (e.g. MGUS, renal impairment or a concurrent malignancy) and found that median concentrations were above normal, indicating that FLC production was raised in response to the HIV infection. Elevated concentrations of ΣFLCs were associated with other adverse prognostic markers, including higher viral load, shorter duration of undetectable viraemia, greater patient age and lower CD4 T-cell count. ΣFLC was also noted to be higher in untreated patients and those positive for hepatitis C virus (HCV). Similar results were reported by Zemlin et al. [858] in sera collected from 366 HIV patients with normal renal function. Elevated sFLC concentrations correlated positively with viral load and negatively with CD4 cell counts, albumin concentration and anti-retroviral treatment. In both of the above studies it was confirmed that sFLC elevations were polyclonal, with normal κ/λ sFLC ratios. Shiels et al. [791] compared sFLC concentrations between HIV patients with (n=252) and without (n=252) clinical acquired immune deficiency syndrome (AIDS). Polyclonal sFLC elevation was associated with a 4-fold increase in the risk of AIDS, whilst a monoclonal elevation was not. The authors suggested that polyclonal B-cell dysfunction may contribute to HIV-related immune suppression and predispose patients to clinical AIDS events.

Emerging evidence suggests a prognostic role for sFLCs in predicting HIV-lymphoma risk [787][792]. Lymphoma is the leading cause of cancer-related death among HIV-infected patients (Chapter 31) [793][794]. Non-Hodgkin lymphoma (NHL) is one of the AIDS-defining malignancies, and HIV-infected individuals have a 60- to 200-fold higher risk of developing NHL compared with that of the general population [793][794]. Likewise, HIV-infected patients are at increased risk of developing Hodgkin lymphoma (HL), with a 5- to 15-fold higher risk compared with that of the general population (Section 31.2) [795].

There are conflicting data on the association between elevated total immunoglobulin levels and NHL risk in HIV-infected individuals [796][792]. However, emerging evidence suggests there is a prognostic role for sFLCs in predicting HIV-lymphoma risk. Landgren et al. [792] studied 4,635 HIV infected individuals, 66 of whom developed NHL. Elevated κ or λ sFLC concentrations were present 2 to 5 years prior to NHL diagnosis, and were significantly associated with an increased NHL risk. The risk of NHL was 3.8- or 8.1-fold greater in patients with elevated κ or λ sFLC concentrations.

The prognostic value of elevated sFLCs in predicting HIV-lymphoma was also shown by Bibas et al. [787]. Of 6513 participants studied, 86 developed lymphoma. After excluding patients with comorbidities that may have caused elevated sFLCs (e.g. renal impairment or autoimmune disease), the remaining cohort comprised 46 patients. Of these, 30 patients developed NHL and 16 developed HL. In patients who subsequently developed lymphoma, summated κ + λ sFLC (ΣFLC) concentrations 2 years prior to lymphoma diagnosis were significantly higher than those of lymphoma-free HIV-infected controls (Figure 35.12). In multivariate analysis, elevated ΣFLCs (defined as >2-times the upper limit of normal) remained a significant predictor of lymphoma risk and was independent of CD4 T-cell count. The authors concluded that the measurement of polyclonal sFLCs merits consideration for introduction into routine clinical practice for HIV patients [787]. Tittle et al. [797] measured sFLCs in 264 patients with HIV-associated lymphoma. There was no significant difference in sFLC measurements between the three major histological subtypes (HL, diffuse large B-cell lymphoma and Burkitt lymphoma) at lymphoma diagnosis. In addition, elevated κ or λ concentrations or an abnormal κ/λ sFLC ratio did not influence overall survival.

Baptista et al. [798] highlighted a potential utility of sFLCs in monitoring HIV-related lymphoma patients. The sFLC concentrations at lymphoma diagnosis (46 samples) were compared with sFLC concentrations at complete response (28 samples). Serum κ, λ and ΣFLC concentrations were significantly lower at complete response compared with those at lymphoma diagnosis, indicating that further study of the potential utility of sFLCs for monitoring is warranted.