Can we learn from researching chronic fatigue in chronic illness - the case of HIV?
Whilst disagreement over diagnostic classification in CFS/ME has
arguably hampered research in this area , we suggest that the study of
fatigue in other chronic illnesses may alternatively help our
understanding of fatigue as a symptom complex, and provide pointers as to
For example, we have recently studied fatigue and associated symptoms
in 100 unselected HIV-infected outpatients and compared with 166 healthy
persons, and 74 patients with CFS (as defined by CDC 1994 Fukuda
criteria). We find that half of HIV-infected patients (50/99, 51%) suffer
excessive fatigue , and that HIV-infected patients appear to fall into
two relatively binary groups, one significantly fatigued, and one
comparable with healthy persons (see Figure 1, left). Among HIV-infected
patients, we found correlation between fatigue and symptoms of autonomic
dysfunction  (r=0.65, p<0.001). This physiological disturbance has
been well demonstrated in CFS as well as in association with fatigue in
other chronic diseases [4 5], although further research is needed to
determine its biological significance.
In terms of biological markers of HIV infection, current or previous
immune function (as determined by CD4 lymphocyte count), or plasma HIV
viral load were not associated with fatigue severity, however duration of
HIV infection was predictive of fatigue in a manner suggestive of
underlying fatigue sub-groups within this population. Thus, most patients
diagnosed with HIV prior to 1998 were fatigued (71%), whereas only a
subset of patients diagnosed after this date were fatigued (45%) (Figure
1, right). Those patients with longstanding HIV-infection and fatigue had a
high frequency of prior exposure to mitochondrially-toxic anti-retroviral
drugs , as well as clinical evidence of the metabolic syndrome of anti-
retroviral associated lipodystrophy. This plausibly suggests a metabolic
or mitochondrial contribution to the fatigue seen in the longstanding
patient group. In contrast, these clinical features were not observed in
the more recently diagnosed group, suggesting other biological or
psychosocial factors are important in driving fatigue in these patients.
Future rational strategies in fatigue management are likely to need
to take into account fatigue sub-types, and this approach may potentially
be of benefit in both CFS, and chronic disease-associated fatigue.
1. Hawkes N. Dangers of research into chronic fatigue syndrome. BMJ
2. Prince MI, James OF, Holland NP, Jones DE. Validation of a fatigue
impact score in primary biliary cirrhosis: towards a standard for clinical
and trial use. J Hepatol 2000;32(3):368-73.
3. Schrezenmaier C, Gehrking JA, Hines SM, Low PA, Benrud-Larson LM,
Sandroni P. Evaluation of orthostatic hypotension: relationship of a new
self-report instrument to laboratory-based measures. Mayo Clin Proc
4. Rowe PC, Calkins H. Neurally mediated hypotension and chronic
fatigue syndrome. Am J Med 1998;105(3A):15S-21S.
5. Flachenecker P, Rufer A, Bihler I, Hippel C, Reiners K, Toyka KV,
et al. Fatigue in MS is related to sympathetic vasomotor dysfunction.
6. Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M,
Samuels DC, et al. Mitochondrial aging is accelerated by anti-retroviral
therapy through the clonal expansion of mtDNA mutations. Nat Genet 2011.
Competing interests: JLN has received funding from ME Research UK and the ME Association