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HIV-associated fatigue in era of highly active antiretroviral therapy: novel biological mechanisms?


Senior Member
CFS/ME patients were used as controls

HIV-associated fatigue in the era of highly active antiretroviral therapy: novel biological mechanisms?

HIV Med. 2013 Apr;14(4):247-51. doi: 10.1111/j.1468-1293.2012.01050.x. Epub 2012 Sep 23.

Payne BA, Hateley CL, Ong EL, Premchand N, Schmid ML, Schwab U, Newton JL, Price DA.

Department of Infection and Tropical Medicine, Royal Victo, ria Infirmary, Newcastle-upon-Tyne, UK. brendan.payne@ncl.ac.uk



The aim of the study was to determine the prevalence and risk factors for HIV-associated fatigue in the era of highly active antiretroviral therapy (HAART).


A cross-sectional survey of 100 stable HIV-infected out-patients was carried out. Severity of fatigue was measured using the Fatigue Impact Scale (FIS).

Symptoms of orthostatic intolerance (dysautonomia) were evaluated using the Orthostatic Grading Scale (OGS).

Data for HIV-infected patients were compared with those for 166 uninfected controls and 74 patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (encephalopathy) (ME).


Ninety-one per cent of HIV-infected patients were on HAART and 78% had suppressed plasma HIV viral load (≤ 40 HIV-1 RNA copies/mL).

Fifty-one per cent of HIV-infected patients reported excessive symptomatic fatigue (FIS ≥ 40), and 28% reported severe fatigue symptoms (FIS ≥ 80).

The mean FIS score among HIV-infected patients was 50.8 [standard deviation (SD) 41.9] compared with 13.0 (SD 17.6) in uninfected control subjects, and 92.9 (SD 29.0) in CFS patients (P < 0.001 for comparison of HIV-infected patients and uninfected controls).

Among HIV-infected patients, fatigue severity was not significantly associated with current or nadir CD4 lymphocyte count, HIV plasma viral load, or whether on HAART.

Prior dideoxynucleoside analogue (d-drug) exposure (P = 0.016) and the presence of clinical lipodystrophy syndrome (P = 0.011) were associated with fatigue.

Additionally, fatigue severity correlated strongly with symptomatic orthostatic intolerance (r = 0.65; P < 0.001).


Fatigue is very common and often severe in HIV-infected out-patients, despite viral suppression and good immune function.

In a subgroup of patients, prior d-drug exposure may contribute to fatigue, suggesting a metabolic basis.

Dysautonomia may also drive fatigue associated with HIV infection, as in other chronic diseases, and CFS/ME, and should be further evaluated with the potential for a shared therapeutic approach.

PMID: 22998022 [PubMed - in process]
I gave each sentence its own paragraph


Senior Member
Some data:
Symptom assessment tools

We administered self-rating scales comprising the Fatigue Impact Scale (FIS) [10] and the Orthostatic Grading Scale (OGS) [11]. The FIS is a 40-item generic fatigue impact scale. A score >= 40 indicates excessive fatigue and >= 80 severe fatigue. The OGS reports symptoms of orthostatic intolerance resulting from orthostatic hypotension. It comprises five items (frequency of orthostatic symptoms, severity of orthostatic symptoms, conditions under which orthostatic symptoms occur, interference with activities of daily living, and standing time before experiencing orthostatic symptoms), each rated from 0 to 4, with the total score as the sum of the items. Studies have shown good correlation between OGS scores and conventional physiological measures of the autonomic nervous system [11]. A score of >= 4 is considered consistent with at least moderate orthostatic intolerance and >= 9 consistent with a formal diagnosis of orthostatic hypotension. These tools have been validated for self-completion in a range of other fatigueassociated chronic diseases, such as primary biliary cirrhosis (PBC) [10].

Fatigue and orthostatic intolerance Symptoms of dysautonomia were common among HIVinfected patients, with 38 of 99 (38%) reporting significant orthostatic intolerance (OGS  4) and 12 (12.1%) with more severe symptoms, suggestive of orthostatic hypotension (OGS  9) [11]. OGS and FIS scores showed a highly significant correlation (r = 0.65; P < 0.001; Fig. 1c). Mean OGS scores were significantly higher in HIV-infected patients compared with uninfected controls [3.57 (SD 3.70) vs. 1.25 (SD 1.47); P < 0.001], but lower than in CFS/ME patients [6.82 (SD 4.31); P < 0.001]. Both OGS (P < 0.001) and history of d-drug exposure (P = 0.006) remained significantly associated with FIS score in HIV-infected patients on multivariate analysis.

It also has a scatterplot of the FIS scores for the three groups. But after that, it is just about the HIV group.


Senior Member
Monmouth, UK
What makes this paper interesting is that it provides evidence that HIV-related fatigue is associated with biological factors: orthostatic intolerance and prior d-drug exposure.

This is in contrast to the view put forward by Simon Wessely that fatigue in HIV was primarly psychosocial, even though the authors of the study he quoted to support this dubious claim had said:
we cannot draw any conclusions about the direction of causality, and whether the association between psychological distress is a cause or a consequence of the fatigue.

My comment on this new HIV-fatigue paper (nb Julia Newton is an author) - and it's relevance to the claims that HIV fatigue has psychosocial causes - is here.


Senior Member
From the discussion section:
What may be driving HIV-associated fatigue in the HAART era? The pathogenesis of fatigue remains poorly understood, but is likely to be complex and involve both physiological and psychological factors. Our data suggest two novel physiological contributors. Firstly, fatigue severity was increased in patients with long-standing HIV infection, past d-drug exposure and LDS. As a result of the strong co-segregation of these factors, it was not possible to establish which factor was the most important predictor of fatigue in this group, but rather patients with these factors represent a subgroup of highly treatmentexperienced HIV-infected patients. Given the established associations between nucleoside reverse transcriptase inhibitor (NRTI) exposure, LDS and acquired mitochondrial injury, it is certainly plausible that such patients show fatigue resulting from metabolic/mitochondrial dysfunction [12–14]. Consistent with this notion, limited data from magnetic resonance spectroscopy (MRS) studies point to a role of muscle mitochondrial dysfunction in fatigue associated with CFS/ME and PBC [15,16]. Secondly, we have shown that symptoms of dysautonomia (orthostatic intolerance) are independently associated with fatigue in HIV-infected patients. Recent evidence suggests that dysautonomia is a key biological driver of fatigue in several chronic diseases including multiple sclerosis (MS) and PBC, as well as CFS/ME [3,6,8,17]. Furthermore, fatigue is well described in vasovagal syncope (VVS), a primary dysautonomia syndrome [18]. Fuller understanding of the mediators of a causal relationship between fatigue and dysautonomia (for example, regulation of oxygen delivery to muscles) is the subject of ongoing research [16].
Sofa, UK
Is it significant that the mean FIS score of CFS patients was almost twice as high as that of the HIV patients?