Trial By Error: New Biopsychosocial Study of Fatigue in HIV Patients

By David Tuller, DrPH

And here’s yet another study from Professor Trudie Chalder and colleagues at King’s College London, this time tackling fatigue in people with HIV, an often debilitating problem. The study, “A Biopsychosocial Approach to HIV Fatigue: A Cross-Sectional and Prospective Analysis to Identify Key Modifiable Factors”, was published online last month by the journal Behavioral Medicine.

The causes of HIV-associated fatigue are multifactorial and not fully understood, so it would be great to find effective ways to address it. (Many of the HIV-positive gay men I know in my age cohort, I’m 63, are dealing with some variant of this.) Some common psychological correlates of HIV infection, such as depression and feelings of social isolation, could contribute to fatigue. Like others experiencing complex health issues, many HIV patients could possibly benefit from receiving psychotherapy along with appropriate medical treatment. By helping people adapt their lives to current circumstances and lower their stress levels, such interventions could lead to improvements in fatigue and other indicators.

So this HIV study should potentially be good news. Unfortunately, it features one of the scientific missteps that have marred other work from biopsychosocial experts: the assumption that a reported association is evidence of a specific causal relationship. First-year epidemiology students are warned not to confuse association with cause, yet these experienced researchers seem not to have learned that fundamental lesson. Moreover, the new study will seem familiar to readers of previous articles from this body of research. No matter what disease is being examined , chronic fatigue syndrome/myalgic encephalomyelitis (as these researchers often call the illness in question), irritable bowel syndrome, HIV, the argument seems much the same.

To wit: Patients are catastrophizing, symptom-focusing, engaging in boom-and-bust activity patterns, and/or holding fearful convictions about the dangers of exertion. Moreover, these cognitions, emotions and/or behaviors are unhelpful and/or dysfunctional and are responsible for generating and/or perpetuating core symptoms. (I don’t really understand how patients can be both fearful of exertion and engaging in boom-and-bust activity patterns. If they’re fearful of exertion, why are they ever booming?)

By way of background, Professor Chalder was a lead investigator of the PACE trial, which was billed as the “definitive” study of CBT and graded exercise therapy for CFS/ME. As many know, PACE has since been exposed as a disaster and its findings definitively refuted; in an open letter, an international roster of distinguished scientists and physicians condemned the study’s methodological lapses and demanded an independent review of the data.

More recently, Professor Chalder was the co-lead investigator in the ACTIB trial, which tested CBT for patients with IBS. Although promoted as a success in the press release issued by King’s College London, ACTIB actually documented that telephone-delivered and web-based CBT, when compared to standard treatment, provided little or no clinically significant benefits in reducing IBS symptom severity, as noted on Virology Blog.

(In addition to its less-than-forthright presentation of the ACTIB findings, the KCL press release failed to mention a salient detail: Professor Chalder’s co-lead investigator, Professor Rona Moss-Morris, has financial ties to a company that licensed the web-based CBT-for-IBS program from the university. This company, Mahana Therapeutics, is promoting the web-based program in a misleading fashion, as Virology Blog has reported.)


In the new study, the researchers recruited 131 patients from HIV outpatient clinics in London. Sixty-four of them, almost half, met criteria for clinically significant fatigue. At that time, as well as a year later, fatigued patients also met some of the study’s outcome thresholds for specific psychological and/or behavioral constructs. The researchers concluded that future interventions should target these specific constructs as well as more general entities like anxiety and depression.

Here’s how the researchers explained their conceptual framework:

“From a biopsychosocial perspective, disease and treatment related factors form only one part of the explanation. Fatigue is multifactorial, influenced by a variety of biological, demographic, psychological, social and behavioral factors, which are poorly understood in HIV…Across a number of chronic conditions negative illness representations, symptom interpretations and heightened symptom focusing have been associated with increased fatigue. According to the cognitive behavioral model of fatigue, believing fatigue is serious, damaging, uncontrollable and incurable and thus must be monitored, can enhance symptom perception and amplify the severity of fatigue.”

As this passage indicates, the researchers’ strategy is to apply their usual theories to various chronic conditions. After documenting the expected associations, they cite their cognitive behavioral model to argue that patients’ worries about “serious,” “damaging,” “uncontrollable” or “incurable” symptoms are themselves partly or largely to blame for their ongoing physical complaints.

In the HIV study, here is how the researchers described the results: “Consistent with our hypotheses, fatigue severity at 1 year was significantly predicted by catastrophizing, symptom focusing, distress and sleep quality after controlling for clinical and demographic variables. These findings provide further support for the biopsychosocial model of fatigue in HIV…It seems that, whilst HIV and treatment related factors may trigger the initial fatigue, psychological and behavioral factors have a key role in fatigue maintenance for people living with HIV.”

To state that psychological and behavioral factors play “a key role” in maintaining fatigue is to describe a causal relationship. (In the relevant sentence, the phrase “it seems” acts like a linguistic speed-bump; it mitigates the weight of the declaration, but only slightly.) In other words, the researchers in the HIV study reported an association and then claimed support for their causal hypothesis, making an assumption about the directionality of impact.

Yet the study results are also consistent with a reasonable alternative explanation in which the causality operates in the other direction. It is plausible that the severity of the fatigue led patients to experience realistic, normal and appropriate levels of concern, which the researchers chose to categorize as “catastrophizing” and “symptom-focusing.” This possibility is not mentioned, a major gap in the paper’s argument. The researchers should have provided a convincing account of why they believe their causal interpretation is the best fit for the data. They did not.

In the study, fatigue at baseline was associated with length of HIV infection but not with medication and blood measures. Current limits of biomedical understanding of the fatigue are not a sufficient or compelling rationale for characterizing anxiety about it as “catastrophizing”, as if such anxiety were indisputably excessive or unwarranted. After all, it should not be surprising that HIV patients who reported greater fatigue were more likely than others to focus on that fatigue and be distressed about it. Nor should it be surprising that, one year later, they were more likely to still be grappling with it.

These associations do not and cannot prove that symptom-focusing was itself a driver of the reported fatigue. The notion that patients prolong their suffering through their own reactions to their suffering is a hypothesis. It might be happening, but this study fails to make the case.

Why does this matter? Because accuracy and clarity are important in science. Moreover, the HIV study seems like part of what a recent article referred to as a campaign by “CBT empire-builders” in the UK to extend their domain. This effort is manifested in the continuing expansion of the National Health Service program known as Improving Access to Psychological Therapies, which I have written about here. Initially focused just on people with mental health disorders, the program now also covers patients with long-term conditions and so-called “medically unexplained symptoms”–a category that includes CFS/ME and IBS.

Now the biopsychosocial crowd is eyeing HIV patients. Any ideas as to what recommendations might emerge from an unblinded trial of CBT for HIV-related fatigue, relying on self-reported outcomes, with treatment-as-usual for the comparison group and with those in the CBT arm being told that CBT has already been shown to alleviate fatigue in multiple illnesses?

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