In the time before potent combination therapy for HIV (commonly called ART or HAART) became available one of the symptoms associated with HIV infection was persistent fatigue. In some cases, the intensity of fatigue was severe and could be disabling. This symptom was generally not linked to depression or other obvious health problems. Moreover, the reason for this fatigue was not clear but it was linked to declining CD4+ cell counts and worsening health.
It is uncertain how common HIV-related fatigue is in the modern era. Given the tremendous benefit of ART on overall health and survival, some researchers expect that HIV-related fatigue may now be less common. A team of researchers at the Royal Victoria Hospital in Newcastle-upon-Tyne in the UK have been studying fatigue in people with HIV infection and in HIV-negative people with Chronic Fatigue Syndrome (CFS) and comparing them to otherwise-healthy HIV-negative people.
The findings from their investigation with 240 participants suggest that, in the present era, fatigue is relatively common and can be severe in HIV-positive people. It appears likely that previous exposure to certain medicines may have played a role in the fatigue seen in some HIV-positive people. This exposure may have caused lasting dysfunction within part of the nervous system called the autonomic nervous system, which, in turn, led to fatigue.
Study details
Researchers recruited three groups of people as follows:
- 100 HIV-positive participants
- 100 healthy HIV-negative people
- 76 HIV-negative people who had been diagnosed with CFS
All participants completed questionnaires that had been previously validated for assessing fatigue and dysfunction of the autonomic nervous system. Also, data collected from the HIV-positive participants’ medical records was used for analysis.
The average profile of the HIV-positive participants was as follows:
- 64% men, 36% women
- age – 47 years
- duration of HIV infection – 8 years
- current CD4+ cell count – 520 cells
- lowest-ever CD4+ count – 194 cells
- 91% were currently taking ART
- 78% of all participants had an HIV viral load of 40 copies/ml or less
- 1% of participants were co-infected with hepatitis C virus (HCV)
Results—Fatigue
Slightly more than half of the HIV-positive participants (51%) reported an excessive degree of fatigue. Moreover, 28% of HIV-positive people reported a severe degree of fatigue.
The intensity of fatigue experienced by HIV-positive participants was significant and at least threefold greater than that reported by healthy HIV-negative people.
HIV-positive people who reported the greatest intensity of fatigue had a level similar to that reported by participants with CFS.
Running on automatic
The part of the nervous system that deals with functions that can occur without conscious involvement is called the autonomic nervous system. There are many functions under the influence of the autonomic nervous system, including the following:
- blood pressure
- breathing
- heartbeat
- control of muscles such as those that are part of the anus and bladder
- sleeping
- temperature control
One consequence of a dysfunctional autonomic nervous system can be orthostatic hypotension (OH). In OH, the following symptoms can occur:
- dizziness upon standing
- blurred vision
- reduced sense of hearing
- difficulty concentrating
- weakness
These symptoms can have other causes, including drug side effects, so having them does not necessarily mean that a person has underlying problems with their autonomic nervous system.
HIV and a dysfunctional autonomic nervous system
Symptoms suggestive of dysfunction within the autonomic nervous system were common among HIV-positive participants, with 38% reporting them. Furthermore, HIV-positive participants tended to report more severe symptoms compared to healthy HIV-negative participants.
Among HIV-positive participants, fatigue was statistically linked to the following factors—having symptoms suggestive of autonomic nervous system dysfunction and exposure to so-called “d-drugs” such as the following:
- d4T (stavudine, Zerit)
- ddI (didanosine, Videx)
- ddC (zalcitabine, Hivid)
Focus on fatigue and HIV
The research team states that “fatigue remains a very common and often severe symptom in [HIV-positive] patients.” Furthermore, they note that “it is likely that this condition is significantly under-recognized.”
The researchers were surprised at the high level of fatigue reported by participants because most had viral loads in their blood of 40 copies/ml or less. Moreover, their CD4+ counts were relatively high at about 520 cells. In the time before the widespread availability of ART, high viral loads and low CD4+ cell counts were associated with severe fatigue.
Possible fatigue factors in the modern era
The underlying cause(s) of fatigue in some ART users in the modern era is likely complex and could involve biological and psychological factors. However, none of the HIV-positive participants had untreated depression or anxiety (although the research team cannot fully exclude that some patients may have had undiagnosed depression). What might the possible biological factors be? Some clues have emerged from the present study. The researchers found that many HIV-positive participants with severe fatigue tended to have the following features:
- long-standing HIV infection
- previous exposure to d-drugs
- lipodystrophy syndrome – obvious signs of change in body shape due to the loss of the fatty layer just under the skin (particularly in the face, arms and legs) and a redistribution of fat (resulting in a large belly)
The research team was unable to assess which of these three factors had the most important bearing on fatigue because all three factors were so commonly seen together among people with fatigue.
d-drugs and their discontents
The d-drugs are now known to damage structures called mitochondria—the energy-producing parts of a cell, particularly in nerves. One d-drug, d4T, has been linked to the development of the lipodystrophy syndrome. It is therefore possible that past exposure to d-drugs may have damaged nerves and muscles, predisposing some HIV-positive people to fatigue. Certainly, in the case of HIV-negative people with CFS, other researchers using magnetic resonance imaging (MRI) have found that muscle cells may have damaged mitochondria.
Dysfunction within
Another important new finding from the UK study was the link between fatigue and symptoms suggestive of dysfunction within the autonomic nervous system.
Emerging research suggests that dysfunction within the autonomic nervous system plays an important role in perhaps inciting and intensifying fatigue in several chronic diseases, such as the following:
- multiple sclerosis (MS)
- primary biliary cirrhosis (PBC)
- CFS
In an exciting development, the UK’s Medical Research Council has recently funded several research projects to explore autonomic nervous system dysfunction and fatigue in CFS. This research may in the future help researchers better understand fatigue in other chronic conditions, including HIV (Brendan Payne, MD, personal communication).
Strengths and weaknesses
The cross-sectional nature of the present study means that its findings are not definitive. Cross-sectional studies are cheaper and less cumbersome than larger studies that run for several years. The present study did have several strengths, including its size and the fact that there were three different groups that could be compared against each other. Moreover, the research team should be praised for initiating an investigation into a subject that is difficult to study, such as fatigue.
What to do?
Lead researcher Brendan Payne, MD, suggests that physicians and nurses “actively look for fatigue in their HIV-positive patients.” Dr. Payne also suggests an integrated approach to managing this fatigue, similar to what has been proposed for patients with primary biliary cirrhosis. As part of such an approach, doctors would first perform investigations to rule out common causes of fatigue. In HIV infection this would likely include assessments for anemia, diabetes, dysfunction of the thyroid gland, depression, less-than-normal levels of testosterone, co-infections, deficiencies of vitamin B12 and other nutrients, sleep disturbances and so on.
In clinical trials of the treatment of HIV-related fatigue, researchers in the U.S. have found that the drug modafinil (Provigil) and its analogues (armodafinil, Nuvigil) can sometimes provide relief.
Acknowledgement
We thank infectious disease specialist Brendan Payne, MD, for his research assistance, helpful discussion and expert review.
—Sean R. Hosein
REFERENCES:
- Payne B, Hateley C, Ong E, et al. HIV-associated fatigue in the era of highly active antiretroviral therapy: novel biological mechanisms? HIV Medicine. 2012; in press.
- Kaslow RA, Phair JP, Friedman HB, et al. Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study. Annals of Internal Medicine. 1987 Oct;107(4):474-80.
- Darko DF, McCutchan JA, Kripke DF, et al. Fatigue, sleep disturbance, disability, and indices of progression of HIV infection. American Journal of Psychiatry. 1992 Apr;149(4):514-20.
- Hollingsworth KG, Newton JL, Taylor R, et al. Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clinical Gastroenterology and Hepatology. 2008 Sep;6(9):1041-8.
- Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle and Nerve. 2009 Dec;40(6):1043-53.
- Jong E, Oudhoff LA, Epskamp C, et al. Predictors and treatment strategies of HIV-related fatigue in the combined antiretroviral therapy era. AIDS. 2010 Jun 19;24(10):1387-405.
- Niepel G, Bibani RH, Vilisaar J, et al. Association of a deficit of arousal with fatigue in multiple sclerosis: Effect of modafinil. Neuropharmacology. 2013 Jan;64(1):380-8.
- Al-Harthy N, Kumagi T, Coltescu C, et al. The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice. Hepatology. 2010 Aug;52(2):562-70.
- Abbas G, Jorgensen RA, Lindor KD. Fatigue in primary biliary cirrhosis. Nature Reviews. Gastroenterology & Hepatology. 2010 Jun;7(6):313-9.
- Jones DE, Hollingsworth KG, Taylor R, et al. Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. Journal of Internal Medicine. 2010 Apr;267(4):394-401.
- Kanjwal K, Karabin B, Kanjwal Y, et al. Autonomic dysfunction presenting as postural orthostatic tachycardia syndrome in patients with multiple sclerosis. International Journal of Medical Sciences. 2010 Mar 11;7:62-7.
- Kanjwal K, Karabin B, Kanjwal Y, et al. Autonomic dysfunction presenting as orthostatic intolerance in patients suffering from mitochondrial cytopathy. Clinical Cardiology. 2010 Oct;33(10):626-9.
- Hollingsworth KG, Newton JL, Robinson L, et al. Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis. Journal of Hepatology. 2010 Jul;53(1):155-61.
- Jones DE, Sutcliffe K, Pairman J, et al. An integrated care pathway improves quality of life in Primary Biliary Cirrhosis. Quarterly Journal of Medicine. 2008 Jul;101(7):535-43.
- Rabkin JG, McElhiney MC, Rabkin R. Modafinil and armodafinil treatment for fatigue for HIV-positive patients with and without chronic hepatitis C. International Journal of STD and AIDS. 2011 Feb;22(2):95-101.
- Rabkin JG, McElhiney MC, Rabkin R. Treatment of HIV-related fatigue with armodafinil: a placebo-controlled randomized trial. Psychosomatics. 2011 Jul-Aug;52(4):328-36.