CATIE News

4 December 2020 

Study explores pain in HIV-positive people

  • Researchers in Ireland and the UK have been studying the issue of pain in HIV-positive people
  • They found that chronic pain is relatively common in people with HIV, particularly in those aged over 50 years
  • The researchers call for “effective approaches” to help manage chronic pain in HIV-positive people

The widespread use of potent combination HIV treatment (ART) has resulted in scientists projecting that many HIV-positive people will have near-normal life expectancy. As HIV-positive people age, they are at increased risk for developing other health conditions, or comorbidities. These can include higher-than-normal blood pressure, abnormal levels of cholesterol, type 2 diabetes, thinner-than-normal bones, and so on. Another issue that appears to be more common in older HIV-positive people is chronic pain.

In a study called Poppy, researchers in Ireland and the UK found that HIV-positive people over the age of 50 generally reported higher rates of pain than HIV-negative people of a similar age. Now, a new analysis from Poppy has further explored the issue of pain. Researchers found that “widespread pain was more commonly reported” in HIV-positive people. Furthermore, older HIV-positive people were more likely to report widespread pain than younger people. HIV-positive people who had experienced periods of time when their immune system was very weak (less than 200 CD4+ cells/mm3) and who had other factors were at heightened risk for having widespread pain as a health issue. The researchers called for “greater awareness and interventions to support the management of pain” in HIV-positive people.

Study details

Poppy recruited different groups of people, as follows:

  • HIV-positive people aged 50 and older – 699 people; the researchers called this group “older”
  • HIV-positive people under the age of 50 – 374 people; the researchers called this group “younger”
  • HIV-negative people over the age of 50 – 304 people; this group was used for the purpose of comparison

In the study’s database, the HIV-negative people were matched to the HIV-positive people based on age, gender, ethnicity and sexual orientation.

The classification of pain was based on the 2019 American College of Rheumatology criteria.

About 90% of participants in each of the study’s three groups used paper diagrams of the body to show researchers where they were affected by pain.

The average profile of the HIV-positive people in the study was as follows:

  • age – 54 years
  • 82% men, 18% women
  • 72% of the men were gay or bisexual
  • BMI (body mass index) – 25.7 kg/m2
  • major ethno-racial groups: white – 87%; black – 13%
  • CD4+ count – 637 cells/mm3
  • lowest-ever CD4+ count – 188 cells/mm3
  • 91% of participants had a suppressed viral load (less than 50 copies/mL), as they were on ART

Results – Location of pain

According to the research team, the body parts of HIV-positive people commonly affected by pain, as reported by study participants, were as follows:

  • lower back – 30%
  • upper legs – 28%
  • lower legs – 25%
  • upper back – 19%
  • shoulders – 16%

Older HIV-positive people had at least two parts of the body affected by pain. Younger HIV-positive people tended to have one body part affected by pain. This finding in younger HIV-positive people was similar to that of HIV-negative people.

Widespread pain was reported by the following proportions of people:

  • older HIV-positive people – 19%
  • younger HIV-positive people – 13%
  • HIV-negative people – 10%

HIV-positive people who had widespread pain had been exposed to a greater number of anti-HIV drugs and had been taking ART for longer than HIV-positive people without widespread pain. HIV-positive people who had experienced significant immune suppression in the past were also more likely to have widespread pain.

Making sense of the findings

1. Note that the present analysis from Poppy assessed pain at one point in time. Such studies are called cross-sectional and are good at finding associations, but they cannot prove a link between a cause or event with an effect or outcome. In the case of the Poppy study, the researchers were not able to find the precise cause(s) of pain. However, cross-sectional studies are a good way to begin to explore a medical issue. The findings from the Poppy study are generally in line with those from other studies.

The researchers with Poppy were unable to obtain a detailed history of participants’ exposure to certain drugs. For instance, a group of drugs called “d-drugs” are notorious for their association with painful nerves in the feet, legs and arms. These drugs are:

  • d4T – stavudine (Zerit)
  • ddC – zalcitabine (Hivid)
  • ddI – didanosine (Videx)

The d-drugs were once widely used, beginning in the late 1980s, but are no longer recommended by treatment guidelines because modern treatments are much safer.

2. The finding of widespread pain being associated with the use of ART over a long period of time needs to be treated cautiously. Longer use of ART could have arisen because of a prolonged time with HIV infection. The longer a person has lived with HIV raises the possibility that they could have been exposed to d-drugs in the past. This association may not be applicable to people who were diagnosed with HIV and treated with ART in the modern era, when d-drugs are no longer used.

3. Some other studies have found that HIV-positive people who spent prolonged periods without treatment were at heightened risk for developing painful nerves in the legs and feet—peripheral neuropathy. In Poppy, researchers stated that “longer exposure to a low CD4+ cell count is a risk factor for widespread pain.” This could have contributed to an increased risk for pain for at least three reasons:

  • Untreated HIV infection is associated with elevated levels of chemical messengers (cytokines) produced by the immune system. These chemical messengers also incite and sustain inflammation. High levels of some cytokines have been associated with increased susceptibility to pain in experiments with animals.
  • Researchers in Canada and other countries have found through lab experiments that HIV-infected cells release viral proteins that can inflame and injure nerve cells. This could lead to pain.
  • During periods of low CD4+ cell counts, the immune system is unable to keep germs from spreading within the body. Under such circumstances, a common viral co-infection in HIV-positive people called CMV (cytomegalovirus) can infect nerve cells in the hands, feet and legs, causing injury.  

Bear in mind

The Poppy study has uncovered that widespread chronic pain is relatively common in some HIV-positive people, even those who currently have an undetectable viral load while on ART. Previous research by the Poppy team found that chronic pain degrades quality of life. The Poppy researchers stated: “Our findings highlight the need for clinicians to be alert to possible chronic and severe pain in [HIV-positive people], particularly those who may have been on long-term suppressive ART, and for development of effective approaches to support the management of pain in this population.”

—Sean R. Hosein

Resources

Nerve Pain and NumbnessA Practical Guide to HIV Drug Side Effects

Frailty, nerve injury and falls in middle-aged and older HIV-positive peopleCATIE News

REFERENCES:

  1. Sabin CA, Harding R, Bagkeris E, et al. The predictors of pain extent in people living with HIV. AIDS. 2020 Nov 15;34(14):2071-2079.
  2. Sabin CA, Harding R, Bagkeris E, et al. Pain in people living with HIV and its association with healthcare resource use, well being and functional status. AIDS. 2018 Nov 28;32(18):2697-2706.
  3. Simpson DM. Selected peripheral neuropathies associated with human immunodeficiency virus infection and antiretroviral therapy. Journal of Neurovirology. 2002 Dec;8 Supplement 2:33-41.
  4. Simpson DM, Tagliati M. Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. JAIDS. 1995 Jun 1;9(2):153-61.
  5. Bloch M, John M, Smith D, et al. Managing HIV-associated inflammation and ageing in the era of modern ART. HIV Medicine. 2020 Oct;21 Supplement 3:2-16.
  6. Yarchoan R, Perno CF, Thomas RV, et al. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988 Jan 16;1(8577):76-81.
  7. Lambert JS, Seidlin M, Reichman RC, et al. 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. New England Journal of Medicine. 1990 May 10;322(19):1333.
  8. Browne MJ, Mayer KH, Chafee SB, et al. 2',3'-didehydro-3'-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. Journal of Infectious Diseases. 1993 Jan;167(1):21-9.
  9. Merlin JS, Westfall AO, Heath SL, et al. Brief Report: IL-1β levels are associated with chronic multisite pain in people living with HIV. JAIDS. 2017 Aug 1;75(4):e99-e103.
  10. Guo H, Gao J, Taxman DJ, et al. HIV-1 infection induces interleukin-1β production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. Journal of Biological Chemistry. 2014 Aug 1;289(31):21716-26.
  11. Chi X, Amet T, Byrd D, et al. Direct effects of HIV-1 Tat on excitability and survival of primary dorsal root ganglion neurons: possible contribution to HIV-1-associated pain. PLoS One. 2011;6(9):e24412.