Study Finds Chronic Jet Lag-like Body Clocks in PLWH

People living with HIV (PLWH) had a “mistimed circadian phase” and a shorter night’s sleep compared with HIV-negative individuals with a similar lifestyle, according to findings that suggest both a possible mechanism for increased comorbidities in PLWH and potential solutions.

“It is very well known that sleep problems are common in people living with HIV, and many different reasons for this have been proposed,” co-author Malcolm von Schantz, PhD, professor of chronobiology at Northumbria University in Newcastle upon Tyne, United Kingdom, told Medscape. “But the novelty of our findings is the observation of delayed circadian rhythms.”

The mistimed circadian phase in PLWH is linked to later sleep onset and earlier waking and has “important potential implications” for the health and well-being of PLWH, wrote senior author Karine Scheuermaier, MD, from the University of the Witwatersrand, in Johannesburg, South Africa, and co-authors.

Until now, research on sleep in HIV has focused primarily on its homeostatic components, such as sleep duration and staging, rather than on circadian-related aspects, they noted.

“If the lifestyle‐independent circadian misalignment observed in the current study is confirmed to be a constant feature of chronic HIV infection, then it may be a mediator both of poorer sleep health and of poorer physical health in PLWH, which could potentially be alleviated through light therapy or chronobiotic medication or supplements,” they suggested.

HIV Endemic in Study Population

The study analyzed a random sample of 187 participants (36 with HIV and 151 without) in the HAALSI (Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study, which is part of the Agincourt Health and Socio-demographic Surveillance System.

The study population ranged in age from 45 to 93 years, with an average age of 60.6 years in the HIV-positive group and 68.2 years in the HIV-negative group. Demographic data, Pittsburgh Sleep Quality Index score, and valid actigraphy (measured with an accelerometer for 14 consecutive days) were available for 172 participants (18% with HIV). A subgroup of 51 participants (22% with HIV) also had valid dim light melatonin onset (DLMO) data, a sensitive measure of the internal circadian clock. DLMO was measured for a minimum of 5 consecutive days with hourly saliva sampling between 17:00 and 23:00 while sitting in a dimly lit room.

In 36 participants (16% with HIV) with both valid actigraphy and DLMO data, circadian phase angle of entrainment was calculated by subtracting DLMO time from habitual sleep onset time obtained from actigraphy.

After adjustment for age and sex, the study found a slightly later sleep onset (adjusted average delay of 10 minutes), earlier awakening (adjusted average advance of 10 minutes), and shorter sleep duration in PLWH compared with HIV-negative participants.

At the same time, melatonin production in PLWH started more than an hour later on average than in HIV-negative participants, “with half of the HIV+ group having an earlier habitual sleep onset than DLMO time” the authors wrote. In a subgroup of 36 participants both valid actigraphy and DLMO data, the median circadian phase angle of entrainment was smaller PLWH (-6 minutes vs +1 hour 25 minutes in the HIV-negative group).

“Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants,” they added.

Asynchrony Between Bedtime and Circadian Time

“Ideally, with this delayed timing of circadian phase, they should have delayed their sleep phase (sleep timing) by an equal amount to be sleeping at their optimal biological time,” Scheuermaier explained to Medscape. “Their sleep onset was delayed by 12 minutes (statistically significant but biologically not that much) while their circadian phase was delayed by more than an hour.” 

Possible consequences of a smaller phase angle of entrainment include difficulty in initiating and maintaining sleep, the authors wrote. “The shorter, potentially mis-timed sleep relative to the endogenous circadian cycle observed in this study provides objectively measured evidence supporting the abundant previous subjective reports of poor sleep quality and insomnia in PLWH.”

They noted that a strength of their study is that participants were recruited from rural South Africa, where HIV prevalence is not confined to the so-called “high-risk” groups of gay men, other men who have sex with men, people who inject drugs, and sex workers.

“Behavioral factors associated with belonging to one or more of these groups would be strong potential confounders for studies of sleep and circadian phase,” they explained. “By contrast, in rural Southern Africa, the epidemic has been less demographically discriminating… There are no notable differences in lifestyle between the HIV- and HIV+ individuals in this study. The members of this ageing population are mostly beyond retirement age, living quiet, rural lives supported by government remittances and subsistence farming.”

Direct Evidence Warrants Further Study

The study is “unique” in that it provides “the first direct evidence for potential circadian disturbances in PWLH,” agreed Peng Li, PhD, who was not involved in the study.

“The assessment of dim light melatonin onset in PLWH is a strength of the study; together with actigraphy-based sleep onset assessment, it provides a measure for the phase angle of entrainment,” said Li, who is research director of the Medical Biodynamics Program, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, Massachusetts.

But actigraphy has limitations that affect the interpretation of the results, he told Medscape.

“Without the help of sleep diaries, low specificity in assessing sleep using actigraphy has been consistently reported,” he said. “The low specificity means a significant overestimation of sleep. This lowers the value of the reported sleep readouts and limits the validity of sleep onset estimation, especially considering that differences in sleep measures between the two groups are relatively small, compromising the clinical meaning.”

Additionally, he explained that it’s not clear whether sleep onset in the study participants was spontaneous or was “forced” to accommodate routines. “This is a limitation in field study as compared with in-lab studies,” he said.

Li also pointed to the small sample size and younger age of PLWH, suggesting the study might have benefited from a matched design. Finally, he said the study did not examine gender differences.

“In the general population, it is known that females usually have advanced circadian phase compared to males… More rigorous design and analyses based on sex/gender especially in this often-marginalized population are warranted to better inform HIV-specific or general clinical guidelines.”

The study was supported by the Academy of Medical Sciences. The authors did not mention any competing interests. Li reported grant support from the BrightFocus Foundation. The study is not directly related to this paper. He also receives grant support from the NIH through a Departmental Award, Harvard University Center for AIDS Research and a Pilot Project, HIV and Aging Research Consortium. The projects are on circadian disturbances and cognitive performance in PLWH.

J Pineal Res. 2022 Oct 29;e12838. Full text

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

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