Fat redistribution in
people with HIV who have ever taken thymidine analogues and/or didanosine (TA/ddI)
can persist through time, while increasing cardiovascular risk factors,
according to a Danish study published in the 15 March issue of AIDS.
More specifically, the
redistribution of adipose tissue (fat) as visceral adipose tissue (VAT) rather
than subcutaneous adipose tissue (SAT) is still observed in people living with
HIV who once took TA/ddI, even though they discontinued these drugs many years
ago.
In addition, these
individuals have an excess risk of hypertension, high levels of total cholesterol
and low HDL (‘good cholesterol’), even years after treatment discontinuation.
This most probably results from VAT accumulation.
Thymidine analogues (zidovudine,
also known as AZT, and stavudine, also known as d4T) are antiretrovirals from
the nucleoside reverse transcriptase inhibitors (NRTIs) family. Didanosine
(ddI) is also an NRTI. These older antiretrovirals are now rarely prescribed.
Both types of drugs are
known to cause body fat alterations: loss
of fat from just under the skin (subcutaneous adipose tissue loss, or SAT
loss), and accumulation of fat around the organs (visceral adipose tissue
accumulation, or VAT accumulation, also known as ‘fat belly’). The phenomenon
is generally considered a ‘redistribution’ of fat from some body compartments
to others – for example, from limbs and buttocks to the abdomen – that so many
people with HIV have experienced.
The investigators reached
their conclusions after comparing 761 persons living with HIV who were included
in the Copenhagen Comorbidity in HIV infection study (COCOMO) to 2283 HIV-negative
individuals from the Copenhagen General Population Study (CGPS), who were age
and sex-matched with their HIV-positive counterparts.
Previous work by the same
researchers identified abdominal obesity as common in people living with HIV in
the current era. Therefore, they were prompted to examine:
- whether fat redistribution from the subcutaneous to the visceral
compartments of the body was characteristic of people living with HIV
- whether thymidine analogues and/or didanosine (TA/ddI), taken in the
past, continued to have a role in fat redistribution
- whether TA/ddI was associated with cardiovascular risk factors.
To answer the
questions, they looked for an association between prior HIV treatment with TA/ddI
with VAT, SAT and VAT-to-SAT ratio, respectively; and additionally, with
hypertension, raised total cholesterol and low HDL.
To be included in the
study, participants were required to have an available abdominal CT-scan (which
uses x-rays to create a cross-sectional picture of the belly area) and to be
over forty years old. They had to answer questionnaires on their demographics,
physical activity and smoking. Their height, weight and body mass index (BMI) were
measured, as well as blood pressure, total cholesterol and HDL. Also, SAT and
VAT areas, and the SAT-to-VAT ratio were calculated.
Not surprisingly, results
show that in terms of geographical origin, smoking status, physical activity
and body mass index, there were some differences between COCOMO and CGPS study
participants. For example, the rate of current smoking in the former group
(25.7%) was twice as high as in the latter (12.1%), a trend that has been
reported by many other studies.
Of the 761 HIV-positive
participants, 451 (60.5%) had previously been or were still on TA/ddI. Six
individuals were still taking one of the drugs. Globally, their mean ‘cumulative
exposure period’ (total amount of time
that a person was exposed to these antiretrovirals)
was 6.6 years, and the mean time since discontinuation was 9.4 years.
The study did not tease
out any difference in the amount of between HIV-positive in general (those who
had taken the drugs and those who had not) and HIV-negative participants.
However, more specific analyses showed that participants with HIV who had ever
been on these antiretrovirals had a more significant VAT accumulation (115.5 cm2)
than the “unexposed”, be they HIV positive (88.9 cm2) or
HIV negative (106.5 cm2).
Broadly speaking, in
persons living with HIV, SAT area was smaller than in HIV-negative individuals.
As for the VAT-to-SAT ratio, it was higher in HIV-positive participants than in
HIV-negative individuals, and this difference was even more pronounced in those
who had been on TA/ddI. Additionally, no association was found between
cumulative exposure to TA/ddI, or time since discontinuation, and SAT, or
VAT-to-SAT ratio.
Other important findings
of the study:
- each year of exposure to TA/ddI was associated with a 3.7 cm2
larger VAT area
- the duration of antiretroviral therapy was associated with larger VAT
area, and even more so in individuals with HIV who had been on TA/ddI
- in people living with HIV, VAT area was associated with a higher risk of
hypertension, raised cholesterol and low HDL (though the role of TA/ddI in this
association was not clear)
- among those who had taken TA/ddI, there was no association between time
since discontinuation of the drugs and VAT area (in other words, a larger VAT
area can remain the same, even years after TA/ddI discontinuation, contrary to
what many doctors and patients had hoped for).
Together with the
association between cumulative exposure to TA/ddI and VAT area, and the higher
risk of cardiovascular factors, the last result quoted above supports the hypothesis
that TA/ddI side-effects on fat are not only long-lasting, but irreversible.
The researchers comment:
“Taken together, these results suggest a cumulative and harmful effect of TA
and/or ddI affecting VAT accumulation, which appears to be irreversible in the
time frame considered in the present study”.
They also state that
in our era of less toxic antiretrovirals and, consequently, decreased attention
towards HIV-associated fat redistribution syndrome, these study findings show
that some individuals living with HIV might need more intensive cardiovascular
prevention interventions than others.