As
antiretroviral regimens do not eradicate HIV infection, the current therapy
paradigm involves a commitment to indefinite therapy. Long-term adherence to
some regimens, particularly PI-based ones, is challenging due to requirements of
high tablet volume, dietary restrictions and increased fluid intake. Improving
the poor pharmacology of PIs by using booster co-therapies, such as low dose
ritonavir improves administration characteristics but may also increase the
number of important drug interactions. Additionally, ritonavir, and other
protease inhibitors are known to cause elevation of blood lipids and may be less
well tolerated in persons with hepatitis co-infections.
Short-term,
effective therapy is associated with an increase in body weight and an
improvement in nutritional status, although both plasma triglycerides, total and
LDL cholesterol may elevate soon after therapy initiation.
Longer-term (> 1 year) therapy has been associated with persistence of
these lipid elevations, insulin resistance sometimes accompanied by new-onset
diabetes mellitus, and abnormal body fat distribution. This may involve
peripheral fat loss, localized or truncal fat gain or both. It has not been
clearly established if all these phenomena are inter-related although unifying
theories have been proposed. Both PIs and nucleoside analogs (NAs) have been
suggested to play a role in the pathogenesis of these changes and are hence both
potential targets of switching strategies. Hypertriglyceridemia and reduced high
density lipoprotein (HDL) cholesterol, but not diabetes mellitus or fat
redistribution were recognized as complications of HIV-1 infection, and most
typically wasting prior to the availability of PI.
A
definition for the syndrome(s) to enable consistent case definition in studies
does not currently exist. Reported clinical manifestations of the fat
redistribution syndrome are heterogeneous and range from central or localised
adiposity alone to peripheral fat wasting or combinations of both. Central
adiposity, at least in males, appears mainly secondary to visceral fat
accumulation and may be best assessed by CT scanning. Localised problems include
breast enlargement, or development of cervical fat pads (or ëbuffalo
humpsí). Peripheral fat wasting, generally presents with increased vein
prominence as well as loss of facial fat pads such as the temporalis and naso-labial
pads. The prevalence of these clinical mainfestations is not known but appears
to increase with time on antiretroviral therapy.
These
changes have both significant psychological and social consequences for
individuals with HIV infection. The conference included 2 studies evaluating the
impact of fat redistribution on quality of life. A German group evaluated 250
patients who had commence ART in 1996 (mean time since start of ART 36 months)
using a standardized physician and patient questionnaire and visual analogue
scales. Patients were mostly (80%) male with a mean age of 39 years. Physicians
diagnosed lipodystrophy in 36% of the cohort. Patients with lipodystrophy all
reported loss of quality of life in at least one of the measured domains: 63%
for social contact, 68% on daily performance and sexuality and 83% on self
esteem. The authors also reported some specific physical changes were linked
particular diminished ratings. For example, abdominal enlargement was
significantly associated with diminished sexual and self esteem ratings, leg and
arm changes with daily performance and social functioning (1). In a survey of 74
attendees at a workshop on body shape changes where 78% of respondents reported
body shape or metabolic changes thought related to ART, 30% of these individuals
had changed therapy and 7% interrupted ART specifically due to these problems.
In general (83% of cases), amongst those changing therapy, only the agent
perceived as causative of the problem was changes. The authors, from Gay Menís
Health Crisis New York, concluded that patient perceptions around metabolic and
body shape changes are driving treatment decisions and potentially therapy
outcomes (2). These needs are driving a host of studies evaluating the outcome
of therapy switches.
Given
the known, theoretical and observational associations of metabolic and clinical
changes with PIs, most of the studies currently reporting data have evaluated
changes in HIV disease markers, clinical and biochemical parameters following
changes from a PI based to a PI sparing regimen.
The
reasons for considering switching to a PI sparing regimen include to address
metabolic and fat redistribution problems but also
Improve
adherence; reduce tablet load, remove food requirements, reduce dosing
frequency
Reduce
the risk of clinically important drug interactions and
Managing
an actual or possible PI toxicity including diarrhoea, recurrent renal
calculi, etc.
In
principle, two main outcomes should be looked at to evaluate the success or
otherwise of switching. Firstly, that no harm is done and secondly, that benefit
is gained. More specifically this can be measured as
Maintaining
of virological control (most reported studies have focussed on patients with
good virological control on PI-based therapy)
Maintaining
of CD4 responses (and immune function) and
Improving/resolving/preventing
of toxicity
Improving
adherence and Quality of life
Three
drugs have been evaluated in switching studies. The non-nucleosides Efavirenz (EFV)
and nevirapine (NVP) and the potent nucleoside analog Abacavir (ABC).
In general, the reports are not studies, per se, but observed clinical
cohorts, thus the observations must be placed in the context of not knowing what
would have had happened to a group of patients maintained on therapy.