More about fatigue

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From a previous email posted by Jules on a study recently publishedThe treatment of HIV-related fatigue

Reported interventions for fatigue in

HIV-infected patients can be subdivided into medication and psychological

interventions.

Medication

In an 8-week, placebo-controlled trial, HIV-infected

patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM),

fourth edition, diagnosis of major depression were randomized to fluoxetine,

testosterone cypionate at an initial dose of 200 mg biweekly, which was

increased to 400 mg biweekly or placebos. The Clinical Global Impressions (CGI)

Scale, a standard clinician-rated instrument to evaluate mood outcome in

clinical trials, was used to measure responses. Scores of 1 (‘very much

improved’) or 2 (‘much improved’) on this seven-point scale were used to

define responses. One hundred and twenty-three men were enrolled in the study;

90 (73%) completed the 8-week trial, with 30 completers in each study arm. All

but four patients had total serum testosterone levels within the reference

range at study baseline. The response rates after 8 weeks of treatment were 54%

for the fluoxetine, 44% for the placebo and 47% for the testosterone group.

These differences were not significant. Using a more than 50% decline in the

Hamilton Depression Rating Scale score to define clinical response, differences

between treatment groups remained insignificant. In an intention-to-treat

analysis, response rates were 52, 61 and 51% for fluoxetine, testosterone and

the placebo, respectively. In the logistic regression analysis adjusted for

other explanatory variables, the response rate of the testosterone group was

significantly higher than that of the fluoxetine and placebo groups [75]. Study

limitations include the rather small sample size. Given the high placebo

response rate, it would require large samples to find a difference in outcome

and the effect size would remain modest. The finding in this study that

testosterone but not fluoxetine alleviated fatigue suggests that, in this

patient sample, the fatigue was not only secondary to depression, but rather an

independent problem. Use of testosterone was also evaluated in a clinical trial

including HIV-infected men with diminished libido and one additional symptom of

clinical hypogonadism (e.g. low mood, low energy, involuntary weight loss). Out

of a study population of 108 men, 73 had clinical fatigue as rated by the

clinician. After 12 weeks of treatment with testosterone, 71% had much more

energy and none of them had to stop participation in the study because of

side-effects. These men had significantly better scores on the CFS and VAS

energy scales. The mean dose of testosterone cypionate used by the respondents

was 385 mg, injected intramuscular biweekly [54]. Another study on testosterone

supplementation included HIV-infected men with a CD4 cell count below 400

cells/μl and clinical hypogonadism. A 6-week double-blind trial followed by 12

weeks of open-label maintenance treatment with biweekly injections of

testosterone cypionate was done in 70 patients. About 80% of the patients had

testosterone levels within the reference range. After 6 weeks, erectile

dysfunction and mood disorder improved significantly in the patients taking

testosterone. Among all patients, a trend was observed to report a greater

decline in CFS scores compared with placebo, and significantly more so for

those with fatigue at baseline. For those randomized to testosterone, mean

change in serum testosterone levels between baseline and week 5 did not differ

between responders and nonresponders. Interestingly, for those randomized to

placebo, the mean testosterone increase in placebo responders significantly

exceeded that in placebo nonresponders. After 18 weeks, all measures of

depressive symptoms, distress, quality-of-life satisfaction and enjoyment,

fatigue, libido and erectile response showed a statistically significant

improvement from study baseline. No difference in response rate was found

between men with serum testosterone levels below versus within the laboratory

reference range among the 38 men randomized to receive testosterone. Study

limitations include the brief duration of the double-blind phase of treatment.

The significant increase in testosterone levels between baseline and week 5 is

an example of the variability in testosterone levels [76]. In a double-blind,

placebo-controlled, randomized clinical trial, Knapp et al. [77] found that

weekly intramuscular injections of 300 mg testosterone enanthate for 16 weeks

in men with involuntary weight loss was associated with a significant

improvement in energy/fatigue measured by the Medical Outcomes Study-Short Form

30. The studies were all done in male patients.

A precursor of both androgenic and estrogenic

steroid hormones, dehydroepiandrosterone (DHEA), was also studied for its

effect on HIV-related fatigue in a sample containing 39 men and six women with

depressed mood (DSM-IV criteria) or a Hamilton Rating Scale for Depression

score of 8 or higher, including either depressed mood or loss of interest plus

low energy. In an 8-week, open-label trial, 81% of the sample responded. A

respondent was defined by a CGI rating of 1 or 2 after using DHEA for 8 weeks,

whereas nonrespondents did not show significant changes in fatigue scores.

After randomization of the respondents for a 4-week double-blind

placebo-controlled discontinuation trial, no difference in relapse rate was

observed between those receiving DHEA and those receiving the placebo [78].

DHEA administration caused large increases in serum DHEAS levels during the

study, but there was no influence on serum testosterone levels among men over

time. Nevertheless, the muscle mass increased, and this raised questions about

the mechanism of effect. Levels of serum testosterone did increase dramatically

in the two women included. The high response rate and no relapse during the

double-blind continuation phase of this open label trial are suggestive of a

placebo effect. However, this does not explain the maintenance of physiological

effects during the double-blind phase. The sample size and study design are not

suited to come to conclusions. There were not enough female completers to

analyse data by sex.

HIV-associated wasting, defined as involuntary

weight loss of at least 10% over the preceding 12 months, may be treated with

recombinant human growth hormone (rhGH). rhGH treatment-mediated improvements

in exercise physiological and functional performance have been documented in

patients with adult growth hormone deficiency. Although body mass significantly

increased after rhGH treatment, the changes in fatigue scores measured by

Profile of Moods Scale (POMS) between the rhGH group and the placebo group were

not significant [79].

Multiple psychostimulants have been studied for

their effects on HIV-related fatigue. Wagner et al. [80] included 19

HIV-infected patients with a DSM-III-R depressive disorder diagnosis,

debilitating low energy and CD4 cell counts less than 200 cells/μl. Fatigue

scores improved significantly among all persons completing the open-label trial

of 6 weeks of dextroamphetamine, with a mean maximum daily dose of 18 mg. Of

the sample, 95% were defined as CGI 1 or 2 respondents. This study was an open-label

trial conducted in the early cART era. It was followed by a placebo-controlled

trial in 23 patients with a DSM-IV depressive disorder diagnosis and

debilitating fatigue. The intervention group taking dextroamphetamine showed a

significant improvement on the Chalder Fatigue Scale (CFS) and Visual Analog

Scale (VAS). The patients receiving the placebo showed a smaller, but still

significant, improvement on the CFS, but no significant improvement on the VAS

[80,81]. In a study on ambulatory patients with persistent fatigue (for at

least 2 weeks or more) randomized to the placebo or a trial of methylphenidate

hydrochloride (Ritalin) or pemoline (Cylert) had significantly lower fatigue

scores on the Piper Fatigue Scale and the VAS after 6 weeks of treatment,

compared with patients receiving a placebo. Patients with major depression or

other psychiatric disorders were excluded [82]. Modafinil, another studied

psychostimulant had a response rate of 80%, defined by a CGI 1 or 2 rating in a

4-week, open-label trial in patients with clinically significant fatigue as

defined by interference with activities of daily living, including employment.

Respondents had higher baseline fatigue scores and showed both statistically

and clinically significant improvement on the Fatigue Severity Scale, whereas

the mean score for the nonrespondents actually increased [83]. For all studies

on psychostimulants, the patient numbers are limited and the study period is

relatively short. Persistent fatigue was defined by fatigue lasting for at

least 2 weeks or more. One could question this definition in the light of

HIV-related fatigue. Nevertheless, most studies do not define duration of

fatigue at all.

Psychological interventions

A study in women with AIDS who reported a

moderate-to-low baseline quality of life compared with 10-week, group-based,

cognitive-behavioural stress management and expressive supportive therapy

intervention with an individual psychoeducational condition on quality of life.

Quality of life was measured before and after intervention using the MOS-HIV. A

significant effect was noted for the total quality-of-life score, cognitive

functioning, health distress and overall health perceptions, such that women in

both conditions improved over the course of the study. No interactions or time

effects were observed for energy/fatigue [84]. Another study with a sample of

19 HIV-infected patients on cART, without AIDS, divided patients into

relaxation techniques, psychotherapy or nonpsychiatric treatment, according to

the patient's desire for stress management. A significant improvement in POMS

fatigue scores was reported after the use of relaxation techniques. A posthoc

t-test indicated no difference in effectiveness between relaxation,

psychotherapy and nonpsychiatric treatment [85]. Regards, VergelPoWeRUSA.org