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CHAPTER 8
ASSOCIATION BETWEEN DIARRHEA AND QUALITY
OF LIFE IN HIV INFECTED PATIENTS RECEIVING
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
A. Tramarin,
N. Parise
S. Campostrini
D. Yin
M.J. Postma
R. Lyu
R. Grisetti
A. Capetti
A.M.Cattelan
M.T. Di Toro
A. Mastroianni
E. Pignattai
V. Mondardini
G. Calleri
E. Raise
F. Starace
for the Palladio Study Group
Published in Quality of Life Research (2004) 13:243-50
Abstract
Diarrhea is a common symptom that many HIV patients experience either as
a consequence of HIV-infection or of highly-active antiretroviral therapy
(HAART). A multicenter, prospective observational study was conducted in
11 AIDS clinics in Italy to determine the effect of diarrhea on health-related
quality of life among patients receiving HAART. The study enrolled 100
consecutive HIV positive patients who had diarrhea while on HAART. For
each enrolled patient a control patient with matching disease stage who did
not have diarrhea was identified using existing data from another
prospective observational study conducted in 34 AIDS clinics (including the
11 in current study). Quality of life was measured by MOS-HIV Health
Survey (MOS-HIV). Paired t-test and multiple regression analysis were
used to compare the quality of life among patients with and without
diarrhea. Mean patient age was 40±7 years; 69% were male. Mean CD4 cell
count was 342± 239 cells/mm3; 59% had AIDS. Of the cases, 49 patients
had severe diarrhea (>5 bowel movements or >3 watery per day) and 46
patients had moderate diarrhea (3-5 bowel movements). Compared to
matched control patients, cases experiencing diarrhea while on HAART had
significantly lower MOS-HIV scores in all domains. The significant adverse
effect of diarrhea on quality of life should be considered when choosing the
appropriate antiretroviral drugs regimen.
Introduction
Next to viral suppression, improvement of quality of life is one of the
primary objectives of antiretroviral therapy [1]. Since 1997, expert consensus
guidelines have recommended the use of 2 nucleoside reverse transcriptase
inhibitors (NRTIs) and a protease inhibitor (or 2 protease inhibitors) for the
treatment of established HIV infection [2]. The combination of 2 NRTIs and
a nonnucleoside reverse transcriptase inhibitor (NNRTI) has recently
become part of the recommended regimens [1, 3].
The use of these highly active antiretroviral therapies (HAART) is
associated with side effects that pose difficulty with adherence and pose a
challenge to both physicians and patients to achieve the objectives of
antiretroviral therapy, including quality-of-life improvement. Fat
maldistribution, hyperglycemia/diabetes mellitus, hyperlipidemia have been
reported in patients receiving HAART. Diarrhea is also a relatively common
179
side effect of some antiretroviral treatments. For example, the incidence of
diarrhea associated with protease inhibitors ranges from 0 to 56% (33 to
56% for amprenavir; 14 to 32% for nelfinavir; 13 to 22% for ritonavir; 12 to
20% for saquinavir; and 0 to 4.6% for indinavir) [4]. An additional cause of
diarrhea among HIV infected patients is opportunistic bowel infections (e.g.
Salmonella, Cryptosporidium, Isospora, Cytomegalovirus).
Bowel infections and HAART-associated diarrhea may have an acute or a
chronic clinical course. Abdominal pain from acute diarrhea may be steady,
colicky, intermittent or cramping with occasional exacerbation. Chronic
diarrhea is less painful but has a greater impact on the daily life of patients.
It is well known, for example, that in patients with irritable bowel the
embarrassing nature of this symptom causes an emotional upset, which is
experienced as major limit in social life [5].
Some regard HAART-associated diarrhea as a minor nuisance but its effect
on patient quality of life is yet not well understood. Previous studies found
that diarrhea and related illnesses had a negative effect on the quality of life
of HIV-infected patients [6-7]. However, these studies were conducted in the
early 90’s when HAART was not available. Diarrhea may have implications
on quality of life and, in turn, on adherence. This may influence the
prescribing of antiretroviral regimens. The aim of this study is to estimate
the effect of diarrhea on health related quality of life in HIV-infected
patients receiving HAART.
Methods
Study design
This study used data from two cohort studies of HIV patients and was based
on a case control study design. Cases were taken from a group of patients
enrolled in a prospective observational study conducted in 11 AIDS clinics
in Italy from June 2000 to February 2001. All adult patients experiencing
diarrhea while on HAART were conceived as cases. Controls were taken
from another prospective, observational study conducted in 34 AIDS clinics
in Italy between 1998-99 (the Palladio study) [8]. The Palladio study also
included those 11 clinics participating in the first study, from which cases
were drawn. All patients enrolled in the Palladio study received a HAARTregimen including indinavir. For each case patient, a control patient without
diarrhea and with at least matching CDC-disease stage was selected from
180
the control cohort. Patient quality of life was measured in both studies by
Medical Outcome Study HIV Health Survey questionnaire (MOS-HIV) [ 9].
Patient-related data
As indicated, cases were adult HIV-infected patients (aged 18 years or
older) on HAART, visiting their physician and reporting diarrhea. Patients
enrolled had diarrhea within 7 days of visit. Cases had to be under treatment
with any combination including at least 3 antiretroviral agents in use in the
AIDS clinics at February 2001. All selected controls had a triple
combination including indinavir and the following NRTIs: zidovudine,
lamivudine, stavudine, didanosine, zalcitabine. Demographic and clinical
information such as CD4 cell counts and plasma viral loads were obtained
from both studies.
Cases and controls were classified into one of nine disease stages based on
their clinical presentation (i.e., asymptomatic, symptomatic, AIDS defining
events) and CD4 cell count (<=200 cells/mm3, 200-499 cells/mm3, >=500
cells/mm3).
Severity of diarrhea was defined in four grades: Grade 1: 3 to 5 stools per
day; Grade 2: 5 to 7 stools or 3 to 5 watery stools per day; Grade 3: more
than 7 stools or 5 to 7 watery stools per day; and Grade 4: with more than 7
watery stools per day. Grade 1 diarrhea was considered moderate (mild or
transient or increased looseness per day). From grade 2 to grade 4 diarrhea
was conceived as severe. This classification was based on the assumption
that intensity and duration of diarrhea associated abdominal pain, rarely has
an impact on quality of life higher than fecal incontinence [6]. For this
reason, the number of bowel movements was considered more important for
classifying diarrhea. A number of 5 movements or watery stools per day
was considered relevant for the risk of fecal incontinence and limitation to
social life.
Identification of matched controls
The matched control patients were those that did not report specific adverse
events potentially associated to HAART and/or generic symptoms inducing
the physicians to stop the therapy within the 6 months (i.e. control patients
were asymptomatic or had only negligible symptoms at the moment of
enrollment). The primary matching criterion was disease stage. CD4-cell
counts (within 10 cells/mm3) and the nearest age were used as additional
181
matching criteria if two or more patients matched according to the first
criterion.
MOS-HIV
Cases and controls in both cohorts were invited to complete the MOS-HIV
questionnaire. The MOS-HIV questionnaire was adapted from the SF-20
questionnaire by Wu et al. to address specific quality-of-life issues for
persons with HIV disease by removing questions not relevant to HIVinfected persons and adding questions that assess relevant aspects of health,
specifically for HIV-infected persons [9]. The MOS-HIV questionnaire
measures 10 dimensions of health comprising general health perception,
physical function, role function, social function, cognitive function, bodily
pain, mental health, energy/fatigue, health distress, and quality of life. One
further item assesses health transition. Dimensions of the MOS-HIV are
scored on a 0-100 scale where higher scores indicate better health. The
questionnaire has been validated and adapted in many countries and is
widely used in clinical trials [10].
Statistics
Paired t-test was used to compare MOS-HIV domain-specific quality of life
scores (differences 6 months –baseline) between patients with diarrhea and
their matched controls. All statistical tests were 2-tailed; results with a pvalue of < 0.05 were considered significant.
To confirm the result obtained from the case control study design, a
stepwise linear regression analysis has been performed. All diarrhea and
control patients were taken together and the score in each dimension of
MOS-HIV Health Survey at 6 months was assumed as dependent variable.
The inclusion in the diarrhea group (yes/no) was considered as the
independent variable of major interest. Age, CD4 count, plasma viral load,
gender and CDC disease stage were considered as covariates. The order of
including covariates into the model was based on each covariate’s individual
effect on the squared multiple correlation coefficient (R2).
182
Results
Patient Characteristics
We enrolled 100 and 432 adult HIV-infected patients as cases and potential
controls, respectively. Of these potential controls, 340 patients had a full 6
months follow up. Further, after the exclusion of patients who experienced
adverse events while on HAART, 271 patients remained to be matched to
the 100 cases. A matched control was identified for 96 of the 100 case
patients. No appropriate matches were found for the remaining 4 patients.
Table 1 describes the socio-demographic and clinical characteristics of cases
and matched controls at enrollment.
Patients with
diarrhea
(n = 96)
Patients without
diarrhea
(n = 96)
40.2 ± 6.8
38.4 ± 7.5
68.8%
74.0%
CD4 cell counts
(cells/mm3,
mean ± 1 standard deviation)
341.6 ± 239.0
335.7 ± 221.4
Plasma vRNA load
(thousand copies/mm3,
mean ± 1 standard deviation)
14 ± 89
14 ± 77
32
17
13
13
0
0
96
0
0
0
Patients Characteristics
Age
(mean years ± 1 standard deviation)
Gender
(percent male)
Protease inhibitor regimen (number of
patients)
Nelfinavir
Indinavir
Ritonavir
Saquinavir
Amprenavir
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NNRTI regimen (number of patients)
Efavirenz
Nevirapine
Delavirdine
14
10
2
0
0
0
NRTI regimen (number of patients)
Zidovudine
Lamivudine
Zidovudine + Lamivudine
Stavudine
Didanosine
Zalcitabine
Abacavir
18
59
18
54
13
18
12
37
70
15
52
15
9
0
Table 1. Demographic, clinical and therapeutic characteristics
Patients with diarrhea and their matched controls had the same distribution
over disease stage. Eighteen (18.7%) were in the stage A of CDC 93
classification (stage A1: 14; stage A2: 2; stage A3: 2); thirty-three (34.3%)
were in stage B (stage B1:10; stage B2: 13; stage B3:10); and forty-five
(46.9%) had AIDS (stage C1: 10; stage C2:8; stage C3: 27).
They had similar age (mean 40 ± 7 vs. 38 ±7.5 years), CD4 cell count (342
± 239 vs. 336± 221 cells/mm3), RNA viral load (14,000 ± 89,000 vs. 14,000
± 77,000 copies/mL). About 70% of the patients were male in both groups.
All patients received HAART-regimens including a combination of NRTIs
and a protease inhibitor (or 2 protease inhibitors) or an NNRTI. Lamivudine
and stavudine were the most commonly prescribed NRTIs in both groups.
Among patients with diarrhea, prescribed protease inhibitors included
nelfinavir (n=32), indinavir (n=17), ritonavir (n=13) and saquinavir (n=13).
Four of these patients received both indinavir and ritonavir and 2 patients
received ritonavir and nelfinavir. The NNRTIs prescribed to cases included
efavirenz (n=14), nevirapine (n=10) and delavirdine (n=2). All control
patients received indinavir as a part of their HAART-regimen.
Among the 96 patients with diarrhea, about 51% had severe diarrhea (36
patients with grade 2, 6 with grade 3, 7 with grade 4) and 49% had mild
diarrhea (grade 1).
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Quality of Life Measures
Compared to their matched controls, patients with diarrhea had significantly
lower scores in all 11 MOS-HIV domains. Figure 1 shows the differences in
average MOS-HIV domain scores with 95% confidence intervals for cases
and controls. These differences ranged from 8 for domains, such as physical
and cognitive functioning, to 19 for social functioning. These differences
indicate that HIV-infected patients without diarrhea had significantly better
quality of life compared to patients with diarrhea.
Differences in MOS-HIV Scores
30
20
19*
18*
17*
15*
13*
11*
10
8*
17*
10*
16*
8*
0
GH PF
RF PN SF MH EF HD CF QL HT
MOS-HIV Domains
Legenda: * p < 0.05, Paired t-test.;
general health (GH), physical -function (PF), role-function (RF), social-function (SF), pain
(PN), mental health (MH), energy/fatigue (EF), health distress (HD), cognitive- functioning
(CF), quality of life (QL), health transition (HT).
Figure 1. Differences in MOS-HIV domain scores between patients without
diarrhea and those with diarrhea
185
We also compared the quality-of-life scores between the two groups by their
disease stage. Among AIDS patients, statistically significant differences in
MOS-HIV domain scores were found in 5 domains comprising general
health, social functioning, energy/fatigue, quality of life, and health
transition. Among HIV-positive patients, patients with diarrhea had
significantly lower scores in all domains (Figure 2).
Better
QoL
100
90
MOS-HIV Scores
80
70
60
50
40
30
Worse
QoL
20
GH
PF
RF
PN
SF
MH
EF
MOS-HIV Domains
HD
CF
QL
HT
HIV patients with diarrhea (n = 39)
AIDS patients with diarrhea (n = 57)
HIV patients without diarrhea (n = 39)
AIDS patients without diarrhea (n = 57)
Legenda: general health (GH), physical -function (PF), role-function (RF), social-function
(SF), pain (PN), mental health (MH), energy/fatigue (EF), health distress (HD), cognitivefunctioning (CF), quality of life (QL), health transition (HT).
Figure 2. HIV/AIDS disease stage - specific MOS-HIV domain scores
186
For patients with diarrhea, we also explored the association between
quality-of-life score and the severity of diarrhea. Difference was observed in
2 domains where patients with severe diarrhea had lower scores in role and
social functioning compared to patients with mild diarrhea (Figure 3 ).
Better
QoL
100
MOS-HIV Scores
90
80
70
60
50
40
30
Worse
QoL
20
GH
PF
RF
PN
SF
MH
EF
HD
CF
QL
HT
MOS-HIV Domains
Patients with moderate diarrhea (n = 46)
Patients with severe diarrhea (n = 50)
Legenda: general health (GH), physical -function (PF), role-function (RF), social-function
(SF), pain (PN), mental health (MH), energy/fatigue (EF), health distress (HD), cognitivefunctioning (CF), quality of life (QL), health transition (HT).
Figure 3. MOS-HIV domain scores of HIV infected patients with moderate
and severe diarrhea
Table 2 shows the regression analysis coefficients for each MOS-HIV
domain for cases (n=100) and those patients from the control cohort with
full information available (n=340). The results of the regression analysis
are consistent with those of the case-control analysis. The presence of
diarrhea is always significant with the exception of the domain score for
cognitive function (p = 0,444).
187
MOS-HIV Dimensions
General Health (GH)
Physical Function (PF)
Role Function (RF)
Pain (PN)
Social Function (SF)
Mental Health (MH)
Energy/Fatigue (E/F)
Health Distress (HD)
Cognitive Functioning (CF)
Quality of Life (QL)
β diarrhea
(stepwise)
-28.7
-10.5
-13.6
-13.5
-17.3
-18.3
-26.1
-14.0
-4.2
-31.4
p-value
R2 **
.000
.047
.009
.012
.001
.001
.000
.010
.444*
.000
.166
.110
.149
.058
.152
.093
.177
.073
.017
.139
Legenda:
* p > 0.05;
** full specifications of estimated functions:
GH= -.230*stage -.287*diarrhea.;
PF = -.289*stage -.105*diarrhea;
RF= -.268*stage -.157*viral load -.136*diarrhea;
PN = -.169*stage -.135*diarrhea;
SF = -.208*stage-.108*viral load -.124*gender -.117*age -.173*diarrhea;
MH = -.119*stage -.153*viral load; EF =-.261*diarrhea -.184*stage -.175*viral load.183*diarrhea;
HD = -.154*stage -.109*viral load-.140*diarrhea;
CF = -.128*stage;
QL = -.160*viral load -.314*diarrhea.
Table 2. Results from the regression analysis (regression coefficients and
their significance).
Discussion
Viral suppression is the primary goal of antiretroviral therapy in HIV.
However, improving patient quality of life is a further important objective,
the more as a better quality of life may also influence patients' adherence to
antiretroviral therapy. Using observational data, this study examined the
relationship between diarrhea and HAART and its detrimental effect on
quality of life. Each patient was asked to fill out the MOS-HIV
questionnaire in the time periods considered and a case-control approach
was used, matching by disease severity, CD4 cell count and age. By
controlling for these major characteristics it was possible to assess the likely
impact of diarrhea on quality of life in HIV-patients receiving HAART.
We observed significant differences in quality-of-life outcomes in all MOS188
HIV domains between the case patients and matched controls. Whilst HIVpositive patients with diarrhea had significantly lower score in all domains,
AIDS-patients had statistically significant differences in MOS-HIV domain
scores in only 5 domains. These results are consistent with those published
by other investigators, who also reported different impacts on quality-of-life
outcomes between asymptomatic and AIDS patients after the start of
effective antiretroviral therapy [11]. The role of HAART-related toxicity was
considered a sufficient explanation for decreases in quality of life in
asymptomatic HIV patients. In contrast, the overall positive outcome of
HAART on quality of life is so high in AIDS patients to justify any
concomitant negative effects of HAART-associated toxicity.
In this study, severity of diarrhea was found to be associated with poor
quality of life of HIV-patients. A statistical significant difference was found
between patients with moderate and severe diarrhea in 2 domains of MOSHIV: social function and role function. A similar classification of diarrhea
severity was used by another study [6]. It concluded that diarrhea was
considered severe by patients over the cutoff point of 5 bowel movements
per day. The presence (or the possibility) of fecal incontinence was
considered as the major factor limiting social life and, in turn, affecting
quality of life. A confirmation of this conclusion has also been reported in
studies examining the impact of diarrhea on quality of life in elderly with
gastrointestinal disease [12].
The infection with HIV results in a chronic disease. There is a decline in
functional status and many manifestations and symptoms that may
compromise the sense of well being. Cunningham examined the impact of
constitutional symptoms (weight loss, mialgyas, fever, night sweats,
diarrhea, fatigue/exhaustion) on quality of life of HIV-infected patients.
Diarrhea, weight loss and fever were the symptoms associated with worse
scores of quality of life and with progression of the disease [13]. In an earlier
study, Watchel et al. found that neurologic symptoms, constitutional
symptoms, dyspnea and diarrhea were commonly present among patients
with AIDS [14]. The presence of symptoms was the strongest indicator of
lower MOS-HIV scores in these patients. Similarly, HIV-related symptoms
were found to be strongly associated with physical and mental health in the
HIV-Cost and Service Utilization Study [15]. Health related quality-of-life
measures often include symptoms. In a recent paper, Lorenz examined the
association of several symptoms with two single items global measures of
health related quality of life (i.e. perceived health, perceived quality of life)
189
and an association of diarrhea with worse perceived quality of life was
found [16].
Moderate diarrhea is often underreported by HIV patients to their physicians
[17]
. However, it has been documented that patients with chronic diarrhea
have 50% higher charges resulting from more physician visits and
diagnostic testing and have more disability days and absenteeism [18]. We
note that, in general, use of HAART has reduced morbidity and mortality
[19-21]
and hospital service use [22-23] drastically, in developed countries.
Recent reviews of studies that examined the cost-effectiveness of HAART
regimens concluded that HAART was remarkably cost-effective for the
treatment of HIV infection, despite its sometimes (costly) adverse effects
[24,25]
.
Compared to the use of a randomized-controlled-trial design, in which one
group of patients is on HAART and the other receives placebo, limitations
of our observational design should be noted. In addition, we acknowledge
that in identifying controls comorbidity was not formally taken into account
(e.g. hepatitis comorbidity). Furthermore, control patients may not always
have reported all symptoms to their physicians but, in this case, it would
involve a potential underestimation of the investigated effect. Although
patients are matched according to CDC disease stage, CD4 cell counts, and
age, potential differences such as patient location, treatment history,
socioeconomic status, and other intrinsic characteristics may still exist
between patients who did and did not have diarrhea. However, current
standards in HIV-treatment do not allow the set-up of a clinical trial as
specified above. Therefore, current conclusions should often rely on
observational investigations, such as ours. Furthermore, if the intervention
effect remains sufficiently large after accounting for potential major
confounding factors as we did, it is at least hypothesized that the symptom
(diarrhea) does have an impact on the outcomes (MOS-HIV dimensions)
being analyzed [24].
190
Conclusion
The list of possible etiologies of diarrhea is wide: it may be attributed to
infectious agents, gastrointestinal malignancies, HIV enteropathy, idiopathic
etiology. However, in the era of HAART, medications may be an important
cause of diarrhea in HIV/AIDS- patients. We found that, diarrhea is
associated with lower quality of life in this patient group. Therefore, careful
consideration must be given when choosing antiretroviral medications for
patients infected with HIV in order to reduce the potential incidence of
avoidable drug-induced diarrhea, ensure better quality of life and enhance
treatment adherence.
191
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The members of the Palladio Study group are the followings:
Alessandria: Azzini M, Mantia E; Asti: Biglino A, Degioanni M; Aviano:
Tirelli U, Schioppa O; Belluno: Caruso G; Bologna1: Chiodo F, Borderi M,
Donzelli C; Bologna2: Gritti F, Coronado O; Bolzano: Mian P, Paternoster
C; Brescia: Carosi G, Torti C; Como: Vigevani GM, Pusterla L; Cremona:
Carnevale G; Ferrara: Ghinelli F, Carradori S; Forlì: Cancellieri C;
Genova1: Piersantelli N, Lorusso C; Genova2: Bassetti D; Genova3:
Pagano G, Camera M; Legnago (VR) Parrinello A, Rovere P; Mantova:
Scalzini A, Alessi F; Mestre: Borri A, Panese S; Milano1: Milazzo F,
Rizzardini G; Milano2, Cargnel M, Grisetti R; Modena: Esposito R, Del
Borgo C; Rovigo: Carretta M, Masiero G; Padova: Meneghetti F, Scanio F;
Pavia: Filice G, Patruno S; Schio (VI): Marranconi F, Merighi M; Torino1:
Soranzo ML, Macor A; Torino2: Di Perri G, Trieste: Mascioli M, Errera G;
Treviso: Vaglia A, Zanatta A; Trento: Mian P, Paternoster C, Dorigoni N;
Udine: Ciccone L, Panzolli L; Vicenza: De Lalla F; Venezia: Rosini G;
Verona: Concia E, Dal Bravo P.
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