Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia

Article (PDF Available)inAIDS 21(17):2293-301 · December 2007with33 Reads
DOI: 10.1097/QAD.0b013e32828cc8b7 · Source: PubMed
Abstract
African and Asian cohort studies have demonstrated the feasibility and efficacy of HAART in resource-poor settings. The long-term virological outcome and clinico-immunological criteria of success remain important questions. We report the outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Médecins Sans Frontières/Ministry of Health programme in Cambodia. Adults who started HAART 24 +/- 2 months ago were included. Plasma HIV-RNA levels were assessed by real-time polymerase chain reaction. Factors associated with virological failure were analysed using logistic regression. Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline, 95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass index less than 18 kg/m. The median CD4 cell count was 11 cells/microl. A stavudine-lamivudine-efavirenz-containing regimen was initiated predominantly (81.0%). At follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell counts greater than 200 cells/microl and 306 (88.4%) had viral loads of less than 400 copies/ml. Factors associated with virological failure at 24 months were non-antiretroviral naive, an insufficient CD4 cell gain of less than 350 cells/microl or a low trough plasma ART concentration. In an intention-to-treat analysis, 73.6% of patients were successfully treated. Positive results after 2 years of advanced HIV further demonstrate the efficacy of HAART in the medium term in resource-limited settings.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Positive outcomes of HAART at 24 months in
HIV-infected patients in Cambodia
Laurent Ferradini
a,b
, Didier Laureillard
b,c
, Narom Prak
d
,
Chanchhaya Ngeth
d
, Marcelo Fernandez
b
, Loretxu Pinoges
a
,
Gloria Puertas
a
, Anne-Marie Taburet
e
, Nary Ly
f
, Christine Rouzioux
g
,
Suna Balkan
b
, Catherine Quillet
b
and Jean-Franc¸ois Delfraissy
h,i
Objectives: African and Asian cohort studies have demonstrated the feasibility and
efficacy of HAART in resource-poor settings. The long-term virological outcome and
clinico-immunological criteria of success remain important questions. We report the
outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Me
´
decins
Sans Frontie
`
res/Ministry of Health programme in Cambodia.
Methods: Adults who started HAART 24 2 months ago were included. Plasma HIV-
RNA levels were assessed by real-time polymerase chain reaction. Factors associated
with virological failure were analysed using logistic regression.
Results: Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline,
95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass
index less than 18 kg/m
2
. The median CD4 cell count was 11 cells/ml. A stavudine
lamivudineefavirenz-containing regimen was initiated predominantly (81.0%). At
follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had
died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of
survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell
counts greater than 200 cells/ml and 306 (88.4%) had viral loads of less than 400 copies/
ml. Factors associated with virological failure at 24 months were non-antiretroviral
naive, an insufficient CD4 cell gain of less than 350 cells/ml or a low trough plasma ART
concentration. In an intention-to-treat analysis, 73.6% of patients were successfully
treated.
Conclusion: Positive results after 2 years of advanced HIV further demonstrate the
efficacy of HAART in the medium term in resource-limited settings.
ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2007, 21:22932301
Keywords: antiretroviral therapy, Cambodia, HIV, observational cohort,
outcomes
Introduction
African and Asian cohort studies have demonstrated the
feasibility and efficacy of HAART in resource-poor
settings [18]. Adherence to treatment in these settings
was found to be as good or even better than that observed
in northern countries [1,2]. Even if early adherence to
HAART appears to be a crucial factor to ensure
From the
a
Epicentre, Paris, France, the
b
Me
´
decins Sans Frontie
`
res, Paris, France, the
c
Immunological Department, Georges
Pompidou, European Hospital, Paris, France, the
d
Infectious Disease Department, Khmero-Sovietic Friendship Hospital, Phnom
Penh, Cambodia, the
e
Clinical Pharmacy Department, Ho
ˆ
pital Bice
ˆ
tre, Assistance Publique Ho
ˆ
pitaux de Paris, France, the
f
Institut
Pasteur du Cambodia, Phnom Penh, Cambodia, the
g
HIV/Hepatitis laboratory, CHU Necker, EA 3620 Universite
´
Paris-Descartes,
Paris, France, the
h
Clinical Immunology Department, Bice
ˆ
tre Hospital, Kremlin Bice
ˆ
tre, France, and the
i
Agence Nationale de
Recherches sur le Sida, Paris, France.
Correspondence to Laurent Ferradini, Me
´
decins Sans Frontie
`
res, 8 rue Saint-Sabin, 75011 Paris, France.
E-mail: msffr.comed@online.com.kh
Received: 11 February 2007; revised: 7 May 2007; accepted: 11 May 2007.
ISSN 0269-9370 Q 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
2293
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
immunovirological success [9], however, adherence
remains a dynamic process [10] and concerns about its
long-term maintenance at optimal levels in sub-Saharan
Africa have recently been raised [11]. In addition, the
occurrence of progressive antiretroviral drug side effects
might also impair long-term adherence and virological
outcomes of the patients.
Reports on medium or long-term cohorts of patients on
HAART in resource-poor settings are still scarce [6,7],
and are still performed on only a limited number of
patients.
With an estimated HIV prevalence of 1.9% of the adult
population (1549 years) at the end of 2003 and 126 000
individuals living with HIV, Cambodia presents one of
the highest HIV prevalences in south-east Asia [12,13].
Access to antiretroviral therapy (ART) is still limited, and
up to end of June 2006, almost 16 000 of the 30 000
patients supposed to be in immediate need effectively
received ART [14]. The present study aimed to assess
patient outcomes 24 months after HAART initiation in a
Me
´
decins Sans Frontie
`
res (MSF)/Ministry of Health
(MoH) observational cohort in Phnom Penh, Cambodia,
by analysing survival indicators, CD4 cell count
evolution, virological response and pharmacological
characteristics.
Methods
Setting
In collaboration with the MoH of Cambodia, MSF began
an HIV programme in 1997 supporting the Infectious
Disease Department of the Khmero-Sovietic Friendship
(KSF) Hospital in Phnom Penh. The project involved
MoH staff (eight physicians, 17 nurses) and MSF staff (two
physicians, one nurse, four counsellors, two pharmacists),
training, patient education, social support, and adherence
consultations for information and education about HIV/
AIDS disease and treatment. A peer support group was
created to support patient advocacy issues and to
participate in the activities of the clinic. Since 2001,
HAART was offered free of charge to patients either at
World Health Organization (WHO) stage IV (AIDS)
irrespective of CD4 cell count or at WHO stages I, II or
III with CD4 cell counts of 200 cells/ml or less according
to WHO recommendations [15]. Preparation for
HAART initiation is accomplished by three pre-HAART
counselling visits. The initial rst-line regimen proposed
was the association of stavudine, lamivudine and
efavirenz. Patients with intolerance to this combination
were offered other alternative rst line regimens. Clinical
follow-up visits were performed monthly for the rst 6
months then bimonthly. The CD4 T-cell count was
monitored every 6 months and no individual viral load
monitoring was available. Adherence support was
provided at each visit by counsellors through individual
interviews or talk groups. In the case of treatment
failure, a protease inhibitor-based second-line treatment
was available as recommended by WHO [15].
At the end of March 2005, 2048 HIV-infected adult
patients were still on HAART in the programme.
Study population
All adults, aged 18 years or more, who had initiated
HAART for 24 2 months at the date of analysis (31
March 2005) were eligible for the study. Medical
background and follow-up information were routinely
collected at each consultation and entered into FUCHIA
monitoring software (Follow-Up and Care of HIV
Infection and AIDS, Epicentre, Paris).
Cross-sectional survey
Between 13 December 2004 and 31 March 2005, a cross-
sectional survey was conducted to assess the clinical,
adherence and virological status of all patients who had
been receiving HAART for 24 2 months and presented
to the HIV clinic during the study period. CD4 cell
counts were performed using ow cytometry (Facscount;
Beckton Dickinson, Franklin Lakes, New Jersey, USA) at
the Institut Pasteur du Cambodge. Plasma viral load
measures were performed on 808C frozen samples at
the HIV/Hepatitis laboratory, Necker Enfants Malades
Hospital (Paris, France), using real-time polymerase chain
reaction technology, which allows the quantication of
HIV-1 non-B subtypes including those circulating in Asia
[1618]. Positive samples from Thailand and Cambodia
have been studied in parallel with the Cobas Amplicor
HIV-1 Monitor v1.5 test (Roche Diagnostic Systems,
Pleasanton, California, USA) and gave highly correlated
results (data not shown). For viral loads above 400 copies/
ml, HIV-1 reverse transcriptase (RT) genotyping was
performed at the Institut Pasteur du Cambodge [19]. The
resistance proles to antiretroviral molecules were dened
according to Agence Nationale de Recherches sur le Sida
(ANRS) algorithms [20].
Trough plasma concentrations of nevirapine and lopinavir
or 12 h post-dose concentrations of efavirenz were
measured at the Clinical Pharmacology Department,
Bice
ˆ
tre Hospital (Kremlin Bice
ˆ
tre, France) using vali-
dated high performance liquid chromatography assay
[21,22]. Patients were classied by to their trough plasma
concentrations according to the following therapeutic
windows: nevirapine (30008000 ng/ml), efavirenz
(10004000 ng/ml) and lopinavir (30008000 ng/ml)
[23].
The survey was approved by the National Ethics
Committee for Health Research of Cambodia on 3
December 2004. All participants gave their written
informed consent.
2294 AIDS 2007, Vol 21 No 17
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Statistical analysis
Product-limit estimates (KaplanMeier) of survival were
determined for all patients on an intention to treat basis.
Patients alive and in care on 31 March 2005 were right-
censored on the date of their last visit before this date.
Patients who had not attended services for 2 months or
more beyond their last scheduled appointment were
classied as being lost to follow-up, and statistically
considered on their last recorded visit to the clinics. CD4
cell gains were calculated every 6 months after HAART
initiation. Logistic regression analysis was performed to
identify factors associated with viral loads greater than
1000 copies/ml 24 months after HAART initiation.
Variables with a P < 0.05 were included in the multi-
variate analysis. Receiver operating characteristic (ROC)
curve analysis was performed to dene the threshold of
percentage CD4 cell gain between month 12 and month
24, which gives optimum sensitivity and specicity for
the detection of viral load greater than 1000 copies/ml.
Analyses were performed using STATA 8.2 software
(Stata Corp., College Station, Texas, USA).
Results
Among the 2048 HIV-infected patients who were on
HAART up to 31 March 2005 in the programme, 416
adults had started 24 2 months earlier and were
included in the analysis (M24 cohort, Fig. 1). A total
of 247 (59.2%) were men and the median age was 33.6
years [interquartile range (IQR) 30.138.2; Table 1].
Almost all (396/416, 95.2%) were ART naive. Most were
already at an advanced stage of HIV disease when entering
the programme: 192 (46.0%) were at WHO stage III
and 204 (48.9%) were at WHO stage IV. The body
mass index (BMI) was below 18.0 kg/m
2
for 161 out of
387 patients (41.6%) and was below 15.0 kg/m
2
for 40
out of 387 patients (10.3%). Patients were severely
immunocompromised, with a median baseline CD4 cell
count of 11 cells/ml (IQR 360, n ¼ 416) and 297 out of
416 patients (71.4%) had a CD4 cell count below 50 cells/
ml. A total of 337 patients (81.0%) received a rst-line
antiretroviral regimen associating stavudine, lamivudine
and efavirenz, whereas 64 (15.4%) received stavudine,
lamivudine and nevirapine, and 15 (3.6%) received
another rst-line regimen (Table 1).
Clinico-immunological outcomes and patient
survival
The median time of follow-up was 23.8 months (IQR
22.824.0). Among the 416 patients included, 53
patients (12.7%) had died, seven (1.7%) were lost to
follow-up, six (1.4%) were transferred and 350 (84.1%)
still remained on HAART.
Estimates of survival given by the KaplanMeier method
were 0.87 at 12 months [95% condence interval (CI)
0.830.90] and 0.85 at 24 months (95% CI 0.810.88)
when death events were taken into account exclusively
(Fig. 2). Two-thirds of the deaths (35/53, 66.0%)
occurred within the rst 6 months after HAART
initiation (median time to death 3.6 months, IQR
1.79.8).
Positive outcomes of HAART in Cambodia Ferradini et al. 2295
M24 cohort
All adults who started ART
between 11 oct 2002 and 31 may 2003
n = 416
Patients followed on ART after 24 months
n = 350 (84.1%)
Patients included in the
cross-sectional
assessment
n = 346
Deaths n = 53
Lost to follow-up n = 7
Transfer n = 6
Not included
n = 4 (3 refusals)
Fig. 1. Details of the M24 cohort. ART, Antiretroviral
therapy.
Table 1. Baseline characteristics of the patients of the M24 cohort.
Characteristics M24 cohort (N ¼ 416)
Demography
Male [in (%)] 247 (59.2)
Median age [years (IQR)] 33.6 (30.138.2)
ART naive [n (%)] 397 (95.2)
Clinico-immunology
WHO stage at HAART initiation
Stage I/II [n (%)] 21 (5.0)
Stage III [n (%)] 192 (46.0)
Stage IV [n (%)] 204 (48.9)
Body mass index (n) 387
Median [kg/m
2
(IQR)] 18.6 (16.420.4)
< 18 kg/m
2
[n (%)] 161 (41.6)
< 15 kg/m
2
[n (%)] 40 (10.3)
CD4 T-cell counts at initiation (n) 416
Median cells/ml[n (IQR)] 11 (360)
Count < 50 cells/ml[n (%)] 297 (71.4)
Treatment
Initial antiretroviral treatment
d4T/3TC/EFV [n (%)] 337 (81.0)
d4T/3TC/NVP [n (%)] 64 (15.4)
ZDV/3TC/NVP [n (%)] 4 (0.9)
ZDV/3TC/EFV [n (%)] 6 (1.4)
ZDV/3TC/LPV [n (%)] 3 (0.7)
d4T/3TC/LPV [n (%)] 2 (0.5)
Follow-up time on HAART (months)
Median for all patients (IQR) 23.8 (22.824.0)
Outcomes
Deaths [n (%)] 53 (12.7)
Lost to follow-up [n (%)] 7 (1.7)
Transfers [n (%)] 6 (1.4)
Still on HAART [n (%)] 350 (84.1)
ART, Antiretroviral therapy; d4T, stavudine; EFV, efavirenz; IQR,
interquartile range; LPV, lopinavir; NVP, nevirapine; 3TC, lamivu-
dine; WHO, World Health Organization; ZDV, zidovudine.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Among patients with available CD4 cell counts at baseline
(n ¼ 416), the median CD4 cell gain was found to be
þ101 cells/ml (IQR 62137) at 6 months (n ¼ 344),
þ154 cells/ml (IQR 95217) at 12 months (n ¼ 337) and
þ233 cells/ml (IQR 156332) at 24 months (n ¼ 346;
Table 2). Alhough they presented with a very low baseline
CD4 cell count, 259 out of 346 patients (74.9%) had a
CD4 cell count greater than 200 cells/ml at 24 months.
Cross-sectional virological survey of patients
continuing HAART
Among the 350 patients still on treatment after 24 2
months at the date of analysis, four could not be included
(three refusals, one out of time) and 346 were assessed
virologicaly (Fig. 1). Among them, 86 (24.8%) were on
stavudinelamivudineefavirenz, 74 (21.4%) were on
zidovudinelamivudineefavirenz, 115 (33.2%) were
on stavudinelamivudinenevirapine, 50 (14.4%) were
on zidovudinelamivudinenevirapine and 10 (2.9%)
were on other alternative rst-line regimen. Only 11
patients (3.2%) were on a protease inhibitor-based
regimen (lopinavir/ritonavir).
Viral loads were below 40 copies/ml for 276 out of 346
patients(79.8%),were below 400 copies/mlfor306(88.4%)
and below 1000 copies/ml for 315 (91.0%). Among the
40 patients with a viral load above 400 copies/ml (11.6%),
only 15 (4.3%) were above 30 000 copies/ml, correspond-
ing to major virological failure (Table 3).
Overall, in intention-to-treat analysis of the whole M24
cohort (n ¼ 416) taking into account both deaths, loss to
follow-up and missing data (Fig. 1) as treatment failures,
66.3% (95% CI 61.570.8) and 73.6% (95% CI 69.0
77.7) of treatment successes were observed when
considering viral loads as failures when above 40
copies/ml or 400 copies/ml, respectively.
HIV reverse transcriptase genotyping was performed for
the 40 patients with viral loads above 400 copies/ml.
Among interpretable sequences (n ¼ 39), 10 (25.6%) did
not show any drug-resistance-associated mutations, 23
(59.0%) presented with nucleoside reverse transcriptase
inhibitor (NRTI) resistance mutations, and 28 (71.8%)
presented with non-nucleoside reverse transcriptase
inhibitor (NNRTI) resistance mutations. The most
frequent NRTI mutation was the lamivudine-induced
M184V mutation (23/39), the stavudine-induced
T215Y/F mutation (9/39), the T69D/N (7/39) and
the D67N (7/39) mutations. Among NNRTI mutations,
K103N (15/39), Y181C/I (8/39) and G190A/S (8/39)
were most frequently observed (Fig. 3). According to
ANRS algorithms [20], 12 patients with a viral load greater
than 400 copies/ml were resistant to both zidovudine,
lamivudine, stavudine and nevirapine/efavirenz.
Antiretroviral concentrations
The median concentration of efavirenz for 169 patients
was 2946 ng/ml (range < 5031 559 ng/ml), with seven
2296 AIDS 2007, Vol 21 No 17
Time of follow-up (months)
At 12 months
0.87
(95% CI 0.83–0.90)
Probability of survival
0.00
0.25
0.50
0.75
1.00
10020
At 24 months
0.85
(95% CI 0.81–0.88)
Fig. 2. KaplanMeier curve showing the probability of sur-
vival of the patients from the M24 cohort. CI, Condence
interval.
Table 2. Immunological restoration of patients from the M24 cohort.
Baseline
n ¼ 416
6 months
n ¼ 344
12 months
n ¼ 337
18 months
n ¼ 312
24 months
n ¼ 346
CD4 cell count (median cells/ml) 11 134 193 240 274
(IQR) (360) (90198) (139263) (160324) (199371)
% With CD4 cell count
< 50 cells/ml 71.4 6.7 0.9 1.3 0.9
< 200 cells/ml 98.8 75.6 51.9 35.6 25.1
CD4 cell count gain (median cells/ml) þ101 þ154 þ194 þ233
(IQR) (62137) (95217) (131278) (156332)
IQR, Interquartile range.
Table 3. Viral load measures of patients from the M24 cohort
included in the cross-sectional virological survey (n U 346).
Viral load (copies/ml) N % 95% CI Cumulative %
< 40 276 79.8 75.183.9 79.8
40400 30 8.7 6.012.3 88.4
4001000 9 2.6 1.35.1 91.0
10005000 7 2.0 0.94.1 93.0
500030 000 9 2.6 1.35.1 95.7
30 000 15 4.3 2.57.2 100.0
Total 346 100
CI, Condence interval.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
patients (4.1%) having efavirenz levels either undetec-
table (n ¼ 4) or less than 1000 ng/ml (n ¼ 3) and 47
(27.8%) having levels greater than 4000 ng/ml. Median
trough nevirapine concentrations in 165 patients were
5643 ng/ml (range < 2516 971 ng/ml), with two
patients undetectable (1.2%), six patients (3.6%) with
nevirapine levels less than 3000 ng/ml and 21 (12.7%)
with levels greater than 8000 ng/ml. For the 11 patients
on lopinavir/ritonavir at the time of the study, the median
trough plasma concentration of lopinavir was 4962 ng/ml
(range 22158797 ng/ml) with only one patient less than
3000 ng/ml.
Among the 15 patients with low NNRTI trough or 12-h
concentrations at month 24, seven had a viral load
greater than 1000 copies/ml (47%). Among them, three
displayed a wild-type HIV strain with neither NRTI nor
NNRTI-induced RT mutations and had a viral load
greater than 30 000 copies/ml. On the other hand, when
considering patients with high trough plasma antiretro-
viral concentrations, none among the 21 patients who
had high nevirapine concentrations and three out of 47
patients (6.4%) with high efavirenz levels were found to
have a virological failure.
Side effects of patients from the M24 cohort
As a result of drug intolerance, nine patients from the
M24 cohort (2.2%) stopped zidovudine (eight for
anaemia, and one for anaemia and neutropenia), 131
(31.5%) stopped stavudine (50 for neuropathy, 71 for
lipodystrophy, nine for both neuropathy and lipodystro-
phy, and one for mitochondrial toxicity), and four
stopped HAART because of mitochondrial toxicity.
Considering NNRTI, three patients (0.7%) stopped
efavirenz (one for neuropsychiatric disorders and two for
gynaecomasty), and 13 (3.1%) stopped nevirapine (one
for hepatitis, eight for hypersensibility and three for severe
cutaneous rash). The median duration before stopping
the drug was 93 days (IQR 63140) for zidovudine,
13.9 months (IQR 11.816.7) for stavudine, 22 days
(IQR 1228) for nevirapine and between 10 and 674
days for efavirenz (n ¼ 4).
Factors associated with a viral load greater than
1000 copies/ml at 24 months
In order to identify patients at risk of having a detectable
viral load, we analysed the association of distinct factors
present either at baseline, at 12 or at 24 months with a
viral load greater than 1000 copies/ml at 24 months. The
aim here was more to identify the group of patients
potentially needing a decision to switch their treatment
than describing factors associated with virological failures.
For this reason, and because of the well-known existence
of virological blips, we chose 1000 copies/ml as a
reasonable threshold. Higher viral load thresholds could
not be tested because of too small sample sizes.
Using univariate logistic regression analysis, the following
factors were found to be associated with viral loads
greater than 1000 copies/ml at 24 months: age greater
than 35 years (P ¼ 0.008), previous antiretroviral
exposure (P ¼ 0.004), CD4 cell count less than 200
cells/ml(P ¼ 0.001) or between 200 and 350 cells/ml
(P ¼ 0.041), an opportunistic infection between months
9 and 24 (P ¼ 0.041), low plasma antiretroviral concen-
trations at month 24 (P < 0.001) and an insufcient
percentage CD4 cell gain at month 24 (P < 0.001). On
the other hand, hospitalization between months 9 and 24,
antiretroviral drug stops, weight loss between months 12
and 24, BMI at month 24 or being on HAART second
line at month 24 were not statistically associated with a
viral load greater than 1000 copies/ml (Table 4). Other
factors such as sex (P ¼ 0.7) or being a smoker (P ¼ 0.57)
were also not associated. Finally, no criteria present at
month 12 among the following were found to be
predictive of a viral load greater than 1000 copies/ml at
month 24: CD4 cell count (P ¼ 0.68), CD4 cell gain
(P ¼ 0.7), percentage CD4 cell gain (P ¼ 0.14), weight
gain between months 0 and 12 (P ¼ 0.16) or between
months 6 and 12 (P ¼ 0.1).
Positive outcomes of HAART in Cambodia Ferradini et al. 2297
NRTI
NNRTI
15
10
5
0
5
10
15
20
M41L
E44D
K65R
D67N
T69D/N
K70R V75M/T
Y115F
Y181C
L100I
K101E
K103N
V106
Q151M
M184V
C/H/L
Y188
G190A/S
L210W
T215
F/I/S/Y
K219E/Q
P225H
25
Fig. 3. Most frequently found mutations. NNRTI, Non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse
transcriptase inhibitor.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
In the multivariate logistic regression model, evident
interactions between CD4 cell level at month 24 and
percentage CD4 cell gain between months 12 and 24
(M12M24%CD4 gain) were taken into account and a
new variable combining both CD4 cell count and
percentage CD4 cell gain was introduced in the model
(Table 4). Finally, three independent factors at month 24
remain positively associated with a viral load greater
than 1000 copies/ml (Table 4): previous antiretroviral
exposure [odds ratio (OR) 12.6, 95% CI 2.662.8,
P ¼ 0.002], low plasma antiretroviral concentrations at
month 24 (OR 11.1, 95% CI 2.648.4, P ¼ 0.001), and
having both a CD4 cell count less than 350 cells/ml and a
M12M24%CD4 gain of þ23% or less (OR 10.6, 95%
CI 2.251.7, P ¼ 0.003).
ROC curve analysis was used to dene this cut-off of
M12M24% CD4 gain giving the highest sensitivity and
specicity for the detection of viral loads greater than
1000 copies/ml. The percentage CD4 cell gain cut-off at
23% gave optimal sensitivity (66.7%, 95% CI 46.083.5)
and specicity (73.4%, 95% CI 68.078.3).
When combining such criteria to improve the detection
of patients with viral loads greater than 1000 copies/ml
at 24 months, we found that the following association was
2298 AIDS 2007, Vol 21 No 17
Table 4. Logistic regression analysis showing odds ratios for factors associated with virological failure (> 1000 copies/ml) of patients from the
M24 cohort, Phnom Penh, Cambodia (n U 346).
Univariate analysis OR (95% CI) Multivariate analysis OR (95% CI)
Sex
Male 1
Female 1.2 (0.52.4)
Age (years)
< 35 1
35 2.9 (1.36.5) 2.5 (0.96.6)
Previous ART exposure
No 1
Yes 5.3 (1.716.5) 12.6 (2.662.8)
Body mass index
a
(kg/m
2
)
18.5 1
< 18.5 0.8 (0.32.3)
CD4 cell count
a
(cells/ml)
350 1
200350 4.8 (1.121.9)
< 200 11.7 (2.652.5)
M12M24% CD4 cell gain (%)
> þ23 1
þ23 5.4 (2.312.6)
CD4 cell count at M24 & M12M24% CD4 cell gain
CD4 > 350 1
CD4 < 350 & % CD4 cell gain > þ23 2.6 (0.512.7) 2.2 (0.412.0)
CD4 < 350 & % CD4 cell gain þ23 13.1 (2.958.3) 10.6 (2.251.7)
Plasma ART concentrations
Within the therapeutic window 1
Low 11.3 (3.733.8) 11.1 (2.648.4)
On HAART second line
a
No 1
Yes 1.5 (0.212.3)
No. of drug stops
b
01
1 1.1 (0.52.3)
2 0.7 (0.15.4)
Hospitalization
b
No 1
Yes 1.9 (0.74.8)
Opportunistic infection
b
No 1
Yes 3.4 (1.111.3) 3.6 (0.717.5)
M12M24% weight loss (%)
< 51
5 1.0 (0.42.6)
Smoker
No 1
Yes 0.8 (0.351.8)
ART, Antiretroviral therapy; CI, condence interval; OR, odds ratio.
a
At 24 months.
b
Between 9 and 24 months.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
optimal: previous exposure to ART, or CD4 cell count at
month 24 less than 350 cells/ml and a M12M24%CD4
gain of þ23% or less. Using such combined criteria
greatly improved the sensitivity (74%, 95% CI 53.788.9)
with a similar specicity (75%, 95% CI 69.379.4). The
positive and negative predictive values were 20.6%
(95% CI 13.130.0) and 97% (95% CI 93.998.8),
respectively.
Discussion
The present analysis of 416 patients performed 24 months
after HAART initiation in Cambodia found 75% of
treatment successes (patients still followed with a viral load
< 400 copies/ml) in an intention-to-treat analysis and a
0.85 probability of survival at 24 months. Such favourable
outcomes are similar or even better than those reported so
far in western cohorts [24,25], and are remarkable given
the extreme severity of the disease at HAART initiation
(see Table 1) in such a resource-limited setting.
Intensive therapeutic education, counselling and psycho-
social support might explain the very low rate of lost-to-
follow-up patients observed. Such a result was obtained
given an important investment in the recruitment and
training of counsellors. Human resources remain a key
factor in resource-limited settings. As already reported by
other studies in similar settings [6,2631], most of the
deaths occurred during the rst 6 months after HAART
initiation. Advanced clinical stage and low CD4 cell counts
might explain such an increased early mortality. Difculties
in managing opportunistic infections as a result of late
presentation or limited diagnostic and therapeutic tools as
well as malnutrition or immune reconstitution syndrome
might also have played a role in worsening the prognosis of
such patients [3134]. Noteworthy is the fact that 20.4% of
the patients analysed had either nevirapine or efavirenz
concentrations above the therapeutic range without
apparent impairment of their tolerance to the antiretroviral
regimen. The reasons for such high concentrations are
still unclear and do not seem to be related to the low
weight of Asian patients compared with western patients
[35,36].
Progressive immune restoration was observed over time
(Table 2) similar to that reported in similar settings [6,26
28,37] or even in high-income countries for similar
patients [26,38]. It is, however, noteworthy that after 2
years a quarter of the patients remained below 200 CD4
cells/ml probably partly because of late HAART initiation
with very low baseline CD4 cell counts. It has been
reported that patients with poor immune reconstitution
at 6 months (CD4 cell count < 100 cells/ml) have a high
risk of an AIDS-dening event or progression to death at
5 years [39]. As in our case, the long-term outcomes of
patients still below 200 CD4 cells/ml at 24 months remain
largely unknown. Further studies are clearly warranted in
resource-limited settings in order to determine the long-
term outcomes of these patients and understand the
factors governing such poor immune restoration.
The virological results of the M24 cohort revealed that
among 346 patients, 40 (11.6%) presented with a
detectable viral load (> 400 copies/ml), and only 15
(4.3%) were above 30 000 copies/ml. Overall, among
patients with detectable viral loads, 25.6% did not have
any ART-induced RT HIV mutations and three had low
NNRTI trough plasma concentrations corresponding to
non-adherent patients. The mutations observed for the
other patients were those expected under the rst-line
regimen used, and the great majority of patients were
already resistant to nevirapine/efavirenz (93%) or
lamivudine/emtricitabine (79%) (Fig. 3). Overall, these
observations are similar to other rst-line cohort studies
in resource-limited settings describing HIV-1 RT
mutation patterns [7,27,40]. This stresses the importance
of keeping available several distinct second-line molecules
in such settings, and calls upon the international
community to make them really and rapidly affordable.
In this study, genotyping analysis allowed the detection of
non-adherent patients and the selection of appropriate
second-line regimens when necessary. Empiric second-
line regimens given according to the type of rst-line
treatments will have to be evaluated through HIV
genotyping pilot studies.
In any case, the decision of when to switch remains
critical in order to avoid the accumulation of HIV
mutations and preserve the efcacy of the limited number
of second-line molecules available. In resource-poor
settings where access to viral load is largely limited, better
identifying groups of patients at risk of treatment failure
might help design accurate viral load monitoring
strategies. For operational reasons and because of the
existence of potential virological blips, we have chosen
1000 copies/ml as a reasonable threshold in order to
identify the group of patients potentially needing to
switch to a second-line regimen. Logistic regression
analysis revealed that previous ARTexposure or CD4 cell
counts still less than 350 cells/ml with a CD4% gain of less
than þ23% between months 12 and 24 were two factors
strongly associated with viral loads greater than 1000
copies/ml at 24 months. It is noteworthy that no other
characteristics of the patients either at baseline, and
specically the CD4 cell count, or at 12 months of
follow-up were found to be associated with viral loads
greater than 1000 copies/ml at 24 months. A test using
both criteria to identify patients with viral loads greater
than 1000 copies/ml gave a 74% sensitivity, a 74%
specicity and a 21% positive-predictive value. Using
more stringent criteria closer to those recommended by
WHO (a decrease in CD4 cell gain > 30% between
months 12 and 24) gave a lower sensitivity (26%, 95% CI
1146) with a higher specicity (98%, 95% CI 9699)
Positive outcomes of HAART in Cambodia Ferradini et al. 2299
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and only a 54% (95% CI 2581) positive-predictive value.
Therefore, if a decision to switch was made only
according to such stringent criteria, half of the patients
would have been switched inappropriately, and most
patients with viral loads greater than 1000 copies/ml
would have been missed. These observations clearly
emphasize that deciding to switch solely on the basis of
immunological criteria is not an acceptable option and
might even be costly to the programme. Using less
stringent criteria allows the identication of a larger
group of patients including most patients with a viral load
greater than 1000 copies/ml and for whom viral load tests
could be proposed in order to help appropriate decision
making. Such a strategy clearly strengthens the need to
improve access to affordable viral load testing in resource-
limited countries [41].
Data from all patients on HAART for more than 24
months (N ¼ 1036) in this MSF/MoH HIV programme
indicate that almost 25.9% (n ¼ 218) would have fullled
the criteria dened above and would have been proposed
a viral load. Among them, approximately 50 viral loads
greater than 1000 copies/ml would have been detected,
whereas other patients would have had undetectable viral
loads. In settings where viral load access is limited, such a
strategy identifying patients at risk of failure could be
useful to restrict the number of viral loads proposed. Our
analysis is still preliminary, however, and needs to be
strengthened by further studies on larger numbers of
patients. In addition, it appears that the criteria for
suspecting failure might vary greatly according to the
duration of follow-up. Studies analysing success/failure
criteria at distinct timepoints after HAART initiation are
on the way in other MSF programmes.
A model to monitor the virological efcacy of HAART
in resource-limited settings has recently been proposed by
Colebunders et al. [42]. This interesting proposal, mainly
based on patientsclinical history, remains to be validated
and will have to take into account that a large number of
patients still have CD4 cell count less than 200 cells/ml
with WHO stage III or IV manifestations even after
2 years of follow-up. Cost-effectiveness analyses would
also be important to compare the selective viral load
approach with a systematic viral load approach
(proposing a viral load once a year for all patients, for
example) in settings where viral load access and second-
line regimen availability are limited. As a result of the still
high cost of second-line regimens and the complete lack
of a third line in resource-poor settings, further studies
are clearly warranted to determine the appropriate
timepoint for switching to second line, not too early
(being aware of poor adherence) but not too late
(precluding the accumulation of HIV mutations, which
impairs the choice among the limited number of second-
line molecules). The efcacy of second-line regimens
chosen without genotyping information is currently
being assessed in Cambodia.
Acknowledgement
The authors thank Dr Jean-Marc Reynes who was the co-
supervisor of N.Ly.s PhD thesis. They would also like to
thank all the people involved in the study and in the
implementation of the programme at the KSF Hospital
including the MoH of Cambodia, the personnel of the
KSF Hospital, the MSF staff and MSF headquarters. They
would also like to thank the patients and their families for
their participation in the study.
Contributors: D. Laureillard, L. Ferradini, S. Balkan and
J.F. Delfraissy contributed to the study concept and
design. L. Ferradini was the study coordinator. N. Prak,
C. Ngeth, M. Fernandez and G. Puertas actively collected
data in the eld. C. Rouzioux and N. Ly performed
the virological evaluation. A.M. Taburet performed the
pharmacological analysis. L. Ferradini and L. Pinoges
performed the statistical analysis. D. Laureillard, C.
Quillet, L. Ferradini, and J.F. Delfraissy led the writing of
the paper, and all investigators participated in its nal
writing and editing.
The results were presented in part at the International
AIDS Society Conference, Rio de Janeiro, Brazil, in July
2005.
Sponsorship: The study was funded by Sidaction (grant
no. 617-001-00/A015-2) and Me
´
decins Sans Frontie
´
res.
Conflicts of interest: None.
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Positive outcomes of HAART in Cambodia Ferradini et al. 2301
    • "Studies from Cambodia documented the outcomes of ART for short and medium term; the incidence of mortality was 9.1 per 100 person-years which is similar to international standards [31], the two year retention estimate was 85.5% both in a cohort of 416 patients treated in a Médecins Sans Frontières/Ministry of Health program [32], and in a larger cohort of the Sihanouk Hospital Center of HOPE, Phnom Penh [13]. The national program of Vietnam reported retention rates after 6, 12, 24, and 36 months as 88.4% [95% CI: 86.8–89.9], "
    [Show abstract] [Hide abstract] ABSTRACT: Background The outcomes from an antiretroviral treatment (ART) program within the public sector in Myanmar have not been reported. This study documents retention and the risk factors for attrition in a large ART public health program in Myanmar. Methods A retrospective analysis of a cohort of adult patients enrolled in the Integrated HIV Care (IHC) Program between June 2005 and October 2011 and followed up until April 2012 is presented. The primary outcome was attrition (death or loss-follow up); a total of 10,223 patients were included in the 5-year cumulative survival analysis. Overall 5,718 patients were analyzed for the risk factors for attrition using both logistic regression and flexible parametric survival models. Result The mean age was 36 years, 61% of patients were male, and the median follow up was 13.7 months. Overall 8,564 (84%) patients were retained in ART program: 750 (7%) were lost to follow-up and 909 (9%) died. During the 3 years follow-up, 1,542 attritions occurred over 17,524 person years at risk, giving an incidence density of 8.8% per year. The retention rates of participants at 12, 24, 36, 48 and 60 months were 86, 82, 80, 77 and 74% respectively. In multivariate analysis, being male, having high WHO staging, a low CD4 count, being anaemic or having low BMI at baseline were independent risk factors for attrition; tuberculosis (TB) treatment at ART initiation, a prior ART course before program enrollment and literacy were predictors for retention in the program. Conclusion High retention rate of IHC program was documented within the public sector in Myanmar. Early diagnosis of HIV, nutritional support, proper investigation and treatment for patients with low CD4 counts and for those presenting with anaemia are crucial issues towards improvement of HIV program outcomes in resource-limited settings.
    Full-text · Article · Sep 2014
    • "In South Africa, prior to April 2010, the most frequently used NRTI, besides lamivudine, was stavudine due to its limited requirements for laboratory monitoring and its relatively low cost (Gilks et al. 2006; World Health Organization 2007, 2010 ). Stavudine is an effective drug (Gallant et al. 2004; Ferradini et al. 2007), but is also associated with severe side effects, such as dyslipidemias , lipoatrophy and mitochondrial toxicities, notably peripheral neuropathy and lactic acidosis (McComsey & Lonergan 2004; Murphy et al. 2007; Subbaraman et al. 2007; Domingos et al. 2009; van Griensven et al. 2010). As a result of its poor side effect profile, in 2007, the World Health Organization (WHO) recommended reducing stavudine dosage from 40 mg to 30 mg for all adults on antiretroviral therapy (ART) (World Health Organization 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: In April 2010, South Africa replaced stavudine with tenofovir in first-line antiretroviral therapy (ART) despite tenofovir's higher cost. We examined treatment outcomes over 24 months amongst patients initiated on tenofovir-based vs. stavudine-based first-line regimens. Prospective cohort analysis of 3940 patients newly initiating either stavudine-based (April 2009 to March 2010) or tenofovir-based (April 2010 to March 2011) ART in Johannesburg, South Africa. Cox proportional hazards models and Fine and Gray's competing risk regression accounting for death were used to model mortality and loss to follow-up, respectively. Linear and log-binomial regression were used to evaluate associations with immunologic response and unsuppressed virus (≥400 copies/ml), respectively. About 1878 patients prescribed tenofovir and 2062 patients prescribed stavudine were included. One hundred and sixty-six (8.8%) tenofovir and 244 (11.8%) stavudine patients died. Three hundred and fifty (18.6%) tenofovir and 379 (18.4%) stavudine patients were lost to follow-up over 24 months on ART. Adjusted regression models showed tenofovir and stavudine were comparable regarding death, loss to follow-up, immunologic response and virologic status. We found no difference in mortality, loss to follow-up, immunological and virologic outcomes over the first 24-months on ART associated with tenofovir compared with stavudine.
    Full-text · Article · Mar 2014
    • "Previous cross-sectional studies of clinic cohorts, which included patients with virological suppression, found that 4%–16% of patients had drug concentrations greater than <Ctrough; however, this is the first study in a resource-limited setting to measure drug concentrations at time of switch [37–39]. The high prevalence of subtherapeutic drug concentrations, at a time when adherence support should have been intensified, underlines the difficulties HCWs encounter in recognizing and successfully addressing nonadherence. "
    [Show abstract] [Hide abstract] ABSTRACT: Background. High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification. Methods. Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression. Results. One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77–263) and 4.3 log10 copies/mL (IQR, 3.8–4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL. Conclusions. Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.
    Full-text · Article · Aug 2013
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