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was found to have adequate plasma drug levels in a shortterm study [7] and good tolerability, efficacy, and drug
levels in a 48-week study in Thai HIV-infected patients
[8]. However, several generic LPV/r tablets tested in a
dog model showed very variable bioavailability depending on the drug tested, with some compounds having a
bioavailability as low as 1% compared with the LPV/r
brand Kaletra [9].
In order to guarantee quality and facilitate government
purchasing choices, the WHO has drawn up a prequalification list for generic ARVs [10]. However, this list
does not indicate the reasons for exclusion, particularly
quality defects, or if there are no or scanty comparative
bioequivalence studies with the equivalent brand-name
product. Furthermore, the increasing extent of market
competition between generic manufacturers necessitates
dynamic on-going surveillance to monitor the quality and
production of generic medications, as well as combined
in vitro and in vivo studies of patients.
In 2012, a generic LPV/r manufactured in India was
introduced into the Republic of Congo, and our group
had an opportunity to study this drug. We report here on
the case of a French subject of sub-Saharan origin who
visited Brazzaville (Republic of Congo) and received
postexposure prophylaxis following unprotected sexual
intercourse. After admission to the main HIV-treatment
centre (CTA Brazzaville), he received generic ARVs at
the usual doses, containing zidovudine/lamivudine
(AZT/3TC) and LPV/r (200/50 mg; Arga-L, McNeil
& Argus, India).
When he returned to France 2 days later, the patient
presented to our hospital for a follow-up. The physician,
intrigued by the unusual appearance of the LPV/r tablets
(small, flat, circular and white), measured minimal drug
levels (C12 h) in the patients plasma. Concentrations of
LPV and ritonavir (RTV) were undetectable, suggesting
that the patient was noncompliant, that the generic LPV/
r was defective, or there had been poor intestinal
absorption. After checking the WHO prequalification
list, it appeared that Arga-L was not prequalified.
Therefore, we performed qualitative and quantitative
pharmacological analyses to evaluate the content, quality,
and oral bioavailability of the compounds within the
Arga-L tablets and then compared the results with the
reference pharmaceutical formulation, Kaletra (Abbvie,
France).
Coupled liquid chromatography-tandem mass spectrometry analyses of the tablets were performed after
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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2014, Vol 28 No 4
Table 1. Pharmacological analysis of generic lopinavir/ritonavir (Arga-L) and Brand-name lopinavir/ritonavir (Kaletra) in the index case and
control subjects.
Formulation
C12h
PEP subject
Control 1
Control 2
Control 3
Control 4
Median (IQR)
<10
13
14
20
30
14 (1320)
ND
99
96
197
67
98 (89124)
C12 h, concentrations at 12 h; LPV, lopinavir; LPV/r, lopinavir/ritonavir; PEP, post exposure prophylaxis; RTV, ritonavir.
Acknowledgements
D.Z. took care of the index case. D.Z. and G.P. designed
the study. D.Z., S.C., J.G. and M.V. were healthy
volunteers for the pharmacological study. G.P. and M.C.
performed the pharmacological analysis. A.G. and S.D.
provided useful information concerning access to
antiretroviral drugs in Republic of Congo. All authors
wrote the article.
Conflicts of interest
There are no conflicts of interest.
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Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Research Letters
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Africa/ucm119231.htm. [Accessed on 31 October 2013].
DOI:10.1097/QAD.0000000000000170
patients in two calendar periods: the SIndrome Metabolica-1 (SiMOne) study in 2005 [5] and the HIV and
HYpertension (HIV-Hy) study in 2011 [6]. Both surveys
were conducted by the CISAI group (Coordinamento
Italiano per lo Studio Allergia e Infezione da HIV
Italian coordination group for the study of allergies and
HIV infection) with similar investigational procedures.
A total of 1243 patients were enrolled in the SiMOne
study (mean age 43.2 years, 72% men, only white
participants), and 1182 in the HIV-Hy (mean age
45.1 years, 72% men). Before matching, 95 nonwhite
participants were excluded from the HIV-Hy database as
SimOne had enrolled white patients only. The remaining
participants were individually matched by age (same age)
and sex to avoid the influences of these factors when
comparing other characteristics. A total of 1530 HIVinfected patients (765 from the SiMOne and 765 from the
HIV-Hy study, mean age 45.6 9 years, 74% men) were
selected after matching; 800 patients did not find a match
and were excluded from the analysis. The maximum
potential overlapping in the matched subgroup was
limited to 325 (21.2%) patients; however, as they were
strictly matched by age and sex, no patient could
represent his/her own control. To compare high and low
cardiovascular risk patients, odds ratios (ORs) and 95%
confidence intervals (CIs) were calculated using unconditional multiple logistic regressions (low cardiovascular
risk as the reference group). All variables shown in Table 1
were tested for association in the univariate models; if
significant, they were included in the multivariate
equation. Analyses were performed with SAS for
Windows, version 9.1 (SAS Institute Inc., Cary, North
Carolina, USA).
As shown in Table 1, in patients aged 3074 years, the
median 10-year risk for acute cardiovascular events
according to the Framingham risk score (FRS) [7] was
8.6% in 2005 and 7.9% in 2011 (P 0.04). Median
vascular age [8] was 51.0 years (42.064.0) vs. 48.0 years
(40.060.0) (P 0.01). Metabolic syndrome [9] was
present in 40.3 vs. 33.4% (P 0.006). Fasting blood
glucose level, triglycerides, current smoking and lipodystrophy [10] were all significantly higher in 2005 than
in 2011 (P <0.001). The atherogenic index of plasma,
that is the logarithmically transformed ratio of molar
concentrations of triglyceride and high-density lipoprotein cholesterol [11], was significantly more unfavorable
in 2005. Median CD4cell count was lower in 2005
(P <0.0001). As expected, antiretroviral regimens were
markedly different in the two periods. Among nucleoside
reverse transcriptase inhibitors, abacavir was included
in 12.4% and 20.8% of regimens in 2005 and
2011, respectively; lamivudine in 68.0% and 32.9%;
zidovudine in 34.5% and 7.3%; didanosine in 22.5% and
0.8%; stavudine in 18.3% and 0.6%; tenofovir in 28.8%
and 64.0%; and emtricitabine in 0% and 55.8% (all
P <0.0001). As to protease inhibitors, atazanavir was
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Table 1. Clinical and cardiovascular features in HIV-infected patients enrolled in the SiMOne (2005) and HIV-Hy (2011) studies.
Variable
Men
Age, years (mean SD)
BMI, kg m2 (mean SD)
Never smokers
Current smokers
Former smokers
Diabetes
Hypertension
SBP, mmHg
DBP, mmHg
Naive to antiretroviral therapy
ART
Treatment interruption (all causes)
NRTI-based
PI-based
NNRTI-based
NNRTI PI-based
Other
10-year global CVD risk FRS% (median, IQR)
Metabolic syndrome
Total cholesterol, mmol/l (mean SD)
HDL cholesterol, mmol/l (mean SD)
Triglycerides, mmol/l (median, IQR)
Blood glucose, mmol/l (mean SD)
Lipodystrophy
CD4 cell count, cells/ml (median, IQR)
Vascular age (median, IQR)
AIP
566 (74.0)
45.6 9.1
23.8 3.4
222 (29.6)
453 (60.5)
74 (9.9)
73 (9.6)
252 (32.9)
124 16
79 10
118 (15.5)
566 (74.0)
45.6 9.1
24.2 4.0
286 (37.4)
381 (49.9)
97 (12.7)
53 (6.9)
228 (29.8)
123 15
78 10
45 (5.9)
64 (9.9)
85 (13.2)
260 (40.4)
213 (33.1)
22 (3.4)
0 (0)
8.6 (4.515.6)
308 (40.3)
5.02 1.27
1.22 0.43
1.82 (1.182.63)
5.36 1.46
330 (43.5)
442 (284642)
51.0 (42.064.0)
0.20 0.35
16 (2.2)
11 (1.5)
383 (53.4)
278 (38.8)
8 (1.1)
21 (2.9)
7.9 (3.915.6)
236 (33.4)
5.06 1.11
1.19 0.38
1.52 (1.052.19)
5.03 1.00
235 (30.8)
581 (429770)
48.0 (40.060.0)
0.13 0.31
P
n/a
n/a
0.01
0.0002
0.057
0.19
0.23
0.17
<0.0001
<0.0001
0.04
0.006
0.46
0.17
<0.0001
<0.0001
<0.0001
<0.0001
0.01
<0.0001
Sum may not add up to the total because of missing values: Framingham risk score (FRS) and vascular age were calculated in a sample of 1436
patients aged 3074 years. AIP, atherogenic index of plasma; ART, antiretroviral therapy; CVD, cardiovascular disease; HDL, high-density
lipoprotein; HIV-Hy, HIV and HYpertension; IQR, interquartile range; LDL, low-density lipoprotein; n/a, not applicable; NNRTI, nonnucleoside
reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SiMOne, SIndrome Metabolica-1.
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Research Letters
Acknowledgements
The Coordinamento Italiano Studio Allergie e Infezione
da HIV (CISAI) group consisted of the following
members: Paolo Maggi, Chiara Bellacosa, Francesca
Lenoci (Bari); Leonardo Calza (Bologna); Tiziana
Quirino, Barbara Menzaghi (Busto Arsizio); Benedetto
Maurizio Celesia, Maria Gussio, Giuseppe Nunnari
(Catania); Luigi Pusterla (Como); Silvia Carradori
(Ferrara); Canio Martinelli (Firenze); Francesca Vichi
(Firenze); Antonio Di Biagio, Anna Calzi (Genova);
Giovanni Penco, Giancarlo Antonucci (Genova); Ilaria
Caramma, Chiara Molteni, Paolo Bonfanti, (Lecco);
Laura Carenzi, Sara Melzi, Giuliano Rizzardini (Milano);
Marco Franzetti, Teresa Bini, Stefano Rusconi (Milano);
Elena Rosella (ASL 3 Milano); Marzia Franzetti (Padova);
Giuseppe Vittorio De Socio, Enisia Cecchini, Alessandra
Mercuri, Alessio Sgrelli (Perugia); Giustino Parruti, Elena
Mazzotta (Pescara); Patrizia Marconi (Roma); Maria
Stella Mura, Giordano Madeddu, Paola Bagella (Sassari);
Giancarlo Orofino, Marta Guastavigna, Daniela Zeme
(Torino).
The authors had full access to all the data in the study and
take responsibility for the integrity of the data and the
accuracy of the data analysis. G.V.D.S. contributed to
study concept and design. E.R. gave statistical expertise.
G.V.D.S., E.R., G.Pa., and G.S. drafted the article. All
of the authors contributed to analysis, interpretation of
data, and critical revision of the article for important
intellectual content.
Conflicts of interest
No funding has been provided by any private or public
actor beyond the current clinical practice (Public Health
Assistance).
E.R. has received consultancy honoraria from Bayer
and from Elsevier and payment for development of
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DOI:10.1097/QAD.0000000000000181
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