Research Letters

AIDS 2014, 28:607612

Generic antiretroviral drugs in developing

countries: friends or foes?
David Zucmana, Seydou Camaraa, Jerome Gravissea,
Svetlane Dimia, Marc Vassea, Abdon Goudjob, Marion
Choquetc and Gilles Peytavinc
Although second-line generic antiretroviral drugs
are of great value in developing countries, there
are concerns regarding their quality. We studied a
generic Lopinavir/ritonavir (200/50 mg; Arga-L,
India) marketed in the Republic of Congo but
not prequalified by WHO. Despite adequate quantitative and qualitative drug content, Arga-L had a
bio-availablility of 10% compared with Kaletra. To
avoid selection of drug-resistant HIV, rigorous
pharmacological monitoring of generic drugs
not prequalified by WHO must be a priority.
According to UNAIDS [1], 34 million people worldwide
were infected by the HIVat the end of 2011 and, of these,
69% were living in sub-Saharan Africa. Generic products
have greatly reduced the costs of antiretroviral drugs
(ARVs), and have improved access to treatment for HIVinfected patients in developing countries. Clinical trials
with first-line generic drugs have shown excellent results
in sub-Saharan Africa [2]. The majority of ARVs
marketed in resource-limited countries are generics
and their increased availability has transformed AIDS
therapy and generated broad-based gains to health. Since
1995, antiretroviral therapy has saved 14 million life-years
in low-income and middle-income countries, including
9 million life-years in sub-Saharan Africa [1].
However, an inevitable consequence of the widespread
availability of ARVs is treatment failure caused by the
development of new strains of drug-resistant viruses [3].
A subset of individuals who acquire drug-resistant HIV
will transmit their drug-resistant virus to others. This
scenario has a potential impact on mortality and treatment outcomes [4]. Therefore, there is now a need to
scale-up access to second-line generic treatments in these
countries.
Lopinavir/ritonavir (LPV/r) is the cornerstone of
second-line ARVs in the developing world [5,6]. A
growing number of generic LPV/r drugs are now
available, but their quality and safety are still of concern.
There are only very limited published data concerning
the pharmacokinetic and clinical properties of generic
LPV/r drugs. A generic LPV/r product produced by the
Government Pharmaceutical Organization of Thailand

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

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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)

Generic LPV/r (Arga-L)

LPV (ng/ml)
RTV (ng/ml)
<10
108
396
158
896
158 (108396)

Brand-name LPV/r (Kaletra)

LPV (ng/ml)
RTV (ng/ml)
ND
3693
5882
4074
3289
3884 (35924526)

<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.

crushing and dissolution in an appropriate solvent.

Qualitative analysis of the Arga-L tablet identified the
correct drug substances: LPV and RTV. Moreover,
quantitative analysis indicated adequate unit masses of
215 mg of LPV and 50.8 mg of RPV, comparable to those
of Kaletra.

products are made available to patients. National

authorities and funding agencies should require that
such quality-assurance processes are conducted and
approved.

To evaluate oral bioavailability of the drug substances,

C12 h of LPV and RPV were measured in four healthy
volunteers after a single oral dose of the generic LPV/r
Arga-L (400/100 mg) taken during an evening meal. A
1-week wash-out later, the same subjects were given
the brand-name LPV/r product Kaletra (single dose
400/100 mg) and the analysis was repeated.

Acknowledgements

As shown in Table 1, LPV and RTV C12 h after Arga-L

intake were considerably lower than those observed for
the brand-name drug Kaletra, revealing quality issues of
the generic drug.

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.

Thus, despite adequate qualitative and quantitative

composition of the generic Arga-L, when C12 h was
measured in the five subjects (one case of postexposure
prophylaxis and four controls) there was a very low oral
bioavailability of generic lopinavir and ritonavir (<10%)
compared with the brand-name drug. These results also
strongly suggest that bioequivalence studies were not
validated between these two pharmaceutical drugs.

No funding was received for this article.

Because of the low, albeit not null, bioavailability of

lopinavir and ritonavir compounds in the generic Arga-L,
its usage in HIV-infected patients may increase the risk of
virological failure through the emergence of resistance
mutations. Purchasing generic ARVs in accordance with
the WHO prequalification list [10] or the Food and Drug
Administration list [11] is therefore crucial in African
countries because of the risk of disastrous consequences in
terms of public health. The lack of regulations formulated
by Northern countries regarding this issue clearly shows
the need for thorough evaluation of nonprequalified
generics.

Received: 23 September 2013; revised: 28 November

2013; accepted: 28 November 2013.

Our results emphasize the crucial requirement of testing

for human bioequivalence of generic products that
contain LPV/r to guarantee their efficacy before these

Hopital FOCH, Suresnes, France, bFrance Expertise

Internationale, Paris, France, and cPharmaco-Toxicology Department, Hopital Bichat, Paris, France.
Correspondence to Dr David Zucman Hopital Foch,
Service de medecine interne 92150 Suresnes France.
E-mail: d.zucman@hopital-foch.org

References
1. UNAIDS report on the global AIDS epidemic 2012. http://
www.unaids.org/globalreport.
2. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A,
Calmy A, et al. Effectiveness and safety of a generic fixed-dose
combination of nevirapine, stavudine, and lamivudine in HIV1-infected adults in Cameroon: open-label multicentre trial.
Lancet 2004; 364:2934.
3. Messou E, Chaix ML, Gabillard D, Yapo V, Toni TD, Minga A,
et al. Increasing rate of TAMs and etravirine resistance in HIV1-infected adults between 12 and 24 months of treatment: The
VOLTART cohort study in Cote dIvoire, West Africa. J Acquir
Immune Defic Syndr 2013; 64:211219.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Research Letters
4. Cambiano V, Bertagnolio S, Jordan MR, Lundgren JD, Phillips A.
Transmission of drug resistant HIV and its potential impact on
mortality and treatment outcomes in resource-limited settings.
J Infect Dis 2013; 207 (Suppl 2):S5762doi: 10.1093/infdis/
jit111.
5. WHO Consolidated ARV guidelines 2013. http://www.who.int/
hiv/pub/guidelines/arv2013/intro/WHO_CG_table_7.19.pdf
6. Bartlett JA, Ribaudo HJ, Wallis CL, Aga E, Katzenstein DA,
Stevens WS, et al. Lopinavir/ritonavir monotherapy after
virologic failure of firstline antiretroviral therapy in resourcelimited settings. AIDS 2012; 26:13451354.
7. van der Lugt J, Lange J, Avihingsanon A, Ananworanich J, Sealoo
S, Burger D, et al. Plasma concentrations of generic lopinavir/
ritonavir in HIV type-1-infected individuals. Antivir Ther 2009;
14:10011004.
8. Ramautarsing RA, van der Lugt J, Gorowara M, Sophonphan J,
Ananworanich J, Lange JM, et al. Pharmacokinetics and
48-week safety and efficacy of generic lopinavir/ritonavir in
Thai HIV-infected patients. Antivir Ther 2013; 18:249252.
9. Garren KW, Rahim S, Marsh K, Morris JB. Bioavailability of
generic ritonavir and lopinavir/ritonavir tablet products in
a dog model. J Pharm Sci 2010; 99:626631doi:10.1002/jps.
21712.
10. World Health Organization Prequalification programme: http://
apps.who.int/prequal/
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nationalPrograms/FDABeyondOurBordersForeignOffices/Asiaand
Africa/ucm119231.htm. [Accessed on 31 October 2013].

DOI:10.1097/QAD.0000000000000170

Decreasing cardiovascular risk in HIV infection

between 2005 and 2011
Giuseppe V. De Socioa, Giustino Parrutib, Elena
Riccic, Paolo Maggid, Benedetto M. Celesiae, Giovanni
Pencof, Canio Martinellig, Marco Franzettih, Antonio
Di Biagioi, Paolo Bonfantij, Giacomo Puccik, Giuseppe
Schillacik, for the CISAI study group
Cardiovascular risk profile was compared in 765
Italian HIV-infected outpatients enrolled in 2005
and in 765 individually age-matched and sexmatched patients enrolled in 2011. Median
Framingham risk score was 8.6% in 2005 vs.
7.9% in 2011 (P U 0.04); metabolic syndrome was
present in 40.3% vs. 33.4% (P U 0.006). Blood glucose, triglycerides, prevalence of smokers, and
lipodystrophy were all significantly lower in 2011
(all P <0.0001). Cardiovascular risk improved over
a 6-year period in Italian HIV-infected patients.
As HIV-infected individuals have a longer life expectancy
[1], cardiovascular disease has emerged as an important
cause of morbidity and mortality [2]. Current clinical
guidelines mandate nonpharmacological and pharmacological control of major cardiovascular risk factors in HIV
patients [3]. Furthermore, new antiretroviral drugs are
now available, with improved efficacy and safety profiles
[4]. To evaluate whether cardiovascular risk profile and
metabolic syndrome prevalence changed in HIV-infected
Italian patients over the last years, we used data from two
previously described multicenter, nationwide, crosssectional surveys assessing cardiovascular risk in HIV

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

SiMOne, 2005 (n 765)

HIV-Hy, 2011 (n 765)

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.

prescribed to 7.4% of the patients in 2005 and 26.5% in

2011; nelfinavir in 7.9% and 0%; lopinavir in 20.6% and
14.6%; and darunavir was not licensed in 2005 and was
used in 8.2% of the patients in 2011 (all P <0.01).
Regarding nonnucleoside reverse transcriptase inhibitors,
nevirapine use was 15.1% in 2005 and 12.3% in 2011
(P 0.13), efavirenz marginally increased from 21.4% to
25.4% (P 0.08), and etravirine from 0% to 2.1%. A
higher proportion of patients in 2005 were taking
nucleoside reverse transcriptase inhibitors only (13.2% vs.
1.5%, P <0.0001). The proportion of patients at high
cardiovascular risk, defined as having metabolic syndrome
or a 10-year FRS at least 10%, was higher in 2005 (59.0%
vs. 51.4%, P 0.004). Apart from the variables concurring to the definition of cardiovascular risk, in the
univariate analysis higher cardiovascular risk was
associated with BMI (by 1 kg/m2, OR 1.19, 95% CI
1.151.23), protease inhibitor use (OR 1.32, 95% CI
1.061.65, reference no protease inhibitor use), lipodystrophy (OR 1.60, 95% CI 1.292.00), and belonging
to the 2005 survey (OR 1.37, 95% CI 1.111.69). In
the multivariable model including all these significant
factors, they remained significantly associated to high
cardiovascular risk, with minimum changes in the estimates. Among protease inhibitors, lopinavir (but not
atazanavir or darunavir) was associated to high cardiovascular risk (OR 1.38, 95% CI 1.011.90).

Overall, these results show a better immunologic,

metabolic, and cardiovascular risk profile in 2011 as
compared with 2005 among Italian HIV outpatients.
These differences are likely to result from many factors.
First, smoking remained highly prevalent, but was less
frequent in 2011. This may be related to medical
interventions on stopping smoking, as well as to the
adoption of major prevention strategies at the population level against smoking in public places [12]. The
observed risk reduction, though small, may have
important long-term implications. Second, new antiretroviral drugs have a lower impact on glucose and
triglyceride metabolism [3]. The use of thymidinic
drugs and ritonavir was remarkably lower in 2011. Such
changes may have contributed to the significant
improvement in atherogenic lipid profile in 2011.
Conversely, hypertension prevalence was substantially
unchanged. As previously reported, individuals with
HIV infection show a suboptimal hypertension treatment and control rate [6], a loss of the physiological
nocturnal blood pressure reduction [13], and an
increased arterial stiffness [14,15]. The CISAI group
has been performing several medical educational
programs focused on HIV comorbidity, with the aim
of motivating clinicians to improve their clinical practice
as to cardiovascular risk management. This may have
had some impact on the observed findings, as all patients

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Research Letters

included in the study were followed at sites participating

in such educational protocols [5,10,16].
The main strengths of our study were: inclusion of an
unselected multicenter sample of white Italian HIVinfected patients, assisted at sites of ordinary care, in two
different periods, likely to represent the general assisted
population at the same sites; accurate matching of patients
for two of the most relevant features influencing
cardiovascular risk, such age and gender. Limitations
include its cross-sectional design and it being based on a
comparison of selected subgroups from wider study
cohorts.

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

educational presentation from Novartis. A.D.B. has

received consultancy honoraria from Abbott. B.M.S. is
on the speakers bureau for Janssen, MSD, Abbott,
Boehringer, ROCHE and is Board membership for
Gilead, MSD. For the remaining authors, none were
declared. No conflict of interest in this article for all
the authors.
a
Department of Infectious Diseases, Azienda Ospedaliero-Universitaria di Perugia, Perugia, bDepartment
of Infectious Diseases, Pescara Hospital, Pescara,
c
Department of Infectious Diseases, Luigi Sacco
Hospital, Milan, dDepartment of Infectious Diseases,
University of Bari, Bari, eDepartment of Infectious
Diseases, Garibaldi Hospital, University of Catania,
Catania, fDepartment of Infectious Diseases, Galliera
Hospital, Genoa, Genoa, gDepartment of Infectious
Diseases, Careggi Hospital, Florence, hDepartment
of Infectious Diseases, University of Milan, Milan,
i
Department of Infectious Diseases, San Martino
Hospital Genoa, University of Genoa, Genoa, jDepartment of Infectious Diseases, Manzoni Hospital, Lecco,
and kUniversita` di Perugia and Struttura Complessa di
Medicina Interna, Azienda Ospedaliero-Universitaria
di Terni, Terni, Italy.

Correspondence to Giuseppe V.L. De Socio, MD, PhD,

Clinica di Malattie Infettive, Azienda OspedalieroUniversitaria di Perugia, Piazzale Menghini 1, 06129
Perugia, Italy.
Tel: +39 075 5784321; fax: +39 075 5784346;
e-mail: giuseppedesocio@yahoo.it
Received: 18 September 2013; revised: 9 December
2013; accepted: 9 December 2013.

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DOI:10.1097/QAD.0000000000000181

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