Changes in Lipid Profiles in Two Groups of HIV-1 Infected Patients in Cameroon on Two Treatment Regimens with Either Efavirenz or Nevirapine, in Association with Reverse Transcriptase Inhibitors
The aim of this study was to determine the effect of two antiretroviral therapy regimens on lipid profiles. Patients were allocated to two treatment regimens: Nevirapine (NVP) + Stavudine (d4T) + Lamivudine (3TC) (n = 197) or Efavirenz (EFV) + Stavudine (d4T) + Lamivudine (3TC) (n = 181). Serum was prepared from blood samples collected before the start of treatment (Month 0) and at 24 months. Lipids and lipoproteins were measured using colorimetric enzyme assays or by calculation. Overall, there was an increase in all lipid parameters in patients on both treatment regimens at 24 months, although there were individual differences with respect to each lipid parameter that affected the atherogenicity indices for both regimens. Increase of high density lipoprotein cholesterol (HDLC) (42.82%) was significantly larger in patients on the NVP than on EFV (24.03%) (p<0.001), as opposed to Total Cholesterol (TC), triglycerides (TG) And Low Density Lipoprotein Cholesterol (LDLC) that were significantly lower in patient on NVP than on EFV; TG, Very Low Density Lipoproteins (VLDL) and LDLC increased in both regimens. These changes were not much affected by changes in viral load and CD4 cell levels. The changes in the atherogenicity indices showed that the regimen with NVP seems to have less risk of coronary heart disease compared to EFV.
to cite this article:
N.F. Nguemaim, J. Mbuagbaw, T. Nkoa, G. Teto, G.R. Njitchouang, D.J. Pouomogne, A. Same-Ekobo and T. Asonganyi, 2010. Changes in Lipid Profiles in Two Groups of HIV-1 Infected Patients in Cameroon on Two Treatment Regimens with Either Efavirenz or Nevirapine, in Association with Reverse Transcriptase Inhibitors. Journal of Medical Sciences, 10: 25-33.
In untreated HIV infected individuals, particularly those with advanced infection,
lipid abnormalities are common (Grundfeld et al.,
1992; Feingold et al., 1993). Abnormalities
include variations in Low Density Lipoprotein Cholesterol (LDLC) and High Density
Lipoprotein Cholesterol (HDLC) levels (Feingold et al.,
1993; Nguemaïm et al., 2010). Further,
metabolic disorders, which include disturbances in lipid metabolism and increases
in serum level of triglyceride and cholesterol, have been observed in all stages
of HIV-infection (Bernasconi et al., 1998; Mooser
and Carr, 2001; Danwe et al., 2005). Before
the advent of Highly Active Antiretroviral Therapy (HAART), antiretrowviral
drugs such as zidovudine (AZT) were shown to decrease plasma triglycerides levels
(Mildvan et al., 1992).
Combination of antiretroviral therapy (ART) for treatment of HIV type 1 infection
has been associated with fat redistribution, insulin resistance and changes
in plasma lipid concentrations (Mildvan et al.,
1992; Carr et al., 1998, 1999,
2000; Behrens et al., 1999;
Periard et al., 1999; Mulligan
et al., 2000). More dyslipidaemia with different patterns have been
observed in patients receiving protease inhibitor based HAART (Henry
et al., 1998; Bertold et al., 1999;
Carr et al., 1999; Dong et
al., 1999; Roberts et al., 1999; Bonnet
et al., 2000; Bozzette et al., 2003).
A recent study, by Smith et al. (2004) demonstrated
an excess of cardiovascular risk factors in HIV patients receiving HAART (Carr
et al., 1998). Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
based regimens differ from protease inhibitor (PI) based regimens by the marked
increases of LDLC and TG (Van der valk et al., 2001;
Tashima et al., 2003). The NVP-containing regimen
increased total-cholesterol, HDLC concentration and particle size and apolipoprotein
A1 (apo A1) levels at 24 weeks (Clotet
et al., 2003). Although, no clinical data have yet been generated
to support this hypothesis, these differences between ART regimens raised the
expectation that NNRTI-based regimens, particularly in view of their effects
on HDLC, may favourably modify Coronary Heart Disease (CHD) risk compared with
many PI containing regimens. In addition, patients infected with HIV initiating
antiretroviral therapy (ART) containing a Non Nucleoside Reverse Transcriptase
Inhibitor (NNRTI) show fewer atherogenic lipid changes than those initiating
most ARTs containing protease inhibitors (Van Leth et
al., 2004). With respect to the two most commonly used NNRTIs, NVP and
EFV, no detailed comparative study has been reported in Cameroon concerning
their effect on serum lipid profiles. In the present study, we analysed lipid
and lipoprotein changes in two groups of HIV-1 patients on two treatment regimens,
both including Stavudine (d4T) and Lamivudine (3TC) with one group containing
NVP and the other EFV in order to improve the management of HIV-1 infected patients.
MATERIALS AND METHODS
Participants and treatment allocation: Patients enrolled in the present study were more than 15 years (mean 32.62) old. The main exclusion criteria were pregnancy, breastfeeding, abnormal laboratory results at screening and use of drugs which either affect the immune system or lipid parameters (Table 1). Patients took d4T (one tablet of 40 mg twice daily) and 3TC (one tablet of 150 mg twice daily). The first dose of both drugs was taken at 7 am and the second at 7 pm. In addition, patients were randomly allocated to NVP (one tablet of 200 mg twice daily at 7 am and 7 pm), or EFV (one tablet of 600 mg once daily at bedtime or one tablet of 800 mg once daily at bedtime, depending on whether they had associated opportunistic infections treatment, especially tuberculosis drugs). All the patients were Cameroonians and were recruited during the dermatology consultation at the Yaoundé University Teaching Hospital (Cameroon) from September 2007 to September 2009. The study was approved by the National Ethics Committees of the Ministry of Public Health. All patients gave a written informed consent before they were recruited.
Lipid parameters assessment: Serum samples for determination of lipids
and lipoprotein parameters were collected at baseline before start (month 0)
of antiretroviral treatments and at months 3,6,9,12,18 and 24 months. Blood
was taken from participants after 12 h fasting in the dry tubes. After centrifugation
at 3000 g for 10 mn, sera obtained were aliquoted and set aside for analysis
of blood lipids.
||Sampling (eligibility and exclusion)
All samples were stored at -20°C and analysed within a week in the Biochemistry
Laboratory of Yaounde Gynae-Obstetric and Paediatric Hospital according to predefined
protocols using colorimetric enzyme methods. Total cholesterol was determined
using enzymatic method (Allain et al., 1974)
and serum triglyceride was determined as previously described by Buccolo
and David (1973). The HDLC was determined using a heparin manganese precipitation
of Apo B-containing lipoprotein (Warnick and Alberers, 1978)
and serum concentration of LDLC was calculated using the Friedewald equation,
but only when the concentration of TG was below 500 mg dL-1 (Friedewald
et al., 1972). The VLDL (mg dL-1) was calculated as TG/5
according to Friedewald et al. (1972) and the
atherogenicity indices were calculated using TC/HDLC and LDLC/HDLC ratios. The
Viral Load (VL) was measured at Centre Pasteur du Cameroun, Yaoundé laboratory
using ultra sensitive Amplicor 1.5 (Roche Diagnostics, Basel, Switzerland) with
a lower limit quantification of 50 copies mL-1 of blood.
Outcome measurement: The mean percentage changes of TG, TC, HDLC, LDLC,
VLDL, TC/HDLC and LDLC/HDLC ratios, between baseline (Month 0) and month X after
start of treatment were determined for each individual patient using the Van
Leth et al. (2004) formula:
where, X is the time-points of follow-up after the start treatment (baseline
or month 0).
Changes were analysed with respect to sex, Body Mass Index (BMI), CD4 cell counts (<50, 50-200, >200 cells μL-1) or Viral Load (VL) in log10 (< 2.5, 2.5 - 3.5, or > 3.5 log10).
Statistical analysis: All statistical calculations were done using computer
programs Microsoft Excel 2003 and the software SPSS (Statistical Package for
the Social Sciences, SPSS Inc., Chicago, IL, USA) version 12.0. For the differences
between mean percentage changes level of parameters in the two treatment groups
NVP and EFV modelled by repeated measurements were tested for the significance
compared using the Student t-test. Student t-test was also used to compare the
difference between the mean age and the mean of BMI in the two treatment groups
NVP and EFV. Chi-square test was used to compare the percentages between the
two groups of patients. Independent risk factors were assessed by multivariable
analyses including the factors associated with percentage changes of all predefined
variables in the treatment groups. The p-values less than 0.05 were considered
Patients: Of the 540 patients included in this study, 241 (44.63%) were allocated to the NVP treatment group and 230 (42.59%) to the EFV treatment group. Of these, 44 (27.16%) patients in NVP group, 49 (30.25%) in EFV group and 69 (42.59%) who did not start their treatment were excluded from the analysed. This resulted in a final sample size of 197 (52.12%) patients in the NVP group and 181 (47.88%) in the EFV group, making a total of 378 patients at the beginning of t he follow-up period (Table 1). A total of 22 patients (12 on NVP and 10 on EFV) disappeared during the follow-up period, leaving 356 patients at month 24.
The baseline characteristics of the patients included in this study are comparable for patients included in the two treatment regimens (Table 2).
Changes in lipids and lipoproteins: The proportional changes of the
different serum lipid concentration and atherogenicity indices, over 24 months
are graphically depicted in Fig. 1a (for TG), Fig.
1b (for TC), Fig. 1c (for HDLC), Fig. 1d
(for LDLC), Fig. 1e (for VLDL), Fig. 1f
(for TC/HDLC), Fig. 1g (for LDLC/HDLC). Changes at 24 months
were compared to base line values at month zero. All changes within the treatment
groups in lipid and lipoproteins concentration as well as atherogenicity indices
(TC/HDLC, LDLC/HDLC ratios) were statistically significant (Table
||Baseline characteristic of patients included in the study
in brackets indicate percentage. NVP: Nevirapine; EFV: Efavirenz; n: Number;
CD4: Cluster of Differentiation 4; Cells μL-1: Cells per
microliter; SE: Standard error; CDC: Centers for disease control; BMI:
Body mass index; A, B, C categories: Stages of the evolution of the HIV
infection as classified by CDC/OMS in 1993. There was no statistically
significant difference between the two groups of patients in the Table
||Change in serum concentrations of lipids and lipoproteins
||Lipid concentrations (standard error) at baseline and 24 months
and mean percentage changes
Month 0; M24: Month 24; n: Effective; SE: Standard error; a: Mean values
of lipid parameters and atherogenicity indice (SE); b: Mean percentage
change (SE) modelled by repeated measurements; CI: Confidence interval;
NVP: Nevirapine; EFV: Efavirenz; TG: Triglycerides; TC: Total cholesterol;
HDLC: High Density lipoprotein cholesterol; LDLC: Low density lipoprotein
cholesterol; VLDL: Very low density lipoprotein; TC/HDLC and LDLC/HDLC:
Atherogenicity indices; mg dL-1: Milligram per decilitre; n:
Number. *Statistically significant results when the percent increase in
the two group of patients are compared (p<0.05).|
The increase of HDLC was significantly larger in the NVP treatment group (42.82%)
than in EFV treatment group (24.03%) (p<0.001) (Table 3).
In contrast, the increase in TC was significantly smaller in NVP group (26.25%)
than the EFV group (31.57%) (p = 0.043). These changes resulted in the significant
decreased of TC/HDLC ratio in the NVP group (-12.82%) compared to an increase
in the EFV group (10.12%) (p<0.001).
The increase of TG was significantly smaller in the NVP group (29.23%) than in the EFV group (52.50%) (p<0.001), as well as the increase of VLDL (29.06%) in NVP group compared to 48.62% in EFV (p<0.001). The difference in increase of LDLC was also statistically significant (26.34% for NVP group compared to 40.07% for EFV group; p = 0.002) (Table 3).
Effect of sex, Viral Load (VL), Body Mass Index (BMI) and CD4 cell
counts: Some factors associated with changes in lipid concentration were
analysed by a multivariable analysis (Table 4, 5).
According to sex, the increase of HDLC (p = 0.042) and TC (p<0.001) was significantly
smaller in women than in men (Table 4). This resulted in a
greater decrease of TC/HDLC ratio for men (-9.84%) compared to women (7.14%)
(p<0.001) (Table 5). There was a significant increase in
all lipid levels and TC/HDLC ratio in patients a ssociated with a decrease of
VL over 24 months except for LDLC and LDLC/HDLC ratio whose increase was larger
only when VL remained more than 2.5 log10. There was a significant
association between VL (log10) and lipids, except HDLC (p = 0.072)
(Table 4) and LDLC (p = 0.064) (Table 5).
The BMI was significantly associated with increase in all lipid parameters and LDLC/HDLC ratio, except TC/HDLC ratio (p = 0.062) (Table 5).
||Multivariable analysis of some factors associated with percentage
changes in lipid (TG, TC and HDLC) concentrations (SE)
Month 0; M24: month 24; a: Mean values of lipid parameters
and atherogenicity indice (SE); b: Mean percentage change (SE)
modelled by repeated measurements; CI: Confidence interval; M: Male; F:
Female; PI: Percent increase; SE: Standard error; BMI: Body mass index;
kg m-2: Kilogram per millimetre square; mg dL-1:
Milligram per decilitre; Cells μL-1: Cells per microliter;
VL: Viral load; log10: Decimal logarithm; CD4: Cluster of Differentiation
4; TG: Triglycerides; T C: Total cholesterol; HDLC: High density lipoprotein
cholesterol; *statistically significant results (p<0.05). **Statistically
higher significant results (p<0.0001)|
||Multivariable analysis of some factors associated with percentage
changes in lipid (LDLC and VLDL) concentrations (SE) and atherogenicity
Month 0; M24: Month 24; a: Mean values of lipid parameters
and atherogenicity indice (SE); b: Mean percentage change (SE)
modelled by repeated measurements; CI: Confidence interval; M: Male; F:
female; PI: Percent increase; SE: Standard error; BMI: Body mass index;
mg dL-1: Milligram per decilitre; Cells μL-1:
Cells per microliter; VL: Viral load; CD4: Cluster of differentiation
4; LDLC: Low density lipoprotein cholesterol; VLDL: Very low density lipoprotein;
TC/HDLC and LDLC/HDLC: Atherogenicity indices; kg m-2: Kilogram
per millimetre square; log10: Decimal logarithm. *Statistically significant
The CD4 cell counts were in general, positively associated with
changes in lipid parameters and in atherogenicity indices (Table
Initiation of an ART regimen containing NVP or EFV is accompanied by a significant
increase of HDLC with concomitant increases of TG, TC, LDLC and VLDL. The increase
of HDLC was significantly larger in the NVP treatment group compared to the
EFV treatment group as well as the increase of TG, TC, LDLC and VLDL. In the
NVP group, the TC/HDLC and LDLC/HDLC ratios decreased, compared to an increase
in the EFV group. These observations are different from reported changes in
most PI-based ART regimens, in which higher concentration of TC, LDLC and TG
were found without concurrent higher levels of HDLC (Stein
et al., 2003; Fontas et al., 2004)
they also differ from the results of Nunez et al.
(2002) that did not show any differences between NVP and EFV treatment groups.
Present findings agree with those of Van Leth et al.
(2004), who used cases from many countries, including African countries.
HDLC increase and NNRTIs: Present results showed an increase of HDLC
in both treatment groups at 24 months. Increase of HDLC with the use of NVP
or EFV have been described in some previous studies, in patients switching from
a PI-based regimen to a NNRTI-based regimen (Martinez et
al., 1999; Negredo et al., 2002), for
patients initiating treatment with Didanosine, Stavudine and NVP (Van
der valk et al., 2001), in patients treated with EFV and either
Zidovudine with 3TC or Indinavir (Tashima et al.,
2003) in treatment-naive subjects receiving NVP in combination with the
nucleoside analogues Zidovudine/Lamivudine (Fisac et
al., 2004) and in naive patient starting a regimen of Didanosine, d4T
and EFV (Negredo et al., 2002). Apart from the
study by Negredo et al. (2002) which included
patients with similar baseline HDLC levels as in the present study and which
showed increases in HDLC similar to the ones we report here, the others showed
different increase patterns, probably due to differences in viral load, the
PI-based regimen and the degree of strict adherence of the patients to the treatment
protocol. Further, Riddler et al. (2003) also
reported similar variations to ours for TC and LDLC.
Several studies have shown that an HDLC increase is associated with a significant
decrease in mortality from Coronary Heart Disease (CHD) independent of changes
in LDLC (Manninen et al., 1988; Rubins
et al., 1999). Other studies have associated risk of cardiovascular
disease (CVD) with low concentrations of HDLC (Lipid Research
Clinics Program, 1984; Frick et al., 1987;
Castelli, 1988; Gordon et al.,
1989; Assmann et al., 1996; Robins,
2001). Taken together, our results show that the NVP regimen leads to lower
atherogenicity index and so reduces CHD risk better than the EFV regimen. Other
studies have shown that a substitution of IP with Nevirapine in combination
of antiretroviral therapy for 6-12 improved and even normalized dyslipidemia,
glycemia and insuline resistance, whereas HIV suppression was maintained (Molina
et al., 2000; Moyle et al., 2001).
Changes in TG, TC, LDLC, VLDL and atherogenicity indices: Present results
show that EFV causes a greater increase in TG levels than NVP. These results
corroborate those of other authors (Molina et al.,
2000; Negredo et al., 2002; Fisac
et al., 2004). The results are unlikely to be explained by the effect
of d4T, since the proportion of patients in both groups on d4T was virtually
the same (52.12% for the NVP treatment group and 47.88% for the EFV treatment
group). The d4T might however be responsible for the apparent acceleration of
the increase of TC and TG towards the end of the study (Fig. 1),
probably related to the lipodystrophy reported in patients on d4T treatment
(Heath et al., 2001; Dube
et al., 2002; Nolan et al., 2003;
Sattler, 2003; Nolan and Mallal,
2004; McComsey et al., 2004) and the possible
association of HIV-1 infection with the reduced TG clearance following food
intake (Grundfeld et al., 1992). Concentration
of TG had an effect in the calculated values of LDLC and VLDL; however, the
smaller increase in levels of LDLC and TG in the NVP regimen than for the EFV
might suggest that the LDLC and TG results are valid. Furthermore, elevated
cholesterol has been observed with the use of EFV (Martinez
et al., 1999) and NRTIs such as Stavudine (d4T) (Mallal
et al., 2000). A great improvement of atherogenicity indices (TC/HDLC
and LDLC/HDLC) on NVP compared to EFV was observed and this result correlates
those of Ngondi et al. (2007). The low atherogenicity
indices can be explained by the reduction of TC, LDLC and the elevation of HDLC
The HDLC increases were higher in patients on the NVP regimen than those on the EFV regimen. The increase of TG, TC, LDLC and VLDL levels are smaller for patient taking NVP than for those taking EFV. The less atherogenic lipid profile of patients taking NVP in comparison to those taking EFV may be among the various factors to consider when selecting the most appropriate initial ART regimen, particularly for those patients with HIV type 1 with a significant a priori CHD risk like diabetes, or a previous cardiovascular event.
The study was materially support by the Biochemistry Laboratory of Yaoundé Gynae-Obstetric and Paediatric Hospital, the Biotechnology and Immunology Laboratory of the Faculty of Medicine and Biomedical Sciences of the University of Yaoundé I and the Yaoundé University Teaching Hospital, Cameroon. The authors thank all those who gave their informed consent for participation in the study.
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