Introduction
Current guidelines place highly active antiretroviral therapy (HAART) regimens containing protease inhibitors (PI) as the first option for antiretroviral therapy [1]. Long-term data comparing PI-sparing with standard PI-containing HAART regimens are still insufficient [2,3]. However, standard HAART regimens including PI are not able to eradicate HIV-1 infection [4,5] and less potent maintenance therapies following standard PI-containing HAART regimens have not been able to maintain the suppression of HIV-1 replication [6-8]. These data suggest that, at least for the moment, prolonged intensive therapeutic regimens will be required to maintain adequate suppression of viral replication for long periods of time, if not for life.
Several studies have shown an association between insulin resistance and hyperlididaemia [9,10], insulin resistance and fat redistribution [11], hyperlipidaemia and fat redistribution [12,13], and insulin resistance, hyperlipidaemia, and fat redistribution [14] in patients treated with PI. Although most authors link the development of metabolic abnormalities and fat redistribution to PI therapy, others consider that they may be associated with chronic HIV-1 infection itself or that PI therapy may have amplified pre-existing metabolic disorders [15].
Hyperlipidaemia and insulin resistance are well known cardiovascular risk factors [16], and body changes due to abnormal fat distribution may have severe psychological repercussions. Therefore, strategies to prevent or to revert metabolic abnormalities and fat redistribution are urgently needed. This study was designed to assess the effects of switching from PI to the non-nucleoside reverse transcriptase inhibitor nevirapine on metabolic abnormalities of patients with fat redistribution and on CD4 T-lymphocyte counts and plasma HIV-1 RNA levels.
Methods
Patients
Twenty-three consecutive adult chronically HIV-1 infected patients were enrolled in this study. They spontaneously complained of body changes due to fat redistribution and showed laboratory abnormalities in metabolic parameters. Body changes in every patient were confirmed by the doctor taking care of that patient and they were standarized through a questionnaire. That questionnaire included the perception of following possibilities by the patient: increased abdominal girth, enlargement of breasts, buffalo hump, face fat wasting and extremities fat wasting. Antiretroviral therapy prior to enrolment consisted of two nucleoside reverse transcriptase inhibitors and at least one PI. All patients decided to stop PI therapy because of psychological repercussions due to body changes despite sustained virological suppression (<200 HIV-1 RNA copies/ml plasma) for at least the previous 3 months. Nevirapine in escalating dose was offered to each patient in an attempt to maintain virological suppression. The reasons for prescribing nevirapine were that all of the patients were naive for non-nucleoside reverse-transcriptase inhibitors and that nevirapine was the only available drug of that class in Spain at that time. The remaining antiretroviral therapy remained unchanged. Patients were not recommended to change their daily activities and no specific dietary restrictions were imposed.
Data on fasting serum lipids and glucose prior to PI withdrawal was obtained from medical files. Physical examination including measurements of weight, height, waist and hip circumferences, and laboratory tests including metabolic parameters, CD4 T lymphocytes and plasma HIV-1 RNA were performed at baseline and every 3 months. The stage of HIV-1 infection was defined according to the 1993 Centers for Disease Control classification [17]. All patients were recruited from the AIDS Unit at the Hospital Clinic of Barcelona, Spain.
Laboratory determinations
Venous blood samples were drawn in the morning after 12 h overnight fasting. Plasma glucose was measured by the glucose hexokinase method. Total cholesterol and triglycerides were determined by the cholesterol- oxidase and glycerol-phosphatase-oxidase methods, respectively; all three methods were adapted to a DAX-72 analyzer (Bayer Diagnostics, Tarrytown, USA). Insulin was measured by monoclonal immuno- radiometric assay (IRMA, Med-Genix Diagnostics, Fleunes, Belgium).
Triglyceride levels were classified as: normal, <200mg/dl; borderline-high, 200-400mg/dl; high >400mg/dl [18]. Cholesterol levels were considered: normal, <200mg/dl; borderline-high, 200-239mg/dl; high, ≥240mg/dl [18]. For glucose, the following ranges were considered: normal, <110mg/dl; impaired fasting glucose, ≥110-126mg/dl; diabetes, ≥126mg/dl [19]. Fasting insulin resistance index (FIRI) was calculated as described previously [20]. Briefly, FIRI consists of the product of plasma insulin and glucose normalized to an expected glucose of 5mmol/l and insulin of 5mU/l.
The number of CD4 T lymphocytes was measured by flow cytometry. Plasma HIV-1 RNA was measured by a PCR assay (Amplicor HIV Monitor, Roche Diagnostics Systems, Branchburg, New Jersey, USA; lower limit of detection 200 copies/ml).
Anthropometry
Anthropometric measurements were measured by the same experienced nurse. Body weight was measured to the nearest 0.1kg and height to the nearest 1cm. Body mass index (BMI) was calculated as weight divided by squared height (kg/m2). Waist circumference was measured as the narrowest circumference between the lower costal margin and the iliac crest (approximately at the umbilicus) at the end of a gentle expiration. The hip measurement was the maximum circumference at the level of the femoral trochanters. The circumferences were measured using non-stretchable tapes to the nearest 1cm with the subject standing upright. Waist:hip ratio (WHR) was calculated by dividing the waist circumference by the hip circumference.
Cut-off points considered to evaluate anthropometric measurements were taken from the literature: a BMI of 27 was considered as the anthropometric measure dividing line between normal-weight and overweight people [21]; values of WHR of >0.9 for men or >0.8 for women were considered as indicators of abdominal obesity [22].
Statistical analysis
For the purpose of this study, the following six time points were considered: (i) at the onset of initial antiretroviral therapy; (ii) at the commencement of PI therapy; (iii) at the patient‚s perception of body changes; (iv) at the withdrawal of PI therapy and the commencement of nevirapine (baseline); (v) 3 months after PI withdrawal; and (vi) 6 months after PI withdrawal. The values of HIV-1 RNA copies/ml were log-transformed for comparisons. Comparisons of quantitative data at different time points were analysed using paired t tests. Statistical significance was assumed for P<0.05.
Results
Population characteristics
There were 11 women and 12 men. Of note is the fact that the proportion of women in this study (48%) was more than twice the overall proportion of women in the population cared for at the AIDS unit of the hospital (approximately 20%). The median age at baseline was 38 years [25-75% interquartile range (IQR), 34-49 years]. Eleven patients (48%) had AIDS criteria (stage A3, n=3; stage B3, n=1; stage C2, n=1; stage C3, n=6). The PI therapy that was withdrawn was indinavir in 18 patients, ritonavir in two patients, hard-gel saquinavir in one patient, and ritonavir plus hard-gel saquinavir in two patients.
Six patients (26%) had a PI-containing regimen as their initial antiretroviral therapy. In the remaining 17 patients, there was a median of 22 months (IQR, 12-38 months) between the commencement of antiretroviral therapy and the introduction of PI therapy. There was a median of 12 months (IQR, 9-14 months) from the commencement of PI therapy to the awareness of body changes. None of the patients had been taking concurrent therapies affecting carbohydrate or lipid metabolism prior to the awareness of body changes. Median metabolic laboratory parameters at the time of the awareness of body changes were as follows: triglycerides, 322mg/dl (IQR, 279-378mg/dl); cholesterol, 237mg/dl (IQR, 197-266mg/dl); glucose, 93mg/dl (IQR, 86-101mg/dl); insulin, 22mU/l (IQR, 17-26mU/dl); FIRI, 0.175mmol·mU/l2 (IQR, 0.135-0.216mmol·mU/l2). On detection of body changes, all patients but one (8476 copies/ml) had <200 HIV-1 RNA copies/ml, and median CD4 T-lymphocyte counts were 427¥106/l (IQR, 293-644¥106/l). On perception of body changes, the median values of BMI were 24.7kg/m2 (IQR, 23.4-26.2kg/m2) in men and 20.4kg/m2 (IQR, 20.1-23.6kg/m2) in women; median WHR were 0.97 (IQR, 0.94-1.01) in men and 0.84 (IQR, 0.80-0.89) in women.
HIV-1 RNA had been <200 copies/ml a median of 9 months (range, 7-11 months) before the withdrawal of PI therapy and the commencement of nevirapine. There was a median of 3 months (IQR, 2-3 months) from the awareness of body changes to the decision to replace PI therapy by nevirapine. Tolerance of nevirapine was good for all patients.
Evolution of laboratory parameters
Plasma viral load at time point 1 was available only for six patients. The other laboratory parameters (except for insulin that was only available from time point 3) were available for all patients and for all of the time points considered. The means and 95% confidence intervals for triglycerides, cholesterol, glucose, FIRI, CD4 T lymphocytes and HIV-1 RNA levels at each time point of the study are shown in Fig. 1. The values of triglycerides (P=0.0001), cholesterol (P=0.0001) and FIRI (P=0.0001) at time points 3 and 4 were significantly higher than at any other time point. The value of glucose was significantly higher than at other time points only at time point 4 (P=0.02). CD4 T lymphocytes (P=0.0001) were significantly lower and HIV-1 RNA (P=0.0001) was significantly higher at time points 1 and 2 than at any other time point. Changes in triglycerides, cholesterol, glucose, CD4 T lymphocytes and plasma viral load almost invariably preceded the perception of body changes by these patients (data not shown). The proportion of patients with a plasma viral load <200 copies/ml was 23 out of 23 (100%) and 22 out of 23 (96%) after 3 and 6 months of withdrawal of PI therapy, respectively.
Table 1 shows the distribution of the patients according to the values of metabolic laboratory parameters at the different time points considered in the study.
Evolution of anthropometric parameters
Anthropometric parameters were measured only from the withdrawal of PI therapy and the onset of nevirapine. Men had higher values of BMI and WHR than women at any time point of the study. Among the 12 men included in the study, a BMI >27kg/m2 was present in one (8%) at baseline, one (8%) at month 3, and two (17%) at month 6. None of the 11 women included in the study presented with a BMI >27kg/m2 at any time point when this parameter was measured. Among the 12 men included in the study, a WHR >0.9 was present in 12 (100%) at baseline, 11 (92%) at month 3, and 10 (83%) at month 6. Among the 11 women included in the study, a WHR >0.8 was present in eight (73%) at baseline, six (55%) at month 3, and three (27%) at month 6.
Fig. 2 shows the mean and 95% confidence intervals of waist and hip circumferences, WHR and BMI at baseline and at months 3 and 6. On comparing anthropometric parameters at baseline and at month 6, no differences were seen in weight (P=0.8), height (P=1), BMI (P=0.47), and waist circumference (P=0.47). Hip circumference showed a trend towards significance (P=0.07). WHR was significantly lower at month 6 (0.85) than at baseline (0.91) (P=0.048).
Association between subjective perception of body changes and laboratory and anthropometric parameters
Seventeen patients complained of increased abdominal girth (in 15 also of peripheral fat wasting) and six of peripheral fat wasting only before PI withdrawal. Body changes reported by the patients in order of frequency consisted of: increased abdominal girth plus enlargement of breasts plus face and extremities fat wasting (n=6, 100% women); increased abdominal girth plus face and extremities fat wasting (n=5, 20% women); increased abdominal girth plus extremities fat wasting (n=4, 50% women); face and extremities fat wasting (n=4, 25% women); increased abdominal girth plus face fat wasting plus buffalo hump (n=1, 0% women); increased abdominal girth plus buffalo hump (n= 1, 0% women); extremities fat wasting (n=1, 100% women); and buffalo hump (n=1, 0% women). No laboratory or anthropometric parameter at baseline differentiated patients according to sex or to the type of body changes reported.
Subjective improvement of body changes after 6 months was reported in 21 patients (91%) particularly concerning peripheral fat wasting. However, no laboratory or anthropometric parameter at 3 or 6 months distinguished those patients who complained from peripheral fat wasting at baseline from those who did not (data not shown).
Discussion
In our study, metabolic abnormalities passively improved upon replacement of PI by nevirapine after a relatively short time (6 months). That improvement occurred despite the fact that suppression of HIV-1 replication and the CD4 T-lymphocyte counts almost invariably remained unchanged. This fact strongly supports that it was PI therapy itself, and not viral suppression achieved by PI therapy, which was associated with metabolic abnormalities in the population studied.
Most of our patients showed an increased WHR on withdrawal of PI therapy irrespective of clinical manifestations of fat redistribution. Increased WHR is used to indicate a preferential accumulation of adipose tissue in the abdominal region. However, a large body of evidence indicates a modest predictive value of WHR in estimating abdominal adipose tissue [23]. Several components, including bone structure, subcutaneous adipose tissue thickness and muscle volume of the subjects studied, may contribute to the variability in the WHR. Although some imaging methods (sonography, computerized tomography, and magnetic resonance imaging) may provide a more accurate anthropometric measure of intra-abdominal adipose tissue than WHR, the simplicity and low cost of WHR make it a suitable method for use in population studies. WHR significantly decreased over a 6-month period in the population studied. Nevertheless, the extrapolation of changes in WHR as accurate markers of body changes due to fat redistribution in HIV-1-infected patients treated with HAART cannot be inferred from this study.
The passive therapeutic approach that consists of replacing PI by other non-PI drugs (such as non- nucleoside reverse transcriptase inhibitors) with the aim of maintaining an antiretroviral potency strong enough to suppress the replication of HIV-1, may not be useful in certain patients with metabolic abnormalities and fat redistribution. This may particularly be true for those patients who have not achieved suppression of viral replication or those who show intolerance to the alternative drug. Moreover, although an improvement in metabolic abnormalities and fat redistribution was observed after switching from PI to nevirapine in this study, none of the patients admitted to have their body shaped as prior to body changes. We do not know whether these metabolic abnormalities revert completely after PI discontinuation or whether some residual alterations persist. Finally, there are not yet enough data on comparisons between PI-sparing antiretroviral regimens and standard PI-containing regimens: preliminary data indicate that both approaches may display similar potent antiretroviral activity at short-term as first line HAART regimens [2,3], but long-term data are lacking.
Our study had several limitations. First, a limited number of patients were studied. Second, subjects were followed for a relatively short time after the discontinuation of PI therapy and therefore the long-term effects of PI discontinuation are not known. Finally, data are limited to the effects of nevirapine and conclusions cannot be extended to other drugs.
In summary, metabolic abnormalities associated with potent antiretroviral regimens including PI may revert at least partially, whereas suppression achieved may be preserved at least in the middle term after replacing PI by nevirapine.
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© 1999 Lippincott Williams & Wilkins, Inc.