Drug toxicities have been one of the important factors associated with reduced quality of life among HIV-infected patients taking highly active antiretroviral therapy (HAART). Apart from acute toxicities, morphologic and metabolic complications associated with long-term HAART use have been widely described in the developed world. These include abnormalities in fat distribution (lipodystrophy), dyslipidemia, insulin resistance and diabetes, hyperlactatemia, osteopenia, and osteonecrosis.1-3 As access to HAART improves in the developing world, it is important to determine the prevalence of these complications. World Health Organization (WHO)-prequalified fixed-dose combinations of stavudine/lamivudine/nevirapine (d4T/3TC/NVP) and zidovudine/lamivudine/nevirapine (ZDV/3TC/NVP) are being widely promoted in HAART “scale-up” programs. We assessed the prevalence and predictors of morphologic and metabolic complications in patients taking these combinations in western India.
A cross-sectional study was conducted at a tertiary HIV care center in Pune, India. Patients paid for their own drugs, and the institute's ethics committee approved the study.
HIV-infected patients on first-line d4T/3TC/NVP (150 patients) or ZDV/3TC/NVP (30 patients) for >1 year were consecutively recruited from July-December 2003. All patients used fixed-dose combinations of HAART manufactured by Cipla, Ltd., (Mumbai, Maharashwa, India) which have been prequalified by the WHO. We have included only patients on their first-line regimen for more than a year because the body fat changes become more clinically apparent in the 2nd year of treatment.4 Patients having high levels of adherence as assessed by self-report, clinical improvement, and increased CD4 counts and macrocytosis on hemogram were eligible for inclusion. High level of adherence was defined as >95% and was assessed by (verbal) administration of a standard series of questions adapted from Adult AIDS Clinical Trials Group (AACTG) adherence instruments. We used 4- and 7-day recall and global dose missing assessment. The 95% is referable to the 4-day recall data. Clinical improvement was defined as resolution or prevention of HIV/AIDS-associated indicator conditions, weight gain, and reported improvement in sense of well-being. Immunologic improvement is defined as statistically significant increase in the CD4 count at the point of assessment as compared with pretherapy baseline. Macrocytosis was used as a secondary marker of adherence, as this is typically seen in patients on thymidine-based regimens. We chose an mean corpuscular volume (MCV) ≥100/fL as a cut-off to define macrocytosis for study purposes. Patients who had switched from ZDV/3TC/NVP to d4T/3TC/NVP or vice versa were not recruited. Antiretroviral-naive HIV-infected patients not having any HIV-related illness within 8 weeks of assessment were recruited during the same period and served as controls.
Routine demographic information along with body mass index was obtained for all patients. CD4 counts were measured by flow cytometry (Becton Dickinson, CA, USA).
Lipodystrophy, including lipoatrophy, lipohypertrophy, and mixed pattern, was assessed in patients taking HAART by history (self-report) and clinical confirmation or detection during examination by the physician who had been following the case since initiation of therapy. Lipoatrophy was defined as hollowing of cheeks, wasting of extremities, or flattening of buttocks. Lipohypertrophy was defined as increase in the amount of fat in the abdomen, neck, or breasts. Patients having both these features were defined to have mixed pattern.
In addition to lipodystrophy, metabolic complications of HAART therapy were assessed. Blood was collected after a 12-hour overnight fast for glucose and lipid measurement (Beckman Automated analyzer, CA, USA). Dyslipidemia was defined according to the US National Cholesterol Education Program (NCEP) III guidelines.5 These include total cholesterol ≥200 mg/dL, low-density lipoprotein (LDL) cholesterol ≥130 mg/dL, triglycerides ≥150 mg/dL, very high triglycerides ≥500 mg/dL, high-density lipoprotein (HDL) cholesterol ≤40 mg/dL, HDL ≥60 mg/dL, and total cholesterol/HDL) ≥6.5. Fasting hyperglycemia was defined as blood glucose level ≥110 mg/dL.
Data was analyzed using Statistical Package for the Social Sciences (SPSS) 12.0.1 (Chicago, IL). Comparison of baseline characteristics across the 3 groups (ie, controls, d4T/3TC/NVP, and ZDV/3TC/NVP) was carried out by 1-way analysis of variance and contingency coefficient test for continuous and categorical variables, respectively. Frequency of lipodystrophy and metabolic complications between the 2 treatment groups was compared by χ2 test, and metabolic complications across the 3 groups were compared by contingency coefficient test, a measure of association based on the χ2 test. Forward logistic regression (likelihood ratio) was used to determine association of each of the lipodystrophy components with the following independent variables: age, gender, baseline and current CD4 counts, and type and duration of HAART regimen. Logistic regression was also used to determine the association of age, gender, and treatment status, type of treatment, and current CD4 counts with each of the metabolic complications. The Hosmer-Lemeshow goodness-of-fit statistic was used to determine how well the model described the data.
Study Patient Characteristics
A total of 306 consenting patients were studied. Of these, 150 patients taking d4T/3TC/NVP and 30 patients taking ZDV/3TC/NVP served as cases, and 126 patients served as controls. Study entry characteristics of patients are summarized in Table 1. Ninety-four percent had acquired HIV infection by heterosexual transmission. At initiation of therapy, 38.6% and 36.6% of patients had WHO stage IV disease in the d4T/3TC/NVP and ZDV/3TC/NVP arms, respectively (P = 1.0). The mean CD4 cell counts at initiation of therapy in patients on d4T/3TC/NVP and ZDV/3TC/NVP were 116.9 cells/mm3 and 134.4 cells/mm3, respectively, and all patients had CD4 <200 cells/mm3 before starting therapy. The median duration of therapy was 18 months, and patients in the ZDV/3TC/NVP arm were taking HAART significantly longer than patients on d4T/3TC/NVP. At the time of evaluation, mean CD4 counts in the control, d4T/3TC/NVP, and ZDV/3TC/NVP arms were 259.8, 407, and 459.3 cells/mm3, respectively. Only highly adherent patients were enrolled, so all patients reported >97% adherence to their regimens.
The overall prevalence of lipodystrophy among treated patients was 46.1%. Lipoatrophy was documented in 26.7% of patients on d4T/3TC/NVP and in 10% of patients on ZDV/3TC/NVP (P = 0.08). Lipohypertrophy was reported in 23.3% and 16.7% (P = 0.57) and mixed pattern in 10% and 6.7% of patients (P = 0.81) taking d4T/3TC/NVP and ZDV/3TC/NVP, respectively. Body habitus changes were reported by 43.3% of patients, and the remaining were first diagnosed on physical examination. Only use of d4T was associated with development of lipoatrophy on regression analysis (adjusted odds ratio 3.3, 95% CI 1.3-11.3, P = 0.04).
The prevalence of metabolic disturbances is summarized in Table 2. Proportions of patients with NCEP III abnormal elevations of total cholesterol, LDL, and triglyceride levels were significantly higher in the treatment groups and proportion of patients with low HDL (≤40 mg/dL) were significantly higher in control group. There was no significant difference in the proportion of patients with total cholesterol/HDL ≥6.5 among the 3 groups. However, the proportion of patients with total cholesterol ≥240 mg/dL and HDL ≥60 mg/dL was significantly higher in the treatment groups. Very high triglyceride levels were seen only in the d4T/3TC/NVP group. Fasting hyperglycemia was also significantly higher in both the treatment groups. These differences were maintained even after adjusting for other variables (Table 3).
There were no significant differences in the prevalence of dyslipidemia and hyperglycemia between the 2 treatment groups. Among lipid abnormalities, only the prevalence of triglycerides ≥150 mg/dL was significantly higher in patients with lipodystrophy (lipoatrophy P = 0.001, lipohypertrophy P = 0.001, and mixed P = 0.02).
We have demonstrated a high prevalence of lipodystrophy, dyslipidemia, and hyperglycemia among patients taking first-line WHO-recommended HAART regimens in western India. Dyslipidemia and hyperglycemia are well-recognized risk factors for development of coronary artery disease, stroke, and peripheral vascular disease.6
Due to cost, a disproportionate number of patients were taking d4T/3TC/NVP, which may be true all over the developing world. This regimen is also popular because of the fear of development of anemia with ZDV-based regimens in a population already having low hemoglobin levels.
We included patients with very high levels of adherence in our study. This was achieved by careful screening for readiness prior to initiation of therapy, using fixed-dose combinations of HAART regimens, ensuring availability of monthly packs, and reinforcing the importance of adherence at each follow-up visit.
The prevalence of lipodystrophy in our study is similar to some developed country studies that have reported it in 50% of patients taking HAART.7-9 There are limited data on these complications in Asian populations.10,11 Some studies have demonstrated no difference in the prevalence of lipoatrophy and lipohypertrophy among patients taking ZDV- or d4T-based regimens.12 However, a recent review examining the role of nucleoside reverse transcriptase inhibitor (NRTI) therapy in lipodystrophy syndrome provided evidence that lipoatrophy is strongly and specifically associated with use of certain NRTI drugs-d4T more than ZDV.13 We also found that only d4T use was significantly associated with lipoatrophy. However, with longer use of ZDV, lipodystrophy may be seen.
Though an objective case definition for diagnosing lipodystrophy syndrome has been suggested, its reliability in the absence of tools like dual-energy x-ray absorptiometry is low.14 However, a significant proportion of patients have self-reported body habitus changes and were worried because of the similarity of the features (particularly lipoatrophy) with AIDS-related wasting. Thus, treatment-related adverse effects can further stigmatize the HIV-infected population. Additionally, concerns about body habitus changes may lead to lower adherence, and adherence support programs must address this important issue.
Several factors have been identified to be associated with lipodystrophy including age and duration of antiretroviral therapy.15 Duration of therapy has not significantly associated with lipodystrophy in our study, probably because we included only patients who were on treatment for more than a year.
Drugs of the NNRTI class, and particularly NVP, are considered less atherogenic than protease inhibitors (PIs).16 Although NNRTI-based regimens are associated with high total cholesterol and LDL levels, they may also induce an increase in HDL.17 Approaches like switching from PI-based to NVP-based regimens have been studied with this intention.18,19 We did document a positive effect on HDL; however, this was not reflected in the total cholesterol/HDL ratio. On the contrary, we saw a greater proportion of patients with high total cholesterol and LDL. The role of NRTIs, particularly d4T, in development of dyslipidemia has also been documented.20,21 LDL cholesterol is the major risk factor for development of coronary artery disease and is the primary target of therapy for primary and secondary prevention.4 Whether HAART-induced dyslipidemia increases the incidence of coronary artery disease is unresolved.22
We were concerned that patients on HAART showed a significantly increased risk of fasting hyperglycemia, although its prevalence is lower than that of lipodystrophy and dyslipidemia. Fasting hyperglycemia has been associated with PI use, but we documented it in patients who were PI naive.
The pathogenesis of lipodystrophy is unclear, although a complex model involving use of antiretroviral therapies and host and environmental factors has been suggested.23 Depletion of mitochondrial DNA by NRTIs, particularly the thymidine analogues, is the most favored hypothesis for development of body fat changes.
Limitations of our study include the cross-sectional design, nonrandomized treatment allocations, disproportionately smaller number of patients in the ZDV/3TC/NVP arm, and lack of HIV-negative Indian controls. Additionally, morphologic changes were assessed subjectively as dual-energy x-ray absorptiometry was expensive. We also did not determine viral loads and their association with these complications; nor did we determine lactate levels. We did not assess for lipodystrophy in the untreated group because no patient in this group self-reported body habitus changes.
In summary, our study demonstrates a high prevalence of morphologic and metabolic complications among patients taking WHO-recommended first-line generic HAART regimens in western India. Whether this may ultimately translate into higher morbidity from coronary artery disease and strokes is not known. The psychologic and social consequences of lipodystrophy syndrome in the developing world, and their impact on the acceptance of antiretroviral therapy, need to be studied in detail. Although at present the benefit of taking HAART seems to be much higher than the risk of developing these adverse events, access programs should address them. Additionally, access to alternative drugs (eg, tenofovir and abacavir) that may be less offending must be improved. However, use of these drugs will dramatically increase the cost of HAART access programs.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
lipodystrophy; dyslipidemia; India; nevirapine; stavudine