abacavir and Lipodystrophy

Topics: Acquired Immunodeficiency Syndrome; Cross-Sectional Studies; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Female; HIV Infections; Humans; Hyperlipidemias; Incidence; Lamivudine; Lipodystrophy; Male; Randomized Controlled Trials as Topic; Risk Assessment

Switch studies have been carried out to explore changes in side effects in adherence. Discontinuing the protease inhibitor (PI) component of highly active antiretroviral therapy (HAART) regimen is often associated with improved adherence and improved quality of life. Following switching from a PI to a non-nucleoside reverse transcriptase inhibitor or abacavir, there is however a clear trend toward an improved metabolic profile particularly in insulin resistance and triglyceride levels when patients discontinue their PI. Peripheral wasting is likely to be associated with nucleoside analogues and for individuals with isolated fat accumulation, modification of HAART is not recommended. Virological suppression can be maintained following switch if adequate suppression of the virus has been achieved for at least six months prior to switch and the patient has not been previously exposed to suboptimal HAART. Discontinuing the PI preserves this class of agents for future use. Switching however may be associated with other side effects; hypersensitivity, skin rashes, hepatic or neuropsychiatric events.

Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV Protease Inhibitors; Humans; Lipodystrophy; Metabolic Diseases; Nevirapine; Oxazines; Patient Compliance; Reverse Transcriptase Inhibitors

Abacavir has replaced stavudine in antiretroviral therapy (ART) regimens because it has largely been phased out as a result of toxicity concerns; this loss has reduced further the already-limited drug options for children. Few data regarding virologic and metabolic outcomes among children who undergo substitution of stavudine exist. We evaluated the effects of preemptive substitution of abacavir for stavudine in children initially without lipodystrophy and virally suppressed on a stavudine-containing regimen.. At Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa, virally suppressed human immunodeficiency virus (HIV)-infected children ≥36 months of age without lipodystrophy were randomly assigned to continue taking stavudine as part of their ART regimen (n = 106) or to have abacavir substituted for stavudine (n = 107). The children were followed for 56 weeks after randomization in the context of a larger trial of treatment options for ART-experienced children.. The mean age of the children was 4.3 years, and the mean duration of ART before random assignment was 3.5 years. No differences in virological outcomes, CD4 response, growth, or dyslipidemia were noted between the stavudine and abacavir groups. By 56 weeks, children in the abacavir group had less clinically detected lipodystrophy (4.7% vs 16%, respectively), a higher proportion of leg fat relative to total fat (0.243 vs 0.230, respectively; P = .006), and a lower trunk/leg-skinfold ratio (0.547 vs 0.569, respectively; P = .003) than the children in the stavudine group.. Substituting abacavir for stavudine did not compromise virological response to treatment and was associated with significantly less lipodystrophy. These results support recommendations that favor abacavir in this population.

Topics: Anthropometry; Anti-HIV Agents; Body Composition; CD4 Lymphocyte Count; Child, Preschool; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Infant; Lipodystrophy; Male; South Africa; Stavudine; Viral Load

Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls.. In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression.. Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5-4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5-7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5-3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6-4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01).. In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.

Topics: Anthropometry; Anti-HIV Agents; Child; Child, Preschool; Cross-Sectional Studies; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipid Metabolism; Lipodystrophy; Lipoproteins, HDL; Lipoproteins, LDL; Male; Nevirapine; Stavudine; Triglycerides; Viral Load; Zidovudine

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery.. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007).. Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)].. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Atrophy; Body Composition; Chemistry, Pharmaceutical; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Intention to Treat Analysis; Lamivudine; Lipids; Lipodystrophy; Lopinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure

To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir.. NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements.. Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed.. Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

Topics: Adult; Alkynes; Anthropometry; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Glucose; Cholesterol; Cholesterol, HDL; Cyclopropanes; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Triglycerides

Stavudine use is a contributing factor for lipoatrophy, whereas use of abacavir or zidovudine is less likely to cause this complication. The TARHEEL study was a 48-week, open-label study that assessed changes in lipoatrophy after abacavir (86 patients [73%]) or zidovudine (32 patients [27%]), 300 mg twice daily, was substituted for stavudine for 118 human immunodeficiency virus (HIV)-infected patients (HIV type 1 RNA level, <400 copies/mL) with virological suppression who had developed lipoatrophy after > or =6 months of stavudine-based treatment. At week 48, full-body dual-energy x-ray absorptiometry demonstrated a median increase in arm fat of 35%, leg fat of 12%, and trunk fat of 18%, compared with the baseline level. These improvements coincided with fat gain in lipoatrophic areas that was documented by computerized tomography. Results of a "body image" questionnaire showed that a substantial percentage of patients reported some or a lot of fat gain in the arms (22%), legs (18%), buttocks (19%), and face (27%). HIV suppression was maintained over the study period. In conclusion, replacing stavudine with abacavir or zidovudine resulted in improvement in stavudine-induced lipoatrophy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV; HIV Infections; HIV-1; Humans; Lipodystrophy; Male; Middle Aged; RNA, Viral; Stavudine; Treatment Outcome; Viral Load; Zidovudine

Peripheral lipoatrophy may complicate antiretroviral therapy of human immunodeficiency virus (HIV) infection, often related to duration and type of nucleoside analog therapy, and may have a mitochondrial pathogenesis. No proven therapy exists for lipoatrophy, but abacavir is a nucleoside analog that may be less toxic to mitochondria.. To determine if substitution of stavudine or zidovudine with abacavir improves HIV lipoatrophy without affecting control of HIV replication.. Randomized, open-label 24-week study.. Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001.. A total of 111 adults (109 men) with moderate or severe lipoatrophy who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy.. Patients were randomly assigned to switch from stavudine or zidovudine to abacavir, 300 mg twice per day, while continuing all other antiretroviral therapy (n = 54) or to continue all antiretroviral therapy (n = 57).. The primary end point was limb fat mass, measured by dual-energy x-ray absorptiometry; key secondary end points were plasma HIV RNA levels, adverse events, physician-assessed (via subjective measures) lipodystrophy severity, total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate) levels.. There was a significant increase in limb fat in the abacavir group relative to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31; 95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative increases in subcutaneous thigh (P =.01), arm (P<.001), and abdominal (P =.001) fat areas on computed tomography. Switching had no significant effect on secondary end points, including plasma HIV RNA (for unadjusted comparison between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in limb fat mass at week 24 did not correlate with change in subjectively determined perceived lipoatrophy severity (r = -0.06; P =.53 by Spearman correlation). Hypersensitivity to abacavir was seen in 5 patients (10%).. In this sample of lipoatrophic HIV-infected adults, switching from stavudine or zidovudine to abacavir for 24 weeks led to significant, albeit modest, objectively measured increases in limb fat. Clinical lipoatrophy, as assessed subjectively, did not resolve, however, and at the rate of increase observed may take years to resolve with use of this strategy. Longer-term follow-up is needed.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Body Composition; Dideoxynucleosides; Female; HIV Infections; Humans; Lipids; Lipodystrophy; Male; Middle Aged; Quality of Life; Reverse Transcriptase Inhibitors; Stavudine; Tomography, X-Ray Computed; Treatment Outcome; Viral Load; Zidovudine

Lipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution.. Eighty-one HIV protease inhibitor recipients (78 male; mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48.. There was a greater decline in total body fat in the switch group than in the continue group (-1.6 and -0.4 kg, respectively at week 24; P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter.. In predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Carnitine; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Organophosphonates; Quality of Life; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Treatment for HIV-1 infection is complicated by fat redistribution (lipodystrophy). This is associated with insulin resistance concerning glucose uptake. Our aim was to characterize glucose metabolism more comprehensively in HIV-1-infected patients with lipodystrophy. We assessed glucose disposal and its pathways, glucose production, plasma free fatty acid (FFA) levels, and the degree to which these parameters could be suppressed by insulin.. Six HIV-1-infected men on protease inhibitor-based HAART with lipodystrophy (HIV+LD) were studied. The results were compared with those in six matched healthy male volunteers. Insulin sensitivity was quantified by hyperinsulinemic euglycaemic clamp. Glucose production and uptake were assessed by tracer dilution employing 6,6D(2)-glucose.. At post-absorptive insulin concentrations, glucose production was 47% higher in HIV+LD than controls (P = 0.025). During clamp, glucose production was suppressed by 53% in HIV+LD, but by 85% in controls (P = 0.004). Glucose disposal increased in both groups, but by only 27% in HIV+LD versus 201% in controls (P = 0.004). Consequently, insulin-stimulated total glucose disposal was lower in HIV+LD patients (P = 0.006). Non-oxidative glucose disposal as percentage of total disposal did not differ significantly between groups (63% in HIV+LD and 62% in controls). Baseline plasma FFA concentrations were higher (0.60 versus 0.35 mmol/l; P = 0.024), whereas FFA decline during hyperinsulinemia was less (65 versus 85%; P = 0.01) in HIV+LD versus controls.. Post-absorptive glucose production is increased in HIV-1-infected patients with lipodystrophy. Moreover, both the ability of insulin to suppress endogenous glucose production and lipolysis, and to stimulate peripheral glucose uptake and its metabolic pathways is reduced, indicating severe resistance concerning multiple effects of insulin.

Topics: Adult; Anti-HIV Agents; Body Composition; Dideoxynucleosides; Drug Therapy, Combination; Fatty Acids; Glucose; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Reverse Transcriptase Inhibitors

Stavudine (d4T) has been associated with lipoatrophy and hyperlactatemia. In recent studies, d4T has also been related to both hypercholesterolemia and hypertriglyceridemia. Replacing d4T with another nucleoside analogue such as abacavir (ABC) may reduce lactate levels and improve lipoatrophy in the long term. However, the impact of this strategy on the lipid profile is still unclear. In a prospective and randomized study, fasting lipids were examined over 48 weeks in 112 subjects on d4T regimens, 49 of whom replaced d4T with ABC. The substitution of ABC for d4T was found to be safe and provided a reduction in both LDL cholesterol and the total cholesterol (TC)/HDLc ratio, which might impact favorably on cardiovascular risk.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Lipids; Lipodystrophy; Male; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Stavudine

Topics: Dideoxynucleosides; Drug Hypersensitivity; Humans; Lipodystrophy; Protease Inhibitors; Reverse Transcriptase Inhibitors; Skin Diseases

Topics: Absorptiometry, Photon; Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Humans; Lipodystrophy; Male; Reverse Transcriptase Inhibitors

Concerns regarding metabolic perturbations occurring during protease inhibitor (PI)-based regimens have led to investigation of switching from a PI-based to a non-nucleoside reverse transcriptase inhibitor- or abacavir-based regimen. There appear to be considerable benefits to switching from a PI-based regimen to one of these PI-sparing regimens. In particular, patients appear generally pleased with the improved administration characteristics of the new regimens, and improvements in quality of life have been reported. However, resolution of the metabolic abnormalities that may arise during PI therapy is incomplete. Peripheral or subcutaneous fat mass improvements are not evident in the studies reported to date. Weight gain, probably in part due to removal of PI-related dietary restrictions, has been observed and may lead to improvements in appearance. Maintenance of virologic control varies among studies but is generally in the range of 85% to 100% of the patients receiving the PI-sparing regimen. The extent of prior drug exposure (or drug resistance) in patients entering the studies may be a key risk factor for loss of virologic control.

Topics: Acquired Immunodeficiency Syndrome; Adipose Tissue; Alkynes; Benzoxazines; Cyclopropanes; Dideoxynucleosides; HIV Protease Inhibitors; Humans; Lipodystrophy; Nevirapine; Oxazines

Some physicians are beginning to prescribe potent drug cocktails that do not include protease inhibitors. This is a departure from the standard treatment that has included protease inhibitors since their introduction in recent years. Protease inhibitors remain among the most effective and important treatments developed, but there are significant problems, including cross-resistance and patient intolerance. Also, protease inhibitors are associated with serious side effects such as lipodystrophy. Protease-sparing regimens such as abacavir/AZT/3TC and drug combinations that include efavirenz appear to be as effective as protease-inhibitor containing regimens. Results of new treatment approaches are summarized.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Lamivudine; Lipodystrophy; Oxazines; Reverse Transcriptase Inhibitors; Time Factors; Zidovudine