Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN.

Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96 efficacy and safety of darunavir/ritonavir (DRV/r) versus lopinavir/ritonavir (LPV/r). Treatment-experienced, LPV-naive, HIV-1-infected patients were randomised to DRV/r 600/100 mg bid or LPV/r 400/100 mg bid plus optimised background regimen (≥ 2 NRTIs/NNRTIs). 595 patients were enrolled (mean baseline HIV-1 RNA: 4.30 log10 copies/mL; median CD4 count: 232 cells/mm3). At Week 96, more DRV/r than LPV/r patients achieved HIV-1 RNA < 400 copies/mL (66.8% versus 58.9% [intent-to-treat (ITT)/time-to-loss of virological response (TLOVR)], estimated difference 8.7%, 95% confidence interval [CI]: 0.7-16.7), demonstrating the primary endpoint of non-inferiority of DRV/r (p < 0.001); the difference in response was statistically significant (p = 0.034). For the secondary efficacy parameter (HIV-1 RNA < 50 copies/mL) at Week 96, response to DRV/r was 60.4% versus 55.2% for LPV/r (ITT-TLOVR), estimated difference 5.8%, 95% CI: -2.3-13.9. Virological failure (VF; HIV-1 RNA > 400 copies/mL) with DRV/r (13.8%) was nearly half that with LPV/r (25.6%). Discontinuations due to adverse events were 8.1% for both DRV/r and LPV/r. Treatment-related grade 2-4 diarrhoea was 8.1% (DRV/r) versus 15.2% (LPV/r). Increases in triglycerides and total cholesterol were less pronounced with DRV/r. At 96 weeks, noninferiority (HIV-1 RNA < 400 copies/mL) of DRV/r over LPV/r was maintained; the difference in response was statistically significant. VF rate and treatment-related grade 2-4 diarrhoea were lower with DRV/r versus LPV/r.

Alterations in immune function are associated with liver enzyme elevation in HIV and HCV co-infection after commencement of combination antiretroviral therapy.

The cause of liver enzyme elevation during combination antiretroviral therapy in people with human immunodeficiency virus and hepatitis C virus co-infection is unclear. We followed 12 subjects (five with alanine transaminase elevation) for 24 weeks after combination antiretroviral therapy commencement. Immune responses against hepatitis C virus, human immunodeficiency virus and other viruses were assessed by interferon-γ ELISpot. Plasma cytokines, chemokines and anti-hepatitis C virus antibody levels were measured. Those with liver enzyme elevation had higher ELISpot responses both against hepatitis C virus non-structural regions and other viral antigens, and their anti-hepatitis C virus antibody levels were consistently higher, suggesting that reconstitution of both hepatitis C virus-specific and non-hepatitis C virus-specific immune responses may be associated with liver transaminase elevation during combination antiretroviral therapy.

Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients.

OBJECTIVE: ODIN (Once-daily Darunavir In treatment-experieNced patients) was a phase III, 48-week, open-label study comparing once-daily vs. twice-daily darunavir/ritonavir (DRV/r) in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. METHODS: Patients with no DRV RAMs and receiving stable HAART for at least 12 weeks were stratified by HIV-1 RNA (≤ or > 50 000 copies/ml) and randomized to once-daily DRV/r 800/100 mg or twice-daily DRV/r 600/100 mg and an optimized background regimen (≥2 nucleoside reverse transcriptase inhibitors). Primary objective was to demonstrate noninferiority of once-daily vs. twice-daily DRV/r in confirmed virologic response (HIV-1 RNA < 50 copies/ml) at week 48. RESULTS: Five hundred and ninety patients received once-daily (n = 294) or twice-daily (n = 296) DRV/r. Mean baseline HIV-1 RNA was 4.16 log10 copies/ml; median CD4 cell count was 228 cells/µl; and 53.9% had previously used at least one protease inhibitor. At week 48, 72.1% of once-daily and 70.9% of twice-daily patients achieved HIV-1 RNA less than 50 copies/ml (intent-to-treat/time-to-loss of virologic response). The difference in response between once-daily and twice-daily arms was 1.2% (95% confidence interval -6.1 to 8.5%; P < 0.001), establishing noninferiority of once-daily DRV/r versus twice-daily DRV/r. Median CD4 cell count increase was 100 (once-daily) and 94 cells/µl (twice-daily). Virologic failure rate was low and similar for both arms; only one patient (once-daily arm) developed primary protease inhibitor mutations. Once-daily DRV/r had a lower incidence of grade 2-4 triglyceride increases (5.2 vs. 11.0%, P < 0.05). CONCLUSION: Once-daily DRV/r 800/100 mg was noninferior in virologic response to twice-daily DRV/r 600/100 mg at 48 weeks in treatment-experienced patients with no DRV RAMs, and with a more favorable lipid profile. These findings support use of once-daily DRV/r in this population.

Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials.

BACKGROUND: To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy. METHODS: The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729. FINDINGS: 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. INTERPRETATION: Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir. FUNDING: Merck.

Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis.

OBJECTIVE: Present 96-week data from ongoing ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In Naive Subjects) trial. METHODS: Randomized, open-label, phase III trial of antiretroviral-naive patients with HIV-1 RNA at least 5000 copies/ml (stratified by HIV-1 RNA and CD4 cell count) receiving darunavir/ritonavir (DRV/r) 800/100 mg once daily or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose (twice daily or once daily) and fixed-dose tenofovir/emtricitabine. Primary outcome measure was noninferiority of DRV/r vs. LPV/r in virologic response (<50 copies/ml, time-to-loss of virologic response) at 96 weeks (secondary outcome: superiority). RESULTS: Six hundred eighty-nine patients were enrolled. At week 96, significantly more DRV/r (79%) than LPV/r patients (71%) had viral load less than 50 copies/ml, confirming statistical noninferiority (estimated difference: 8.4%; 95% confidence interval 1.9-14.8; P < 0.001; per-protocol) and superiority (P = 0.012; intent-to-treat) in virologic response. Median CD4 cell count increases from baseline were 171 and 188 cells/microl for DRV/r and LPV/r, respectively (P = 0.57; noncompleter=failure). Overall, 4% of DRV/r patients and 9% of LPV/r patients discontinued treatment due to adverse events. Lower rates of grade 2-4 treatment-related diarrhea were seen with DRV/r (4%) vs. LPV/r (11%; P < 0.001), whereas grade 2-4 treatment-related rash occurred infrequently in both arms (3 vs. 1%, respectively; P = 0.273). DRV/r patients had smaller median increases in triglycerides (0.1 and 0.6 mmol/l, respectively, P < 0.0001) and total cholesterol (0.6 and 0.9 mmol/l, respectively; P < 0.0001) than LPV/r patients; levels remained below National Cholesterol Education Program cut-offs for DRV/r. CONCLUSION: At week 96, once-daily DRV/r was both statistically noninferior and superior in virologic response to LPV/r, with a more favorable gastrointestinal and lipid profile, confirming DRV/r as an effective, well tolerated, and durable option for antiretroviral-naive patients.

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells.

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults.

OBJECTIVES: Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels. DESIGN: 48-week substudy of a randomized, open-label, three-arm trial. SETTING: Hospital and community HIV clinics. PARTICIPANTS: 140 HIV-infected adults naive to antiretroviral therapy. INTERVENTION: Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine. MAIN OUTCOME MEASURES: Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r. RESULTS: Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml). CONCLUSION: Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients.

BACKGROUND: An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing. METHODS: Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8. RESULTS: After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (+/-SD) area under the plasma concentration-time curve over 12 h (AUC0-12 h) was 1,284 (+/-958) ng x h/ml when etravirine was administered as 100 mg twice daily (n=33), 3,713 (+/-2,069) ng x h/ml when administered as 200 mg twice daily (n=27) and 2,607 (+/-2,135) ng x h/ml when administered as 800 mg twice daily (n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated. CONCLUSIONS: The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.

HLA-B*5701 screening for hypersensitivity to abacavir.

BACKGROUND: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. METHODS: This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. RESULTS: The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). CONCLUSIONS: HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)

Drug resistance and viral evolution in plasma and peripheral blood cells during structured treatment interruption (STI) and non-interrupted HAART.

BACKGROUND: Highly active antiretroviral therapy (HAART) can successfully reduce plasma and tissue levels of HIV-1 RNA and results in reductions in HIV-related morbidity and mortality, but the slow viral evolution during therapy in cellular reservoirs is a continuing problem. In addition, little remains known how viral evolutionary process may differ between cell-free and cell-associated compartments, over time, in vivo in patients receiving HAART or STI. OBJECTIVES: The main objectives of this study were to assess viral replication kinetics, drug resistance and viral evolution during HAART and STI. STUDY DESIGN: We have conducted a longitudinal study of virus culture kinetics in vitro, molecular analysis of uncultured HIV-1 variants from plasma and PBMC of 6 patients on HAART, 4 patients on STI, and 6 from treatment-naïve patients. RESULTS: Our data suggest that drug resistance mutations remained compartmentalized between plasma and PBMC. The divergent distribution of resistance mutations between plasma and PBMC coincided with divergent env gene evolution in these compartments. In contrast, the HIV strains from therapy-naive patients showed tight genetic and phylogenetic concordance between plasma and PBMC. Both STI and non-STI groups showed the presence of resistance mutations to both RT and protease inhibitors, which correlated with inadequate suppression of viremia and partially with the virus culture isolation in vitro. CONCLUSIONS: Overall, STI for HIV patients has no added advantage over regular HAART at the virologic level and in the diminution of resistance mutations that result in therapy failure. Under both forms of anti-retroviral therapies, virus could be isolated in vitro from the PBMC showing continuing low-level viral replication under suppressive therapy. Overall, these data may be useful in predicting the late emergence of drug resistance mutations via the latent integrated provirus.

Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial.

BACKGROUND: Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS: Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS: Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS: TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

A randomised trial comparing genotypic and virtual phenotypic interpretation of HIV drug resistance: the CREST study.

OBJECTIVES: The aim of this study was to compare the efficacy of different HIV drug resistance test reports (genotype and virtual phenotype) in patients who were changing their antiretroviral therapy (ART). DESIGN: Randomised, open-label trial with 48-week followup. SETTING: The study was conducted in a network of primary healthcare sites in Australia and New Zealand. PARTICIPANTS: Patients failing current ART with plasma HIV RNA > 2000 copies/mL who wished to change their current ART were eligible. Subjects were required to be > 18 years of age, previously treated with ART, have no intercurrent illnesses requiring active therapy, and to have provided written informed consent. INTERVENTIONS: Eligible subjects were randomly assigned to receive a genotype (group A) or genotype plus virtual phenotype (group B) prior to selection of their new antiretroviral regimen. OUTCOME MEASURES: Patient groups were compared for patterns of ART selection and surrogate outcomes (plasma viral load and CD4 counts) on an intention-to-treat basis over a 48-week period. RESULTS: Three hundred and twenty seven patients completing >or= one month of followup were included in these analyses. Resistance tests were the primary means by which ART regimens were selected (group A: 64%, group B: 62%; p = 0.32). At 48 weeks, there were no significant differences between the groups for mean change from baseline plasma HIV RNA (group A: 0.68 log copies/mL, group B: 0.58 log copies/mL; p = 0.23) and mean change from baseline CD4+ cell count (group A: 37 cells/mm(3), group B: 50 cells/mm(3); p = 0.28). CONCLUSIONS: In the absence of clear demonstrated benefits arising from the use of the virtual phenotype interpretation, this study suggests resistance testing using genotyping linked to a reliable interpretive algorithm is adequate for the management of HIV infection.

Enfuvirtide in HIV-1-infected individuals changing therapy to a nucleoside reverse transcriptase inhibitor sparing regimen: the ALLIANCE Study.

The role of the fusion inhibitor enfuvirtide in nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens was assessed in an open-label study of fifty-nine highly antiretroviral drug exposed HIV-1-infected individuals. There was a reduction in plasma HIV-1 RNA of 1.43 (95% confidence interval [Cl]: -2.06, -1.22) log10 copies/ml plasma over 96 weeks, and 44% (95% CI: 31, 58) of individuals had a viral load less than 400 copies/ml. A viral load below detection at 96 weeks was predicted by a baseline genotypic sensitivity score greater than 1. There was an average increase of 67 cells/microl (95% Cl: 15, 120) from baseline CD4+ T-cell count to week 96, and the percentage of patients with CD4+ T-cell counts above 100 and 200 cells/microl increased over the trial. Injection site reactions (ISRs) were less common in people with CD4+ T-cell counts >250 cells/microl at any time during follow-up, and were more severe in patients with lower baseline peripheral fat. Adherence over 48 weeks to enfuvirtide injections ranged from 96.3-99.5%. During the 96 week trial there were two discontinuations due to ISRs and two discontinuations following hypersensitivity reactions. Over the 96 weeks of study lean body mass increased by an average 2.7 kg (95% Cl; 1.7, 3.6 kg). Mean peripheral fat increased by 0.2 kg (95% Cl; -0.2, 0.6 kg). Baseline NRTI-associated toxicities resolved in 17% of participants during follow-up. Enfuvirtide is an important component of antiretroviral therapy in highly treatment-experienced individuals where NRTI sparing may be desirable.

Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study.

OBJECTIVE: To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC). DESIGN: Long-term follow-up (104 weeks) of a randomized, open-label study. SETTING: Seventeen ambulatory HIV clinics in Australia and London. SUBJECTS: Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43). INTERVENTION: At week 24, all control patients could switch to ABC. Of the original 111 patients randomized, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks. MAIN OUTCOME MEASURE: The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008). On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm. Visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve. CONCLUSIONS: In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.

No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.

Correlates of antiviral immune restoration in acute and chronic HIV type 1 infection: sustained viral suppression and normalization of T cell subsets.

Highly active antiretroviral therapy (HAART) has suppressed viral replication and facilitated normalization of T cell subsets, resulting in restoration of immunity against opportunistic pathogens. Induction of full immune restoration in chronically infected individuals, including HIV-specific helper T cell responses, is considered a priority, particularly if immunological control of HIV is to be achieved. Regimens containing dual protease inhibitors (PIs) have provided greater suppression of viremia than single-PI regimens. We therefore conducted a prospective analysis of factors associated with immune restoration after 3 years of therapy in two cohorts of acutely and chronically HIV-infected patients, comparing dual- versus single-PI regimens. Earlier and more durable returns of p24-specific proliferation were demonstrated in patients receiving dual-PI compared with single-PI regimens. Individuals with restored p24 responses had larger reductions in total HIV-specific cytotoxic T lymphocytes (CTLs) associated with stronger viral suppression, but Gag-specific CTLs remained higher, demonstrating that Gag-specific helper T cell responses were a critical component of functional immune restoration. On examination of clinical factors associated with immune restoration, we demonstrated that decreasing activation of CD8+ T cells (%CD8+ CD38+) and increasing proportions of CD4+ T cells were independently associated with restoration of p24 responses. Minimal immune activation, resulting from maximal suppression of viral replication, was required for long-term restoration and maintenance of Gag-specific T cell responses. This study uniquely demonstrates that dual-PI regimens are superior in achieving these levels of virological control and immune restoration in both chronic and acute infection, compared with single-PI or non-PI regimens.

Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial.

CONTEXT: 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. OBJECTIVE: To determine if substitution of stavudine or zidovudine with abacavir improves HIV lipoatrophy without affecting control of HIV replication. DESIGN: Randomized, open-label 24-week study. SETTING: Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001. PARTICIPANTS: 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. INTERVENTION: 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). MAIN OUTCOME MEASURES: 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. RESULTS: 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%). CONCLUSIONS: 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.