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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.

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.

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.

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.

Objective: HIV-specific cytotoxic T lymphocytes (CTL) are believed to play an important role in containing viral replication throughout HIV-1 infection. Previous studies have attempted to quantify the HIV-1-specific CTL precursor frequency during primary HIV infection by using limiting dilution analysis, which almost certainly underestimates the true CTL frequency. Here we use a relatively new technique to quantify HIV-specific CD8 T cells in primary HIV infection., Methods: We have used soluble tetrameric complexes of HLA class I molecules complexed with HIV epitope peptides to study the dynamics and frequency of HIV-specific CD8 T cells in relation to plasma viral load in early HIV infection, in three patients with a highly focused HIV-specific CTL response., Results: We show that the frequencies of HIV-1-specific CD8 T cells in acute infection are significantly higher than previously documented and can be demonstrated well before full seroconversion. These studies also confirm the immunodominance of the B27-restricted response in HIV infection and demonstrate a close temporal relationship between the numbers of circulating HIV-specific CD8 T cells and viral load., Conclusions: These findings strongly suggest that HIV-1-specific CD8 T cells are responding directly to the level of viral replication in early HIV infection and are a major factor in its control. In addition, the data indicate that immunodominance for CD8 T-cell responses is established in the acute phase of HIV infection.