Joseph Gathe

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial.

BACKGROUND The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. METHODS This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. FINDINGS 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI -1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 μmol/L vs 7 μmol/L). INTERPRETATION If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. FUNDING Gilead Sciences.

A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen.

Objective:To evaluate the safety and noninferiority and to explore the efficacy of administration of once-daily versus twice-daily lopinavir/ritonavir (LPV/r) in antiretroviral-naive HIV-1-infected subjects. Design:Randomized, open-label, multicenter, comparative study. Methods:One hundred ninety antiretroviral-naive subjects with plasma HIV-1 RNA level >1000 copies/mL and any CD4+ cell count were randomized to lopinavir/ritonavir at a dose of 800/200 mg administered once daily (n = 115) or lopinavir/ritonavir at a dose of 400/100 mg administered twice daily (n = 75). Subjects also received tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg administered once daily. Results:The median baseline plasma HIV-1 RNA level and CD4+ count were 4.8 log10 copies/mL and 216 cells/mm3, respectively. Before week 48, 20% (once daily) and 29% (twice daily) subjects discontinued. Virologic responses of the subjects through 48 weeks were comparable; 70% (once daily) and 64% (twice daily) achieved an HIV-1 RNA level <50 copies/mL by intent-to-treat, noncompleter = failure analysis. No subject demonstrated LPV or TDF resistance, but 3 subjects (2 in the once-daily group, 1 in the twice-daily group) demonstrated FTC resistance. Mean increases in CD4 count were similar. Diarrhea (16% in the once-daily group, 5% in the twice-daily group; P = 0.036) was the most common moderate or severe study drug-related adverse event. Conclusions:Through 48 weeks, a once-daily regimen of lopinavir/ritonavir + TDF + FTC appears to have similar virologic and immunologic responses in antiretroviral-naive subjects as the same regimen with lopinavir/ritonavir administered twice daily. Both regimens were relatively well tolerated, and no LPV or TDF resistance was observed.

Candida osteomyelitis: report of five cases and review of the literature

Candida species have emerged as important pathogens in human infection. Although a variety of deep-seated candidal infections have been reported, Candida osteomyelitis has rarely been described. Five patients with Candida osteomyelitis are presented, and the 32 adult cases previously reported are reviewed. Candida osteomyelitis is noted as a simultaneous occurrence or late manifestation of hematogenously disseminated candidiasis. Osteomyelitis may not be prevented by a course of amphotericin B adequate to control the acute episode of disseminated candidiasis, particularly in immunosuppressed patients. Less commonly, Candida osteomyelitis presents as a postoperative wound infection. Like bacterial osteomyelitis, the most common presenting symptom is local pain. The insidious progression of infection, the nonspecificity of laboratory data, and the failure to recognize Candida as a potential pathogen may lead to diagnostic delay. Diagnosis can be made by either open biopsy or closed needle aspiration. Successful therapeutic regimens have employed combinations of antifungal therapy (most often amphotericin B) with surgical debridement when indicated. It is anticipated that osteomyelitis will become a more commonly recognized manifestation of hematogenously disseminated candidiasis.

A randomized, double-blind comparison of coformulated elvitegravir/ cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 96 results

Abstract:This ongoing, randomized, double-blind, active-controlled phase 3 international trial demonstrated the noninferior efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) compared with atazanavir boosted by ritonavir (ATV/RTV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) at 48 weeks. Here, we report the week 96 results. Of 708 treated subjects, virological success (Food and Drug Administration snapshot) was maintained at week 96 with EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF (83% vs 82%, difference 1.1%, 95% confidence interval −4.5% to 6.7%). Study drug discontinuations due to adverse events were low (4% vs 6%). Median increases from baseline in serum Cr (mg/dL) in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 (0.12 vs 0.08) were similar to those at week 48 (0.12 vs 0.08). EVG/COBI/FTC/TDF showed similar mean decreases (%) in bone mineral density from baseline vs ATV/RTV + FTC/TDF (hip: −3.16 vs −4.19, P = 0.069; spine: −1.96 vs −3.54, P = 0.049). Overall, week 96 results support durable efficacy and safety of EVG/COBI/FTC/TDF in HIV-1–infected patients.

A Once-Daily Lopinavir/Ritonavir-Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks

Background:Lopinavir/ritonavir (LPV/r)-dosed twice daily has demonstrated durable efficacy in antiretroviral-naive and protease inhibitor (PI) -experienced patients. Study M05-730 compared LPV/r tablets dosed once daily vs. twice daily in antiretroviral-naive subjects. Methods:Six hundred sixty-four subjects were randomized to LPV/r soft gel capsules (SGCs) once daily, SGC twice daily, tablets once daily, and tablets twice daily, all with tenofovir and emtricitabine once daily. At week 8, all SGC-treated subjects were switched to tablets, maintaining randomized dose frequency. The primary efficacy analysis used an intent-to-treat, noncompleter = failure approach to assess noninferiority of the LPV/r once-daily group compared with the twice-daily group. Results:At week 48, 77% of once-daily-dosed subjects vs. 76% of twice-daily-dosed subjects had HIV-1 RNA <50 copies per milliliter (P = 0.715; 95% confidence interval for difference: 5% to 8%). Response rates were numerically similar between the once-daily and twice-daily groups among subjects with baseline HIV-1 RNA ≥100,000 copies per milliliter (75% once daily vs. 74.6% twice daily; P > 0.999) or when analyzed by baseline CD4+ T-cell count (<50, 50 to <200, and ≥200 cells/mm3). Rates of discontinuation and adverse events, including diarrhea, were similar between arms. Among subjects with protocol-defined virologic rebound through week 48, no new PI resistance mutations were detected. Conclusions:At 48 weeks, the antiviral response in the LPV/r once-daily group was noninferior to the twice-daily group when coadministered with tenofovir and emtricitabine in antiretroviral-naive subjects. Efficacy was comparable between the once-daily and twice-daily groups regardless of baseline HIV-1 RNA or CD4+ T-cell count. Safety and tolerability of once-daily and twice-daily dosing was also comparable. No new PI resistance mutations were detected upon virologic rebound.

Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial

BACKGROUND Patients with HIV on antiretroviral therapy might benefit from regimen simplification to reduce pill burden and dosing frequency. We aimed to assess the safety and efficacy of simplifying the treatment regimen for adults with virologically suppressed HIV infection from a ritonavir-boosted protease inhibitor and emtricitabine plus tenofovir disoproxil fumarate (tenofovir) regimen to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir. METHODS STRATEGY-PI is a 96 week, international, multicentre, randomised, open-label, phase 3b trial in which HIV-infected adults with a plasma HIV-1 RNA viral load of less than 50 copies per mL for at least 6 months who were taking a ritonavir-boosted protease inhibitor with emtricitabine plus tenofovir were randomly assigned (2:1) either to switch to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir or to continue on their existing regimen. Key eligibility criteria included no history of virological failure, no resistance to emtricitabine and tenofovir, and creatinine clearance of 70 mL/min or higher. Neither participants nor investigators were masked to group allocation. The primary endpoint was the proportion of participants with a viral load of less than 50 copies per mL at week 48, based on a US Food and Drug Administration snapshot algorithm for the modified intention-to-treat population, which excluded major protocol violations (prohibited resistance or not receiving a protease inhibitor at baseline). We prespecified non-inferiority with a 12% margin; if non-inferiority was established, superiority was tested as per a prespecified sequential testing procedure. This trial is registered at ClinicalTrials.gov, number NCT01475838. FINDINGS Between Dec 12, 2011, and Dec 20, 2012, 433 participants were randomly assigned and received at least one dose of study drug. Of these participants, 293 were assigned to switch to the simplified regimen (switch group) and 140 to remain on their existing regimen (no-switch group); after exclusions, 290 and 139 participants, respectively, were analysed in the modified intention-to-treat population. At week 48, 272 (93·8%) of 290 participants in the switch group maintained a viral load of less than 50 copies per mL, compared with 121 (87·1%) of 139 in the no-switch group (difference 6·7%, 95% CI 0·4-13·7; p=0·025). The statistical superiority of the simplified regimen was mainly caused by a higher proportion of participants in the no-switch group than in the switch group discontinuing treatment for non-virological reasons; virological failure was rare in both groups (two [1%] of 290 vs two [1%] of 139). We did not detect any treatment-emergent resistance in either group. Adverse events leading to discontinuation were rare in both groups (six [2%] of 293 vs four [3%] of 140). Switching to the simplified regimen was associated with a small, non-progressive increase from baseline in serum creatinine concentration. Nausea was more common in the switch group than in the no-switch group, but rates of diarrhoea and bloating decreased compared with baseline from week 4 to week 48 in the switch group, whereas there were generally no changes for these symptoms in the no-switch group. INTERPRETATION Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir might be a useful regimen simplification option for virologically supressed adults with HIV taking a multitablet ritonavir-boosted protease inhibitor regimen. FUNDING Gilead Sciences.

Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ emtricitabine in antiretroviral-naïve subjects: the progress study, 48-week results.

Abstract Purpose: Current antiretroviral regimens recommended for treatment-naïve patients include 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The purpose of this study is to evaluate whether a new NRTI-sparing regimen may provide an alternative for persons for whom traditional regimens may not be the best option.Methods: PROGRESS is a 96-week, randomized, open-label, multicenter trial comparing the efficacy and safety of a boosted protease inhibitor (PI) and an integrase inhibitor (lopi-navir/ritonavir [LPV/r] + raltegravir [RAL]) to a boosted PI and 2 NRTIs (LPV/r + tenofovir/ emtricitabine [TDF/FTC]) in antiretroviral (ARV)-naïve HIV–1–infected adults.Results: A total of 206 subjects were randomized to receive LPV/r + RAL (n=101) or LPV/r + TDF/FTC (n=105) and analyzed for ARV efficacy using the US Food and Drug Administration time to loss of virologic response (FDA-TLOVR) algorithm. The percentage of subjects with plasma HIV-1 RNA <40 copies/mL at week 48 was 83.2% in the LPV/r + RAL group and 84.8% in the LPV/r + TDF/FTC group (P = .850; difference -1.6%; exact 95% CI, -12.0% to 8.8%). As the lower limit of the exact 95% CI for the difference between regimens was at or above the protocol-defined threshold of -20% (as well as the more stringent threshold of -12%), LPV/r + RAL was noninferior to LPV/r + TDF/FTC. The occurrence of treatment-related, moderate/severe adverse events was similar between treatment groups through 48 weeks of treatment.Conclusions: The HIV treatment regimen of LPV/r + RAL resulted in noninferior efficacy and comparable safety and tolerability compared with a traditional NRTI-containing regimen through 48 weeks of treatment. These results support further evaluation of the LPV/r + RAL regimen.

Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naive HIV-1-infected patients.

BACKGROUND This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients. METHODS Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) ≥ 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (≤ 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily. Primary endpoint was sustained virological response (<50 copies/ml) through week 48 using the time to loss of virological response algorithm. Non-inferiority of NVP XR to NVP IR was tested using Cochrans statistic incorporating baseline VL stratum with pre-specified, non-inferiority margin of -10%. RESULTS Among 1,011 patients randomized and treated, virological response at week 48 was 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR with adjusted difference of 4.9% in favour of NVP XR (95% CI -0.1-10.0%), demonstrating non-inferiority of NVP XR to NVP IR. This finding was supported by secondary endpoints. The safety profile of NVP XR was similar to NVP IR, but showed numerically fewer treatment-related adverse events. CONCLUSIONS NVP XR in combination with TDF and emtricitabine was shown to be non-inferior in efficacy to NVP IR with a similar safety and adverse event profile, with the potential for the added convenience of once-daily dosing. TRIAL REGISTRATION ClinicalTrials (NCT): NCT00561925.

Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1―Infected, Treatment-Experienced, CCR5 Antagonist―Naive Subjects

Objectives:To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects. Design:Double-blind placebo-controlled study in the United States and Argentina. Methods:Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4+ cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded. Results:Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were −0.7, −1.6, −1.8, and −1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4+ cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs. Conclusions:TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.

Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients

Objective We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. Methods A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Results Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. Conclusions The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy.