Catherine Butkus Small

Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.

BACKGROUNDnDolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance.nnnMETHODSnING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516.nnnFINDINGSnAnalysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir).nnnINTERPRETATIONnOnce-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group.nnnFUNDINGnViiV Healthcare.

Salmonella meningitis and infection with HIV

Patients infected with HIV demonstrate increased susceptibility to serious infections with non-typhoidal salmonellae. However, no cases of salmonella meningitis have been reported in this population. We now report three cases of salmonella meningitis which occurred in a population of 1800 patients with AIDS or AIDS-related complex at our hospitals. The incidence of meningitis complicating salmonella infection in our HIV-infected population appears to be much higher than that reported in non-AIDS patients (7.5 versus 0.15%). All had cerebrospinal fluid parameters consistent with bacterial meningitis, and two of three revealed organisms on cerebrospinal fluid Gram stain. Two presented with a fulminant illness and died despite therapy; the third developed a brain abscess associated with a relapse of meningitis. Salmonella meningitis should be considered as a cause of acute neurological deterioration in patients at risk for HIV-related disease. Relapses may occur, and mortality is high.

Simplification to Abacavir/Lamivudine + Atazanavir Maintains Viral Suppression and Improves Bone and Renal Biomarkers in ASSURE, a Randomized, Open Label, Non-Inferiority Trial

Objective Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study’s primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients. Design This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥6 months with no history of virologic failure and whose HIV-1 RNA had been ≤75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1∶2 to continue current treatment or simplify to ABC/3TC+ATV. Methods The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers. Results After 24 weeks, ABC/3TC+ATV (nu200a=u200a199) was non-inferior to TDF/FTC+ATV/r (nu200a=u200a97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2–4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3–4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. Conclusions After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol. Trial Registration ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734

The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir.

HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy‐experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long‐term adverse events (AEs). This open‐label, multicentre, noninferiority study enrolled HIV‐1‐infected, treatment‐experienced adults with confirmed HIV‐1 RNAu2009≤u200975 HIV‐1 RNA copies/mL currently receiving tenofovir/emtricitabineu2009+u2009atazanavir/ritonavir (TDF/FTCu2009+u2009ATV/r) for ≥u20096 months with no reported history of virological failure.

Evaluation of cardiovascular biomarkers in a randomized trial of fosamprenavir/ritonavir vs. efavirenz with abacavir/lamivudine in underrepresented, antiretroviral-naïve, HIV-infected patients (SUPPORT): 96-week results

BackgroundRates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy.MethodsThis 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100xa0mg and efavirenz 600xa0mg, both with ABC/3TC 600xa0mg/300xa0mg, in antiretroviral-naïve, HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios.ResultsThis study enrolled 101 patients (51 receiving fosamprenavir/ritonavir; 50 receiving efavirenz): 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96xa0weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL (fosamprenavir/ritonavir 63%; efavirenz 66%) by ITT missing-equals-failure analysis. Treatment-related grade 2–4 adverse events were more common with efavirenz (32%) compared with fosamprenavir/ritonavir (20%), and median lipid concentrations increased in both groups over 96xa0weeks of treatment.ConclusionsIn this study of underrepresented patients, treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96xa0weeks, produced stable or declining biomarker levels except for hs-CRP, including significant and favorable decreases in thrombotic activity (reflected by d-dimer) and endothelial activation (reflected by sVCAM-1). Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia.Trial registrationClinicalTrials.gov identifier NCT00727597

Hepatic safety in subjects with HIV-1 and hepatitis C and/or B virus: A randomized, double-blind study of maraviroc versus placebo in combination with antiretroviral agents

Abstract Background: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. Objective: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV. Methods: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (nu2009=u200970) or placebo (nu2009=u200967) in combination with other antiretroviral agents. Primary endpoint: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5u2009×u2009 upper limit of normal (ULN) if baseline ALTu2009≤u2009ULN or >3.5u2009×u2009 baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. Results: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hys law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. Conclusions: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48u200aweeks of treatment.

Similar neurocognitive outcomes after 48 weeks in HIV-1-infected participants randomized to continue tenofovir/emtricitabine + atazanavir/ritonavir or simplify to abacavir/lamivudine + atazanavir

Human immunodeficiency virus (HIV)-associated neurocognitive disorders can persist in many patients despite achieving viral suppression while on antiretroviral therapy (ART). Neurocognitive function over 48xa0weeks was evaluated using a Cogstate test battery assessing psychomotor function, attention, learning, and working memory in 293 HIV-1-infected, ART-experienced, and virologically suppressed adults. The ASSURE study randomized participants 1:2 to remain on tenofovir/emtricitabine (TDF/FTC) and ritonavir-boosted atazanavir (ATV/r) or simplify to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Neurocognitive z-scores were computed using demographically adjusted normative data and were classified as “impaired” (defined as either a z-score ≤u2009−u20092 or having 2 or more standardized individual test z-scores ≤u2009−u20091); while higher scores (equaling better performance) were classified as “normal”. By z-scores, 54.7% of participants had impaired neurocognition at baseline and 50.2% at week 48. There were no significant differences (pu2009<u20090.05) in the baseline-adjusted performance between treatment groups for any individual test or by z-score. Specific demographic and medical risk factors were evaluated by univariate analysis for impact on neurocognitive performance. Factors with pu2009<u20090.10 were evaluated by backwards regression analysis to identify neurocognition-correlated factors after accounting for treatment, assessment, and baseline. Four risk factors at baseline for impaired neurocognition were initially identified: lower CD4 nadir lymphocyte counts, higher Framingham risk scores, and interleukin-6 levels, and a history of psychiatric disorder not otherwise specified, however none were found to moderate the effect of treatment on neurocognition. In this aviremic, treatment-experienced population, baseline-adjusted neurocognitive function remained stable and equivalent over 48xa0weeks with both TDF/FTC + ATV/r-treated and in the ART-simplified ABC/3TC + ATV treatment groups.

SUPPORT: 48-week results of fosamprenavir/ritonavir vs efavirenz with abacavir/lamivudine in under-represented, antiretroviral-naïve patients

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Infectious Disease in the Aging: A Clinical Handbook Edited by Thomas T. Yoshikawa and Dean C. Norman Totowa, NJ: Humana Press, 2001. 326 pp., illustrated.

Concepts and Principles of Infections and Aging.- Epidemiology of Aging and Infectious Diseases.- Factors Predisposing to Infection.- Clinical Features of Infection.- Role and Importance of Functional Assessment in Infections.- Principles of Antimicrobial Therapy.- Common Infections.- Sepsis.- Bronchitis and Pneumonia.- Tuberculosis in Older Adults.- Infective Endocarditis.- Intra-abdominal Infections.- Infectious Diarrhea.- Urinary Tract Infection.- Bacterial Meningitis and Brain Abscess.- Osteomyelitis and Septic Arthritis.- Skin and Soft Tissues Infections.- Herpes Zoster.- Orofacial and Odontogenic Infections in the Elderly.- Ocular Infections.- Otitis Externa, Otitis Media, and Sinusitis.- Prosthetic Joint Infections in Elderly Patients.- Staphylococcal and Enterococcal Infections.- Fungal Infections.- Viral Infections.- Special or Unique Infectious Disease Problems.- Infections in the Long-Term Care Setting.- Infection Control Programs in Nursing Homes.- Infections in Diabetics.- Vaccinations.- Nutrition and Infection.- Sexually Transmitted Diseases.- Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome.- SARS and West Nile Virus.