Miguel Goicoechea

Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy

BACKGROUND Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Determinants of CD4+ T Cell Recovery during Suppressive Antiretroviral Therapy: Association of Immune Activation, T Cell Maturation Markers, and Cellular HIV-1 DNA

BACKGROUND Suboptimal CD4+ T cell recovery during antiretroviral therapy (ART) is a common clinical dilemma. METHODS We analyzed viral and immunologic predictors of CD4+ T cell recovery in 116 human immunodeficiency virus type 1 (HIV-1)-infected subjects who had suppressed viremia (< or = 50 copies/mL) while receiving ART. Successive measurements of T cell immunophenotypes and cellular HIV-1 DNA levels were obtained before and during receipt of ART. On the basis of increases in the CD4+ T cell count, subjects were classified as immunologically concordant (demonstrating an increase of > or = 100 CD4+ T cells/mm3) or discordant (demonstrating an increase of <100 CD4+ T cells/mm3) after 48 weeks of ART. RESULTS In adjusted analyses, CD4+ and CD8+ T cell activation at baseline was negatively associated with immunologic concordance at week 48 of ART (odds ratio [OR], 0.80 [P = .04] and 0.67 [P = .02], respectively). High memory (CDRA(-)CD62L-) CD8+ T cell counts at baseline (OR, 0.33 [P = .05]) predicted less CD4+ T cell recovery, whereas increased naive CD4+ T cell counts were associated with higher increases in CD4+ T cells (OR, 1.19 [P = .052]). Neither the cell-associated HIV-1 DNA level at baseline (P = .32) nor the cell-associated HIV-1 DNA level at week 48 of ART (P = .42) was associated with immunologic concordance during ART. CONCLUSIONS These results support the potential clinical usefulness of the baseline determination of immune activation and maturation subsets in the prediction of CD4+ T cell recovery during viral suppression. Furthermore, identification of individuals with reduced potential for CD4+ T cell recovery during ART may provide a rationale for the initiation of early therapy for some patients.

Cognitive-behavioral intervention to enhance adherence to antiretroviral therapy : a randomized controlled trial (CCTG 578)

Objective:We conducted a randomized, multi-site, controlled trial of a cognitive-behavioral adherence intervention for patients initiating or changing an antiretroviral (ART) regimen. Design:A 3 × 2 factorial design was used with the primary randomization assigning patients (1: 1: 1) to one of two adherence interventions or usual care. Methods:The five-session adherence interventions consisted of cognitive–behavioral and motivational components, with or without a 2-week pre-treatment placebo practice trial. Intent-to-treat analysis used probability weights and regression tree analysis to account for missing data. Results:A total of 230 patients were randomized; 199 started ART, of whom 74% completed the 48-week study. Electronic monitored adherence outcomes between the two intervention groups did not differ significantly and were thus pooled in analyses. At week 4, 82% of intervention patients had taken at least 90% of their prescribed ART doses, compared with 65% of controls (P < 0.01); this group difference dropped to 12% at week 12 (72 versus 60%; P = 0.15) and 11% at week 24 (66 versus 55%; P = 0.28). Mean adherence in the intervention group was significantly higher than the control group at week 24 (89 versus 81%; P < 0.05) only. There were no group differences with respect to HIV-1 RNA throughout the study. Conclusions:The effects of the cognitive–behavioral intervention on adherence were modest and transient, and no effects were observed on viral load or CD4 cell count. More robust effects may require a more intense intervention that combines ongoing adherence monitoring and individualized intervention ‘dosage’ that matches the need and performance of each patient.

Efavirenz--still first-line king?

Background: Efavirenz is a potent, safe and tolerable non-nucleoside reverse transcriptase inhibitor (NNRTI) recommended as initial therapy. Recently, several new antiretroviral drugs, including second generation NNRTIs, protease-inhibitors, an integrase-inhibitor and a CCR5 inhibitor, have become or will be shortly available. Objective: This article will review relevant efficacy and safety data of efavirenz compared to these novel agents or certain common alternate drugs currently used as initial therapy in treatment-naive patients. Methods: Published articles and conference presentations pertaining to efavirenz and/or the newer antiretroviral agents were evaluated. Results/conclusions: Efavirenz will continue to be preferred initial therapy for now. If longer-term studies of integrase inhibitors and second-generation NNRTIs confirm initial findings, they will eventually supplant efavirenz as preferred first-line agents.

Efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all?

ATRIPLA™ (Bristol-Myers Squibb and Gilead Sciences) is a complete regimen in a single, fixed-dose combination tablet that contains: efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg. Current treatment guidelines recommend this triple combination for initial therapy because of its excellent potency, tolerability and favorable safety profile. Individually, these agents have long half-lifes that allow for once-daily dosing and may provide a pharmacologic bridge for the occasional missed dose. Although several options for once-daily regimens are available, comparative clinical trials are still in progress. This article reviews relevant efficacy and safety data of efavirenz, emtricitabine and tenofovir disoproxil fumarate, compared with other once-daily agents or certain common alternate drugs presently used as initial therapy in treatment-naive patients.

Treatment of Candidal Cholangitis with Caspofungin Therapy in a Patient with a Liver Transplant: Documentation of Biliary Excretion of Caspofungin

Sir—Cholangitis due to candidiasis is a rare infection in patients without predisposing factors, but it has become an increasingly recognized complication in patients who have received a liver transplant [1]. After liver transplantation is performed, strictures may develop in the extrahepatic biliary tract and lead to secondary sludge formation, which can predispose a patient to recurrent cholangitis. Cases of biliary candidiasis in patients with liver transplants are further complicated by the potential for infection with azole-resistant isolates [2] and the potential for pharmacologic interactions between immunosuppressants and other drugs [3]. Here, we present a case of recurrent polymicrobial cholangitis due to infection with Candida albicans in a patient with a liver transplant whose case was conservatively managed with percutaneous drainage and systemic antimicrobial therapy. A 54-year-old man who had received a liver transplant 4 years earlier presented with fever and chills. The patient had been diagnosed 6 months earlier with recurrent cholangitis after imaging studies demonstrated markedly dilated hepatic ducts with numerous filling defects. Alkaline phosphatase levels were 5–10 times the normal level, and cultures of bile samples obtained from the patient were positive for Enterococcus species, Streptococci milleri, anaerobes, and C. albicans. Prior to admission, the patient had undergone multiple failed endoscopic procedures to relieve the biliary obstruction, and his case had been managed with external biliary drainage and chronic suppressive antimicrobial therapy with levofloxacin, metronidazole, and intrabiliary infusions of amphotericin and fluconazole. Microbiological testing of bile samples obtained from the patient at admission again yielded multiple organisms, including yeasts. Management of the patient’s case was further complicated by elevated tacrolimus levels (which were 5 times greater than the target concentration) and chronic renal insufficiency. The principal pathogen involved in the patient’s infection was considered to be Candida species on the basis of a chronic candidal cast along the biliary tree. The patient was administered parenteral caspofungin therapy. The patient’s condition improved, and cultures of additional bile samples again showed the presence of fluconazole-susceptible C. albicans. Tacrolimus levels were adjusted, and the patient was discharged from the hospital and given a regimen of fluconazole in addition to combination amoxicillin-clavulanate for chronic suppressive antimicrobial therapy of polymicrobial cholangitis. Cultures of bile samples obtained from the patient 3 months after hospital discharge showed no growth of C. albicans. After allowing all antifungal agents to washout, biliary excretion of caspofungin was measured by determining caspofungin levels in both serum and bile samples. Serum and bile samples were obtained 1 h after a 70-mg infusion of caspofungin, and additional bile samples were obtained at 2 h and 3 h after the infusion. An agar well diffusion bioassay with C. albicans ATCC 24933 as the assay organism was used to quantify levels of caspofungin in bile and serum samples. Levels of caspofungin in bile samples were as follows: 0.8 mg/mL at 1 h, 1.0 mg/mL at 2 h, and 0.6 mg/mL at 3 h after the infusion. In the serum sample, obtained 1 h after the infusion, the caspofungin level was 3.1 mg/ mL. Bioassays have been successfully used to quantify antifungal agents and are comparable with high-performance liquid chromatography [4, 5]. The decision to use caspofungin therapy in treating our patient was influenced by several factors, including initial concerns over the recent emergence of azole resistance and possible drug interactions with fluconazole and tacrolimus. Finally, the presence of chronic renal insufficiency made treatment with systemic amphotericin a less attractive alternative. To our knowledge, this is the first report to document biliary caspofungin levels in samples obtained from a patient with a liver transplant. The level of caspofungin in the bile sample obtained 2 h after the infusion was ∼30% of the level of caspofungin in the serum sample. This is greater than the in vitro MIC50 of caspofungin for C. albicans (0.12 mg/mL) [6]. Whether this is clinically significant remains to be validated in clinical studies. However, caspofungin therapy may be considered for use in treating candidal biliary infection.

Didanosine Exposure and Noncirrhotic Portal Hypertension in a HIV Clinic in North America: a Follow-up Study

AIMS: To describe: 1) our cohort of patients diagnosed with NCPH in a HIV academic clinic in North America, and 2) longitudinal follow-up and outcomes of patients following NCPH diagnosis. STUDY DESIGN: Retrospective case series. PLACE AND DURATION OF STUDY: Owen clinic, University of California, San Diego, United States, between October 1990 and December 2010. METHODOLOGY: We describe a cohort of patients diagnosed with NCPH in a HIV academic clinic with emphasis on their follow-up and outcomes after NCPH diagnosis. RESULTS: During the study period, eight HIV-infected men were diagnosed with NCPH. All patients were exposed to Didanosine (ddI) for a median of 37 months. One patient died soon after NCPH diagnosis due to a condition unrelated to NCPH. The other seven patients have received B-blocker therapy and annual esophago-gastro-duodenectomy screenings with banding of esophageal varices when indicated and remain still alive. Three patients were on ddI at the time of NCPH diagnosis. In one patient ddI was discontinued shortly after NCPH diagnosis. The other two patients continued to use ddI after NCPH diagnosis and developed recurrent upper gastrointestinal bleeding in the subsequent 2 years, requiring revascularization interventions. The four patients that were already off ddI at the time of NCPH diagnosis have been followed for a median of 6 years. These four patients remained minimally symptomatic for up to 16 years of follow-up from NCPH diagnosis. CONCLUSION: When ddI was discontinued before portal hypertension was clinically apparent the progression of NCPH appeared to subside without major clinical complications.

Abacavir and increased risk of myocardial infarction

This project was initiated as part of the Uganda Women’s Health Initiative (UWHI) involving the University College London Institute for Women’s Health, Mulago Hospital, Makerere University, and Hospice Africa, Uganda. We are grateful to Graham Evans (Project Manager UWHI) for his support and guidance. The UWHI and this project were supported by generous donations from Lee and Roger Myers and Ann-Margaret and John Walton. These funding sources had no involvement in study design, collection, analysis, and interpretation of data in the writing of report or the decision to submit the letter for publication. We declare that we have no confl ict of interest.

Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression

Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24weeks of MVC compared to baseline were 38cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39cells/mm(3) per year before initiation of MVC and 76cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC.

Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients.

Objectives:To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF). Design and methods:This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined. Results:Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (−0.15 log10 per day vs. −0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/106 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/106 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (ρ = −0.529; P = 0.045). Conclusion:In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.