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Objectives Single nucleotide polymorphisms in the cytochrome P450 ( CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system ( CNS) symptoms are limited. Methods We analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial. Kaplan−Meier methods and Cox regression analysis were used to investigate their association with efavirenz plasma levels and CNS events up to 48 months after switching. Results In total, 191 patients with a median age of 41 years, who were 87% male and 85% Caucasian, were enrolled in the study. Variant allelic frequencies were 0.49, 0.93, 0.59 and 0.63 for CYP2B6 516, CYP3A5 392, ABCB1 2677 and ABCB1 3435, respectively. The median efavirenz plasma concentration ( MEPC) was 2.2 mg/L [interquartile range ( IQR) 1.7-2.8 mg/L] and was significantly higher in patients with the deficient CYP2B6 516T . Overall, 242 CNS events were reported in 104 individuals (54%). No correlation was found between MEPC and CNS events. The occurrence of a first CNS event was lower in patients with the CYP2B6 516 G/G genotype vs. CYP2B6 516 T genotypes [50% ( IQR: 40-60%) vs. 66% ( IQR: 56-75%), respectively; P = 0.02]. In an adjusted Cox regression model, there was a tendency towards a higher risk of a first CNS event among carriers of the variant CYP2B6 516 T allele (relative risk 1.4 [95% CI, 0.99-2.1]; P?=?.06), compared with noncarriers. Conclusions The deficient CYP2B6 516 T allele is associated with higher efavirenz plasma drug levels and more frequent CNS-related symptoms. [ABSTRACT FROM AUTHOR]

Objectives These 96-week, ECHO/ THRIVE pooled analyses evaluated data for antiretroviral treatment-naïve, HIV-1-infected adults with viral load ( VL) ≤ 100 000 HIV-1 RNA copies/m L receiving rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed ( ECHO) or investigator-chosen ( THRIVE) nucleoside/tide reverse transcriptase inhibitor ( N[t] RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/m L, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure ( VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the rilpivirine ( n = 368) and efavirenz ( n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval ( CI) -1.7% to 9.7%] and incidences of VF for the resistance analysis ( VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor ( NNRTI) resistance-associated mutations ( RAMs). Among those with VFres, more patients in the rilpivirine group than in the efavirenz group developed N[t] RTI RAMs, mostly M184 I/ V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208-240) cells/μ L in the rilpivirine group and by 206 (188-225) cells/μ L in the efavirenz group. Treatment-related grade 2-4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz ( P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naïve adults with baseline VL ≤ 100 000 copies/m L over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t] RTI RAMs (mostly M184 I/ V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz. [ABSTRACT FROM AUTHOR]

Objectives Interleukin-2 ( IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy ( ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales ( ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein− Barr virus ( EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. Methods A total of 130 ART-naïve patients were randomized to receive IL-2 therapy ( n = 66) or no treatment ( n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction ( PCR), up to 48 weeks after baseline ( BL). Results Four lymphomas occurred, a median of 61 weeks [range 40−94 weeks] after randomization at a median CD4 cell count of 396 cells/μL ( IQR 234-536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 ( IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms ( P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients ( P = 0.8). Conclusions IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy. [ABSTRACT FROM AUTHOR]

Objectives The mechanism of raltegravir ( RAL)-resistant evolutions has not already been elucidated. Because the emergence of RAL resistance is usually initiated by the N155 H mutant, we assessed the role of minor N155 H-mutated variants in circulating RNA and archived DNA in five heavily treated patients experiencing long-term RAL therapy failure and harbouring three different resistance profiles determined by standard genotyping. Methods Allele-specific polymerase chain reaction ( AS-PCR) was used to detect N155 H mutants in longitudinal stored plasma and whole-blood samples before, during and after RAL-based regimens in five patients infected with the HIV-1 B subtype. Results No minor N155 H-mutated variant was found by AS-PCR in either plasma or whole-blood samples collected at baseline and after RAL withdrawal in any of the five patients. During RAL failure, the mutation N155 H was detected at different levels in three patients displaying the N155 H pathway and gradually declined when the double mutant Q148 H+ G140 S was selected in one patient. In two patients with the Q148 H resistance pathway, no N155 H variant was identified by AS-PCR in either viral RNA or DNA. Conclusions The N155 H mutation present at various levels from minority to majority showed no relationship with the three RAL-associated resistance profiles, suggesting that this mutant may not play a role in determining different resistance profiles. Moreover, pre-existing N155 H is very infrequent and, if selected during RAL failure, the N155 H mutant disappears quickly after RAL withdrawal. [ABSTRACT FROM AUTHOR]

Background. The introduction of 2 or 3 fully active drugs in human immunodeficiency virus (HIV)-infected patients receiving failing antiretroviral therapy is a key determinant of subsequent treatment efficacy. The aim of this study was to assess the safety and efficacy of a regimen containing raltegravir, etravirine, and darunavir/ ritonavir for treatment-experienced patients infected with multidrug-resistant HIV. Methods. Patients enrolled in this phase II, noncomparative, multicenter trial were naive to the investigational drugs and had plasma HIV RNA levels 11000 copies/mL, a history of virologic failure while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI), ⩾3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor (NRTI) mutations, and ⩽3 darunavir and NNRTI mutations. The primary end point was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks. Results. A total of 103 patients enrolled in the study. At baseline, genotypic resistance profiles showed a median of 4 primary protease inhibitor mutations, 1 NNRTI mutation, and 6 NRTI mutations. In addition to the investigational drugs, 90 patients (87%) received optimized background therapy that included NRTIs (86 patients) or enfuvirtide (12 patients). At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/ mL. The median CD4 cell count increase was 108 cells/mm3. Grade 3 or 4 clinical adverse events were reported in 15 patients (14.6%). Only 1 patient discontinued the investigational antiretroviral regimen, because of an adverse event. Conclusion. In patients infected with multidrug-resistant virus who have few remaining treatment options, the combination of raltegravir, etravirine, and darunavir/ritonavir is well tolerated and is associated with a rate of virologic suppression similar to that expected in treatment-naive patients. [ABSTRACT FROM AUTHOR]

To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy.A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response.The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/μL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8;P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9;P=0.006), of more than two new drugs (OR 3.0;P<0.0001), of abacavir (OR 1.9;P=0.03), or of lopinavir/ritonavir (OR 3.7;P=0.0002).A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome. [ABSTRACT FROM AUTHOR]

Objective We describe the prevalence, risk factors and outcome of hyperlactataemia (HL) in a cohort of 140 HIV-infected patients. Patients and methods Patients were enrolled consecutively within a 3-month period (July to September 1999) and followed until 31 October 2000. One hundred and forty HIV-infected patients had venous plasma lactate levels measured. HL was defined at baseline by two consecutive lactate levels > 2.1 mmol/L (upper limit of normal). We compared baseline demographic characteristics, immuno-virological parameters, antiretroviral therapy and outcome between patients with HL (cases) or without HL (controls). We described the clinical features of patients with HL. Results Among 129 patients included in the analysis, HL was found in 11 patients (8.5%), all of whom were receiving nucleoside reverse transcriptase inhibitors (NRTIs). Cases were more likely than controls to receive didanosine or stavudine (82% vs. 19%, P = 2.7 × 10-6 and 82% vs. 48%, P = 0.03, respectively). Only 4/11 cases (36%) had symptoms consistent with HL. After a median follow-up of 15 months, lactate level returned to normal in all three patients who discontinued NRTIs, but in only 2/8 patients who did not (P = 0.06). Only one case experienced lactic acidosis and died during follow-up. Mortality rate was similar in cases and controls. Conclusion HL is associated with NRTI use, in particular didanosine and stavudine, and discontinuation of NRTIs seems to be associated with rapid resolution of HL. Lactic acidosis remains rare and the long-term outcome of patients with HL does not seem to be poorer than controls. [ABSTRACT FROM AUTHOR]

Reports on a case of African histoplasmosis, a rare granulomatous infection caused by the dimorphic fungus "Histoplasma capsulatum" var. duboisii (Hcd). Peritoneal involvement in a 27-year-old male Malian infected with Hcd; Effect that steroids associated with antifungal therapy had on the peritonitis; Disagreement regarding his diagnosis.

Background In the ECHO and THRIVE Phase III, randomised, double-blind trials, rilpivirine (RPV, TMC278, EDURANT) 25 mg qd showed non-inferiority compared to efavirenz (EFV) 600 mg qd in antiretroviral (ARV) treatment-naïve, HIV-1-infected adults at Weeks 48 and 96. In Europe, RPV combined with other ARVs is approved for the treatment of ARV-naïve adults with a viral load (VL) ≤100,000 c/mL. We present results from a pooled analysis of Week 96 data from this patient subgroup. Methods Patients received RPV 25 mg qd or EFV 600 mg qd, both with TDF/FTC (ECHO) or TDF/FTC, AZT/3TC or ABC/3TC (THRIVE). Response rate (% VL <50 c/mL, intent-to-treat-time-to-loss-of-virologic response [ITT-TLOVR]), virologic failure in the resistance analysis (VFres) and resistance development, as well as safety and tolerability were evaluated. Results Baseline characteristics were similar between the 368 RPV and 329 EFV patients with baseline VL ≤100,000 c/mL. At Week 96, response rates (RPV 84% vs EFV 80%; difference 4.0% [95% CI: −1.7%, 9.7%]) and VFres percentages (8% vs 6%, respectively; p=0.46) (Table) were similar in each treatment group. A comparable proportion of VFres developed NNRTI resistance-associated mutations (RAMs) in each group. More RPV than EFV VFres developed N(t)RTI RAMs (p=0.02). The increase in mean (95% CI) CD4+ cell count from baseline to Week 96 was 224 (208; 240) cells/mm3 for RPV and 206 (188; 225) cells/mm3 for EFV. Treatment-related grade 2-4 overall AEs, any rash, and neurologic AEs, including dizziness were less frequent for RPV than EFV (all p<0.0001, Fisher's Exact test) (Table). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Breakthrough Rhizopus Infection on Posaconazole Prophylaxis Following Allogeneic Stem Cell Transplantation" in the October 2008 issue.

The aim of preventive measures against human immunodeficiency virus (HIV) is to reduce the incidence of HIV infection in the general population and in high-risk groups, such as men having sex with men (MSM), and to reduce the risk that a given individual will contract or spread the virus. Male and female condoms, post-exposure prophylaxis and circumcision are preventive methods currently recognized or promoted worldwide. Although modest success has been reported in a phase-III vaccine trial, other methods are being evaluated, such as vaginal and rectal microbicides, and pre-exposure prophylaxis (PrEP). Herein, we discuss results from prevention trials, especially those focusing on PrEP and particularly on recent results from ‘on-demand’ PrEP regimens. The efficacy of PrEP (rates of 0%–86%) is strongly correlated with adherence and plasma concentrations of antiretrovirals. Adverse events are rare. Selection of emtricitabine-resistant strains is mainly reported in individuals with an undiagnosed HIV infection using PrEP. PrEP is now strongly recommended in WHO prevention programmes for individuals at substantial risk for HIV with a view to controlling this epidemic by 2030. [ABSTRACT FROM AUTHOR]