Véronique Reliquet

A prospective study of criteria for the diagnosis of toxoplasmic encephalitis in 186 Aids patients

Objective:To define the factors associated with diagnosis of toxoplasmic encephalitis (TE) in AIDS patients; and to establish a rational procedure for the clinician faced with a decision concerning empiric antitoxoplasma therapy. Design:A 15-month prospective multicentre cohort study in France. Methods:One hundred and eighty-six consecutive HIV-positive inpatients undergoing empiric antitoxoplasma therapy for a first episode of presumed TE were monitored. The clinicians initial estimation of the probability of response to antitoxoplasma therapy was recorded. In addition, a validation committee classified cases as TE or non-TE. Results:Among the 186 patients, the following variables were significantly more frequent in TE (n = 113) than non-TE (n = 73) patients: fever (59% versus 40%), headache (55% versus 33%), seizures (22% versus 11%), suggestive lesions on the brain scan (98% versus 76%), positive Toxoplasma serology (97% versus 71%). Median CD4+ lymphocyte count was significantly higher in TE than in non-TE (27 x 106/l versus 11 x 106/l). The rate of TE in patients on systemic antiprotozoal prophylaxis at entry was 43% as compared with 75% in patients without previous prophylaxis. Pre-therapy estimation of response to empiric therapy was highly correlated with final diagnosis. Multivariate logistic regression analysis showed that the following variables contributed independently to the diagnosis of TE: clinicians estimation of response to treatment at entry > 75%; absence of systemic antiprotozoal prophylaxis; seizures; headache; suggestive lesions on CT or MRI brain scan; and positive Toxoplasmaserology. Conclusions:A linear logistic model is proposed which uses significant variables, which are readily available. This model gives good accuracy to classify suspected cases of TE.

Substitution of a Nonnucleoside Reverse Transcriptase Inhibitor for a Protease Inhibitor in the Treatment of Patients with Undetectable Plasma Human Immunodeficiency Virus Type 1 RNA

Seventy-three patients infected with human immunodeficiency virus type 1 (HIV-1) were enrolled in a prospective observational study to investigate the efficacy and tolerance of substituting a nonnucleoside reverse transcriptase inhibitor (NNRTI) for a protease inhibitor (PI) in patients whose plasma viral load (pVL) was controlled by a PI regimen. After a median follow-up of 52 weeks, 63 patients (86.3%) had undetectable pVLs. The incidence of virological breakthrough at 12 months of follow-up was 6.5% (95% confidence interval [CI], 1-20) among patients who had been antiretroviral naive before receiving HAART and 19.2% (95% CI, 6-34) among patients who had been treated with antiretroviral drugs before receiving the PI regimen (P=.10).

Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus.

Twelve heavily pretreated, perinatally infected adolescents in virological failure were treated with a combination of raltegravir, r-darunavir and etravirine, as part of an expanded access program in France. After a 12-month median follow-up, viral load was <400 copies/ml in 11 (<50 in six). No grade > 2 side effects were recorded. Additional data and marketing authorizations are awaited, but preliminary results in adolescents with extensive multidrug resistant virus are encouraging.

Effect of twice-daily nevirapine on adherence in Hiv-1-infected patients: a randomized controlled study

Objective:For optimal adherence, once-daily dosing is best. Whether this applies to antiretroviral therapy is unknown. We thus aimed to determine the effect of once-daily dosing on adherence to nevirapine. Design:A three-phase (3-month observational, 4-month randomized, 5-month interventional) open-label, clinical trial at four French academic medical centres during 2005–2006 among 62 chronically HIV-1-infected subjects with long-lasting viral suppression under a twice-a-day nevirapine-based antiretroviral combination. Methods:Adherence was measured using electronic monitoring devices and validated by sequential plasma drug levels. Participants were randomly assigned to switch to nevirapine 400 mg once-daily (n = 31) or continue nevirapine 200 mg twice-a-day (n = 31). After the randomized phase, participants had an opportunity to choose their antiretroviral dosage. Primary outcome was the mean percentage of adherence. Results:Fifty-two patients qualified for electronic data analysis. During the randomized phase, the mean adherence rate was non-significantly superior by 0.5% in once-daily versus twice-a-day dosing (P = 0.68), adjusting for previous twice-a-day adherence rate (P < 0.0001). Once-daily group increased days without dose [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.0, 2.8; P = 0.04], adjusting for previous drug interruptions (P < 0.0001). In the longitudinal analysis, once-daily dosing was significantly associated with at least two consecutive days without dose (OR 4.4; 95% CI 1.9, 10.3; P < 0.001). Conclusion:Changing from twice to once-daily nevirapine does not improve adherence. Supporting continuous adherence to antiretroviral therapy in the ‘once-a-day era’ remains a challenge, even if more potent regimens can achieve viral suppression at lower adherence levels.

Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients

Objectives:To assess the efficacy, tolerance, and safety of combination antiretroviral therapy with didanosine and stavudine in HIV-infected patients with CD4+ cell counts >100 × 106/l and HIV plasma RNA >104 copies/ml previously treated with other antiretroviral agents for at least 3 months. Design:In this open, multicentre, non-randomized, Phase II pilot study, adult patients were administered didanosine (200 mg twice daily) plus stavudine (40 mg twice daily) for 6 months. Patients for whom the first regimen had led to undetectable HIV RNA levels were offered a second 6-month course of treatment; those who had achieved insufficient immunological and virological gains in the first 6 months were given a new combination. Methods:Primary evaluation of efficacy was based on viral load measured by branched DNA second-generation testing (lower limit of detection, 500 copies/ml) and CD4+ cell counts; secondary evaluations included AIDS-defining events and clinical side-effects. Results:Sixty-five patients with median prior antiretroviral therapy of 24 months (65 with zidovudine, 29 with zalcitabine) were included in the study. At baseline, median CD4+ cell count was 198 × 106/l and median plasma HIV RNA was 80 000 copies/ml (4.9 log10 copies/ml). In this heavily pretreated population, an increase in the mean CD4+ cell count was observed (+70 × 106/l at 24 weeks). In addition, rapid and prolonged antiviral activity was seen, with a mean maximal decrease of 1.1 log10 copies/ml at week 4, a mean decrease of 0.89 log10 copies/ml at week 24, and a plasma RNA viraemia <500 copies/ml achieved in 14% of patients at week 24. Conclusions:Combination therapy with stavudine and didanosine is safe and leads to a sustained antiviral effect, even in patients with prolonged prior antiretroviral exposure and low CD4+ cell counts.

Specific anti-Toxoplasmic IgG antibody immunoblot profiles in patients with AIDS-associated Toxoplasma encephalitis

Among 186 suspected cases of Toxoplasma encephalitis (TE) in HIV-infected patients, 113 were classified as TE and 73 as non-TE. Serum Toxoplasma gondii (T.g.) antibodies were detected by ELISA in 97% of TE vs 71% of non-TE cases (p < 0.001). In the 164 patients positive for T. g. antibodies, the IgG 27 and 32 bands were more frequently present in TE than in non-TE (p = 0.003, p = 0.002, respectively). Among patients with positive T.g. serology, multivariate analysis showed that the presence of an IgG 32 (OR 3.1) or IgG 27 band (OR 2.7) on Western blot was highly indicative of TE independently of each other. Positive T.g. serology, but not anti-T.g. IgG antibody titres, was predictive. Thus, the positivity of IgG 27 and 32 bands on Western blot analysis provides useful data for improving the diagnosis of presumptive TE in HIV-infected patients with suspected TE and positive Toxoplasma serology.

Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1

OBJECTIVES The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1. PATIENTS AND METHODS This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration. RESULTS The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011). CONCLUSIONS The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.

The spectrum of HIV mother-to-child transmission risk

With the implementation of combined antiretroviral therapy (cART) and prevention of mother‐to‐child transmission (MTCT) we observed dramatic decreases in rates of perinatal MTCT of HIV, 0.3% in France in women with plasma viral load (pVL) <50 c/mL at delivery. We describe a case of MTCT which occurred despite virologic suppression of the mother at delivery, the first case in our centre since 2002.

Evaluation of residual viremia and quantitation of soluble CD14 in a large cohort of HIV-infected adults on a long-term non-nucleoside reverse transcriptase inhibitor-based regimen.

Beyond virological suppression and immunologic recovery, the objective of long‐term antiretroviral therapy is to suppress maximally viremia and to control for persistent immune activation. Non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐containing regimens are associated with lower residual viremia. The objective of the study was to evaluate the impact of long term NNRTI‐containing treatment on residual viremia and on monocyte activation in a cohort of patients infected with HIV‐1. To identify factors associated with residual viremia, adult patients infected with HIV on nevirapine or efavirenz‐based therapy with viral load <50 copies/ml for >6 months were included. Residual plasma viremia was quantified using an adapted Cobas/Taqman HIV‐1 assay. Viral loads with no detected signal were considered as <1 copy/ml. Monocyte activation was evaluated by quantitation of plasma sCD14 by ELISA assay at the time of residual viremia measurement. Logistic regression was used to determine factors associated with residual viremia <1 copy/ml. In this cohort of 421 patients on long‐term NNRTI regimen, three quarters had a residual viremia <1 copy/ml. In multivariate analysis, duration of plasma viral load below 50 copies/ml was the only factor associated with residual viremia <1 copy/ml. Soluble CD14 was in the normal range although treatment with nevirapine was associated with a significant lower level of sCD14 compared to efavirenz. Residual viremia <1 copy/ml was frequent in this cohort of patients with long term virological control and confirmed the results of previous studies. Apart from its antiviral effect, nevirapine as well as efavirenz could decrease monocyte activation. J Med. Virol. 85:1878–1882, 2013.

Four year follow-up of simplification therapy with once-daily emtricitabine, didanosine and efavirenz in HIV-infected patients (ALIZE ANRS 099 trial)

BACKGROUND once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine. METHODS the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of <400 copies/mL under a protease inhibitor-based regimen, who were randomized to remain on this regimen or to switch to a once-daily regimen of emtricitabine, didanosine and efavirenz for 48 weeks. An extended 4 year follow-up was available for the 178 patients who switched to the efavirenz-containing regimen, and assessed plasma HIV RNA levels, CD4 cell counts, safety and tolerability. RESULTS after a median follow-up of 42 months, 121 patients (68%) remained on an efavirenz-based regimen, and 62% and 57% had plasma HIV RNA levels of <400 and <50 copies/mL, respectively, in an intent-to-continue analysis with missing data and treatment discontinuation considered as failure. There was a significant increase in CD4 cell count of 41 cells/mm(3). Drug-related adverse events were the main reason for treatment discontinuation in 26 patients (15%), and 15 were reported during the first year of therapy (58%). There was no emergence of clinically defined lipodystrophy, and lipid and glucose profiles were favourable with a significant increase from baseline of high-density lipoprotein cholesterol levels (median increase 12 mg/dL, P < 10(-4)). CONCLUSIONS a once-daily regimen of emtricitabine, didanosine and efavirenz provided a durable antiretroviral response and was well tolerated through 4 years of therapy.