Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia.

BACKGROUND: Reducing drug burden is a key challenge for achieving lifelong suppressive HIV therapy. Dolutegravir, with a high potency, long half-life and high genetic barrier, offers potential for monotherapy. METHODS: This observational single-centre study enrolled all patients with HIV RNA (viral load) <50 copies/mL for at least 12 months, with CD4 >350 cells/mm(3) and with no failure under integrase inhibitor therapy who had switched from suppressive ART to dolutegravir monotherapy (50 mg/day). Primary outcome was proportion of patients with viral load <50 copies/mL at week 24. RESULTS: Twenty-eight patients treated for a median ART duration of 17 years (IQR 11-20), virally suppressed for a median of 79 months (IQR 42-95) and with a median CD4 count of 624 cells/mm(3) (IQR 524-761), were enrolled. Baseline ART consisted of a three-drug (n = 10), two-drug (n = 10) or single-drug (n = 8) regimen with integrase inhibitor exposure in 13 patients. The proportion of patients maintaining viral load <50 copies/mL was 96% (95% CI 79%-100%) at week 4, 100% (95% CI = 85%-100%) at week 8, 93% (95% CI 76%-99%) at week 12 and 92% (75-99) at week 24. Three patients (3.70%; 95% CI 3.4%-10.8%) with prior integrase inhibitor experience had HIV RNA rebound with the presence of resistance mutations. Genotyping of HIV DNA using the Sanger method or ultradeep sequencing showed no integrase inhibitor resistance-associated mutations (RAMs) except for the mutation 74I in a patient on a suppressive elvitegravir regimen. The median within- and between-subject variability of dolutegravir C24 was 25% and 34%, respectively. Nine patients with a year of follow-up remained virally suppressed. CONCLUSIONS: Dolutegravir has the potency to be further investigated as a single ART in randomized studies, particularly in patients with no prior exposure to integrase inhibitors.

Efficacy, safety and predictive factors of virological success of a boosted amprenavir-based salvage regimen in heavily antiretroviral-experienced HIV-1-infected patients.

BACKGROUND: Amprenavir (APV) has been shown to be effective in naive or treatment-experienced HIV-1 infected patients. However, the safety and efficacy of the APV 600 mg/ritonavir (RTV) 100 mg twice a day (bid) combination, the usually recommended dosage for boosted APV, have been less well studied. We assessed the predictive factors associated with virological success of APV/RTV-based regimens. METHODS: Patients in the PharmAdapt study receiving an APV/RTV-containing regimen were included in the study. The predictivity of covariates on virological response at 4 months was analysed according to the data analysis plan. We processed logistic regression using bootstrapping to allow several covariates in the models. RESULTS: Forty patients received an APV/RTV-containing regimen, 38 of whom were male (95%). Risk factors were heterosexual contacts (four patients; 10%), homosexual contacts (31 patients; 78%), and intravenous drug use (four patients; 10%). Twenty-seven per cent of patients were Centers for Disease Control and Prevention Classification System (CDC) stage A, 38% were stage B and 35% were stage C. The median baseline CD4 count was 313 cells/microL [interquartile range (IQR) 211, 414], and the median baseline viral load was 4.4 log(10) HIV-1 RNA copies/mL (IQR 3.7, 4.9). Patients were exposed to a median number of 7.5 (IQR 6, 9) drugs for a median number of 3.8 (IQR 3.3, 4.3) years. The baseline number of resistance mutations was 4 [IQR 3, 5 for nucleoside reverse transcriptase inhibitors (NRTIs), 1 (IQR 0, 2)] for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 6 [IQR 5, 8 for protease inhibitors (PIs)]. At month 4, median viral load decreased to 1.2 log(10) copies/mL (IQR 0.3, 1.6); 50% of patients had a viral load<200 copies/mL by intention-to-treat analysis. The number of APV resistance mutations was associated with viral load changes. Median APV concentration was 1750 ng/mL (IQR 1130, 2520). At month 4, using several cut-offs, neither APV concentration nor the genotypic inhibitory quotient was predictive of viral load changes. Baseline viral load and the number of protease mutations were associated with outcome. CONCLUSIONS: Efficacious APV concentrations need to be determined for antiretroviral-experienced patients. Baseline viral load and the number of mutations on the protease coding region (PRO) were associated with the virological outcome of APV/RTV-based regimens.

Variable virological outcomes according to the center providing antiretroviral therapy within the PharmAdapt clinical trial.

PURPOSE: Differences in virological response between HIV-infected patients at different study centers were analyzed as a substudy of PharmAdapt, a multicenter prospective randomized study to evaluate the utility of therapeutic drug monitoring after a genotypic-based treatment adaptation. RESULTS: After 12 weeks, the percentage of patients participating in PharmAdapt with HIV RNA < 200 copies/mL ranged from 17% to 69% between centers providing antiretroviral care. In a multivariate analysis, independent factors predictive of viral load <200 HIV RNA copies/mL at Week 12 included: lower baseline viral load, lower nonnucleoside reverse transcriptase inhibitor resistance, lower protease inhibitor resistance, and the center providing antiretroviral therapy. To evaluate the final factor, study sites were divided into two groups based on Week 12 HIV RNA values above or below the median. CONCLUSION: Using this definition, observed differences between centers included the use of stavudine, abacavir-, and/or efavirenz-based regimens and use of online expert advice.

[Pseudotumoral abdominal granuloma concomitant with immune reconstitution after antiretroviral treatment]. / Granulome abdominal pseudo-tumoral contemporain de la reconstitution immunitaire sous traitement anti-rétroviral.

BACKGROUND: Use of powerful multiple-drug antiretroviral regimens can significantly raise CD4+ counts restoring immune function, but in certain cases, leading to inflammatory reactions. CASE REPORT: An HIV-infected patient developed a mycobacteriosis of the digestive tract when his CD4 count fell below 5/mm3. He was given antimycobacterial treatment in combination with an effective triple antiretroviral regimen. At two years, the clinical situation was controlled with persistent optimal response (CD4 = 338/mm3 HIV-RNA < 500 copies/ml); the antimycobacterial regimen was discontinued. One year later the patient still had a CD4+ count above 500/mm3 but developed a voluminous mesenteric mass invaded by a CD68+ histiocyte proliferation. No causal agent could be identified. The clinical course was favorable after reintroducing antimycobacterial treatment combined with short-term corticosteroid therapy. DISCUSSION: Reconstitution of the immune system after long-term use of the new antiretroviral therapies raises the question of whether anti-infectious prophylaxis should be maintained. However, possible reactions to earlier pathogens after restoration of specific immunity would warrant secondary prophylaxis even in patients responding to powerful antiretroviral combinations.

Provirus copy number to predict disease progression in asymptomatic human immunodeficiency virus type 1 infection.

To evaluate the prognostic value of provirus copy number through quantitative DNA polymerase chain reaction (PCR) in early stages of human immunodeficiency virus type 1 (HIV-1) infection, 42 untreated and asymptomatic HIV-1-seropositive subjects with baseline CD4+ cell counts > 200 x 10(6)/L were included in a prospective study and followed over a median of 27 months. Disease progression was defined as decrease in CD4+ cells to < 200 (14 events). At enrollment, provirus copy number was associated with CD4+ cell count and percentage, serum IgA, and p24 antigenemia. Elevated provirus copy number above 20 allowed identification of patients at high risk of a subsequently decreasing CD4+ cell count, even after adjusting for baseline CD4+ cell count (P = .003). Measuring provirus copy number by PCR at early stages of HIV-1 infection could offer a useful early means to predict progression to AIDS.

Randomised, double-blind, placebo-controlled trial of ditiocarb sodium ('Imuthiol') in human immunodeficiency virus infection.

83 patients with human immunodeficiency virus (HIV) infection (CDC groups II, III, or IV-A) were randomised in a crossover trial of sodium-diethyldithiocarbamate (ditiocarb sodium, 'Imuthiol') (10 mg/kg body weight given orally once a week) against placebo. Each arm of the trial lasted 16 weeks. The disease did not progress to CDC-defined acquired immunodeficiency syndrome in the ditiocarb group but did so in 4 patients in the placebo group (3 between week 0 and 16, 1 between week 17 and 32). Ditiocarb was also associated to a significantly greater extent than placebo with relief of constitutional symptoms, improvement in clinical status (including shrinkage of enlarged spleen and lymph nodes), and improvement in immune function (as measured by CD4+ cell count and skin test reactivity). When placebo was replaced by ditiocarb, similar improvements were observed, whereas symptoms slowly reappeared and CD4+ cell levels progressively declined when ditiocarb treatment was replaced by placebo.