Eplerenone,a selective aldosterone blocker,in mild-to-moderate hypertension

BACKGROUND: Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS: This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS: Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS: Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.     

Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection

HIV type 1 (HIV-1) persists within resting CD4(+) T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10(-4)) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4(+) T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4(+) T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4(+) T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.     

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.     

Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma

An international, Phase II trial was conducted to assess two doses of ofatumumab, a human CD20 monoclonal antibody, combined with cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), prednisone (100 mg days 3–7) and vincristine (1·4 mg/m²) (O‐CHOP), as frontline treatment for follicular lymphoma (FL). 59 patients with previously untreated FL were randomized to ofatumumab 500 mg (n = 29) or 1000 mg (n = 30) day 1, with CHOP on day 3 every 3 weeks for six cycles. Median duration of FL was 0·1 years for both dose groups; 34% and 38% of patients had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores in the 500‐ and 1000‐mg dose groups, respectively. Overall response rate was 90% for the 500‐mg group and 100% for the 1000‐mg group. 62% of patients achieved complete response (CR)/unconfirmed CR (CRu). 76% of patients with FLIPI score 3–5 attained CR/CRu. Longer follow‐up time is needed for analysis of survival end points. The most common Common Terminology Criteria grade 3–4 investigator‐reported adverse events were leucopenia (29%) and neutropenia (22%). No deaths have been reported. O‐CHOP was safe and efficacious in patients with previously untreated FL, including high‐risk FLIPI groups. This trial was registered at www.clinicaltrials.gov (NCT00494780).     

Antiviral agents and HIV prevention: controversies, conflicts, and consensus

Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.     

Antiretroviral Therapy for Prevention Is a Combination Strategy

In the past several years, the debate of “treatment vs prevention” has shifted with the introduction of the concept of “treatment as prevention,” (TasP), stemming from a series of compelling observational, ecological, and modeling studies as well as HPTN 052, a randomized clinical trial, demonstrating that use of ART is associated with a decrease in HIV transmission. In addition to TasP being viewed as 1 intervention in a combination strategy for HIV Prevention, TasP is, in and of itself, a combination of multiple interventions that need to be implemented with high coverage in order to achieve its potential impact.     

Predicting Partner HIV Testing and Counseling Following a Partner Notification Intervention

Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6-24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.