Does HAART Efficacy Translate to Effectiveness? Evidence for a Trial Effect

Background: Patients who participate in clinical trials may experience better clinical outcomes than patients who initiate similar therapy within clinical care (trial effect), but no published studies have evaluated a trial effect in HIV clinical trials. Methods: To examine a trial effect we compared virologic suppression (VS) among patients who initiated HAART in a clinical trial versus in routine clinical care. VS was defined as a plasma HIV RNA #400 copies/ml at six months after HAART initiation and was assessed within strata of early (1996–99) or current (2000–06) HAART periods. Risk ratios (RR) were estimated using binomial models. Results: Of 738 persons initiating HAART, 30.6 % were women, 61.7 % were black, 30 % initiated therapy in a clinical trial and 67 % (n = 496) had an evaluable six month HIV RNA result. HAART regimens differed between the early and current periods (p,0.001); unboosted PI regimens (55.6%) were more common in the early and NNRTI regimens (46.4%) were more common in the current period. Overall, 78 % (95%CI 74, 82%) of patients achieved VS and trial participants were 16 % more likely to achieve VS (unadjusted RR 1.16, 95%CI 1.06, 1.27). Comparing trial to non-trial participants, VS differed by study period. In the early period, trial participants initiating HAART were significantly more likely to achieve VS than non-trial participants (adjusted RR 1.33; 95%CI 1.15, 1.54), but not in the current period (adjusted RR 0.98; 95%CI 0.87, 1.11). Conclusions: A clear clinical trial effect on suppression of HIV replication was observed in the early HAART period but not i

Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review.

The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB

Pathophysiology of sepsis-related cardiac dysfunction: driven by inflammation, energy mismanagement, or both?

Sepsis is a systemic inflammatory response that follows bacterial infection. Cardiac dysfunction is an important consequence of sepsis that affects mortality and has been attributed to either elevated inflammation or suppression of both fatty acid and glucose oxidation and eventual ATP depletion. Moreover, cardiac adrenergic signaling is compromised in septic patients and this aggravates further heart function. While anti-inflammatory therapies are important for the treatment of the disease, administration of anti-inflammatory drugs did not improve survival in septic patients. This review article summarizes findings on inflammatory and other mechanisms that are triggered in sepsis and affect cardiac function and mortality. Particularly, it focuses on the effects of the disease in metabolic pathways, as well as in adrenergic signaling and the potential interplay of the latter with inflammation. It is suggested that therapeutic approaches should include combination of anti-inflammatory treatments, stimulation of energy production, and restoration of adrenergic signaling in the heart