Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study

Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals. In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed. A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naïve with CD4 count > 500 cells/µL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/µL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year. Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants. START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials. © 2012, SAGE Publications. All rights reserved

How does tuberculosis relate to HIV positive and HIV negative drug users?

OBJECTIVES—(1) To compare the incidence of active tuberculosis in HIV positive and HIV negative drug users. (2) To describe the main characteristics of the tuberculosis cases.
DESIGN—A prospective study was performed from 1986 to 1996 as part of an ongoing cohort study of HIV infection in Amsterdam drug users.
METHODS—Data from the cohort study, including HIV serostatus and CD4-cell numbers, were completed with data from the tuberculosis registration of the tuberculosis department of the Amsterdam Municipal Health Service. Analyses were carried out with person time and survival methods.
RESULTS—Of 872 participants, 24 persons developed culture confirmed tuberculosis during a total follow up period of 4000 person years (0.60 per 100 py, 95% CI: 0.40, 0.90). Nineteen cases were HIV positive (1.54 per 100 py, 95% CI: 0.86, 2.11) and five HIV negative (0.18 per 100 py, 95% CI: 0.08, 0.43). Multivariately HIV infection (relative risk: 12.9; 95% CI: 3.4, 48.8) and age above 33 years (RR: 6.8; 95% CI: 1.3, 35.0, as compared with age below 27) increased the risk for tuberculosis substantially. Additional findings were: (1) 13 of 22 pulmonary tuberculosis cases (59%) were detected by half yearly radiographic screening of the chest; (2) tuberculosis occurred relatively early in the course of HIV infection at a mean CD4 cell number of 390/µl; (3) an estimated two thirds of the incidence of tuberculosis observed among HIV positive cases was caused by reactivation; (4) all but one patient completed the tuberculosis treatment.
CONCLUSION—HIV infection increases the risk for active tuberculosis in Amsterdam drug users 13-fold. The incidence of tuberculosis in HIV negative drug users is still six times higher than in the overall Amsterdam population. In the absence of contact tracing and screening with tuberculin skin tests, periodic chest radiographic screening contributes substantially to early casefinding of active tuberculosis in Amsterdam drug users.


Keywords: tuberculosis; drug users; epidemiology; HIV infection; longitudinal studie

Aerosolised pentamidine for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome Aerosol de pentamidina no tratamento da pneumonia por Pneumocystis carinii em pacientes com a síndrome da imunodeficiência adquirida

The goal of this study was to evaluate inhaled pentamidine for the treatment of patients with mild and moderate Pneumocystis carinii pneumonitis. Eight adults with AIDS and pneumocystis pneumonia (4 with a first episode and 4 with a repeat pneumocystosis) received daily inhalations of aerosol pentamidine isethionate for 21 days. Six patients were treated with doses of 300 mg of pentamidine and the remaining 2 received 600 mg every day. In the 300 mg treatment group, 2 individuals showed discrete and transient neutropenia. However, both subjects that received 600 mg of aerosol pentamidine daily developed leukopenia. One of them had major toxicity (overall severe intolerance of 12.5%) that required drug discontinuation and did not allow any analysis of the treatment efficacy. Of the 7 evaluable patients, 6 (88%) completed the treatment successfuly. One subject of the 300 mg regimen experienced an early recurrence. In conclusion, inhaled pentamidine is an effective treatment for mild and moderate cases of P. carinii pneumonia. It is less toxic than standard anti-pneumocystis therapy and is suitable for outpatient use.<br>O objetivo deste estudo consistiu em avaliar pentamidina inalatória para o tratamento de pneumonia leve a moderada, causada por Pneumocystis carinii. Oito adultos com a síndrome da imunodeficiência humana e pneumocistose (4 apresentando o primeiro episódio e 4 na vigência de pneumocistose de repetição) receberam inalações diárias de isetionato de pentamidina por 21 dias. Seis pacientes foram tratados com doses de 300 mg de pentamidina e os 2 restantes receberam 600 mg diariamente. No grupo de 300 mg, 2 indivíduos desenvolveram neutropenia leve e transitória. Porém, ambos os pacientes recebendo 600 mg de pentamidina aerosol apresentaram leucopenia. Um deles teve toxicidade importante (intolerância global de 12,5%), que levou a suspensão da droga e impediu a avaliação da sua eficácia. Entre os 7 pacientes que puderam ser avaliados, 6 (86%) completaram o tratamento com sucesso. Um paciente que recebeu 300 mg de pentamidina diariamente teve uma recorrência precoce. Em conclusão, a pentamidina inalatória representa uma modalidade terapêutica eficaz contra a pneumonia por Pneumocystis carinii. E menos tóxica do que as drogas usadas convencionalmente e também pode ser administrada ambulatorialmente

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

10.1371/journal.pone.0139981PLoS ONE1010e013998