When to start antiretroviral therapy: The need for an evidence base during early HIV infection

Background Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/μl should initiate ART. However, it remains controversial whether ART is indicated in asymptomatic HIV-infected persons with CD4 counts above 350 cells/μl, or whether it is more advisable to defer initiation until the CD4 count has dropped to 350 cells/μl. The question of when the best time is to initiate ART during early HIV infection has always been vigorously debated. The lack of an evidence base from randomized trials, in conjunction with varying degrees of therapeutic aggressiveness and optimism tempered by the risks of drug resistance and side effects, has resulted in divided expert opinion and inconsistencies among treatment guidelines. Discussion On the basis of recent data showing that early ART initiation reduces heterosexual HIV transmission, some countries are considering adopting a strategy of universal treatment of all HIV+ persons irrespective of their CD4 count and whether ART is of benefit to the individual or not, in order to reduce onward HIV transmission. Since ART has been found to be associated with both short-term and long-term toxicity, defining the benefit:risk ratio is the critical missing link in the discussion on earlier use of ART. For early ART initiation to be justified, this ratio must favor benefit over risk. An unfavorable ratio would argue against using early ART. Summary There is currently no evidence from randomized controlled trials to suggest that a strategy of initiating ART when the CD4 count is above 350 cells/μl (versus deferring initiation to around 350 cells/μl) results in benefit to the HIV+ person and data from observational studies are inconsistent. Large, clinical endpoint-driven randomized studies to determine the individual health benefits versus risks of earlier ART initiation are sorely needed. The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/147 webcite

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial.

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation

Discontinuation of Prophylaxis against Mycobacterium avium Complex Disease in HIV-Infected Patients Who Have a Response to Antiretroviral Therapy

BACKGROUND Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy

A Controlled Trial of Isoniazid in Persons with Anergy and Human Immunodeficiency Virus Infection Who Are at High Risk for Tuberculosis

BACKGROUND Patients with human immunodeficiency virus (HIV) infection and latent tuberculosis are at substantial risk for the development of active tuberculosis. As a public health measure, prophylactic treatment with isoniazid has been suggested for HIV-infected persons who have anergy and are in groups with a high prevalence of tuberculosis. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial of six months of prophylactic isoniazid treatment in HIV-infected patients with anergy who have risk factors for tuberculosis infection. The primary end point was culture-confirmed tuberculosis. RESULTS The study was conducted from November 1991 through June 1996. Over 90 percent of the patients had two or more risk factors for tuberculosis infection, and nearly 75 percent of patients were from greater New York City. After a mean follow-up of 33 months, tuberculosis was diagnosed in only 6 of 257 patients in the placebo group and 3 of 260 patients in the isoniazid group (risk ratio, 0.48; 95 percent confidence interval, 0.12 to 1.91; P=0.30). There were no significant differences between the two groups with regard to death, death or the progression of HIV disease, or adverse events. CONCLUSIONS Even in HIV-infected patients with anergy and multiple risk factors for latent tuberculosis infection, the rate of development of active tuberculosis is low. This finding does not support the use of isoniazid prophylaxis in high-risk patients with HIV infection and anergy unless they have been exposed to active tuberculosis

Comparison of the Outcomes of Individuals With Medically Attended Influenza A and B Virus Infections Enrolled in 2 International Cohort Studies Over a 6-Year Period: 2009-2015.

BACKGROUND: Outcome data from prospective follow-up studies comparing infections with different influenza virus types/subtypes are limited. METHODS: Demographic, clinical characteristics and follow-up outcomes for adults with laboratory-confirmed influenza A(H1N1)pdm09, A(H3N2), or B virus infections were compared in 2 prospective cohorts enrolled globally from 2009 through 2015. Logistic regression was used to compare outcomes among influenza virus type/subtypes. RESULTS: Of 3952 outpatients, 1290 (32.6%) had A(H1N1)pdm09 virus infection, 1857 (47.0%) had A(H3N2), and 805 (20.4%) had influenza B. Of 1398 inpatients, 641 (45.8%) had A(H1N1)pdm09, 532 (38.1%) had A(H3N2), and 225 (16.1%) had influenza B. Outpatients with A(H1N1)pdm09 were younger with fewer comorbidities and were more likely to be hospitalized during the 14-day follow-up (3.3%) than influenza B (2.2%) or A(H3N2) (0.7%; P < .0001). Hospitalized patients with A(H1N1)pdm09 (20.3%) were more likely to be enrolled from intensive care units (ICUs) than those with A(H3N2) (11.3%) or B (9.8%; P < .0001). However, 60-day follow-up of discharged inpatients showed no difference in disease progression (P = .32) or all-cause mortality (P = .30) among influenza types/subtypes. These findings were consistent after covariate adjustment, in sensitivity analyses, and for subgroups defined by age, enrollment location, and comorbidities. CONCLUSIONS: Outpatients infected with influenza A(H1N1)pdm09 or influenza B were more likely to be hospitalized than those with A(H3N2). Hospitalized patients infected with A(H1N1)pdm09 were younger and more likely to have severe disease at study entry (measured by ICU enrollment), but did not have worse 60-day outcomes

Rates of Tuberculosis Infection in Healthcare Workers Providing Services to HIV-Infected Populations

Objective: To assess the prevalence of tuberculosis (TB) or a positive skin test in healthcare workers (HCWs) providing services to human immunodeficiency virus (HIV)-infected individuals and to determine prospectively the incidence of new infections in this population. Design: This prospective cohort study enrolled 1,014 HCWs working with HIV-infected populations from 10 metropolitan areas. Purified protein derivative (PPD) tuberculin skin tests were placed at baseline and every 6 months afterwards on those without a history of TB or a positive PPD. Demographic, occupational, and TB exposure data also were collected. Setting: Outpatient clinics, hospitals, private practice offices, and drug treatment programs providing HIV-related healthcare and research programs. Participants: A voluntary sample of staff and volunteers from 16 Community Programs for Clinical Research on AIDS units. Results: Factors related to prior TB or a positive skin test at baseline included being foreign-born, increased length of time in health care, living in New York City, or previous bacille Calmette-Guerín vaccination. The rate of PPD conversion was 1.8 per 100 person years of follow-up. No independent relation was found between the amount or type of contact with HIV-infected populations and the risk of TB infection. Conclusion: These data provide some reassurance that caring for HIV-infected patients is not related to an increased rate ofTB infection among HCWs in these settings

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection