Ann M. Labriola

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Smoking-related health risks among persons with HIV in the strategies for management of antiretroviral therapy clinical trial

OBJECTIVES We sought to determine smoking-related hazard ratios (HRs) and population-attributable risk percentage (PAR%) for serious clinical events and death among HIV-positive persons, whose smoking prevalence is higher than in the general population. METHODS For 5472 HIV-infected persons enrolled from 33 countries in the Strategies for Management of Antiretroviral Therapy clinical trial, we evaluated the relationship between baseline smoking status and development of AIDS-related or serious non-AIDS events and overall mortality. RESULTS Among all participants, 40.5% were current smokers and 24.8% were former smokers. Adjusted HRs were higher for current than for never smokers for overall mortality (2.4; P < .001), major cardiovascular disease (2.0; P = .002), non-AIDS cancer (1.8; P = .008), and bacterial pneumonia (2.3; P < .001). Adjusted HRs also were significantly higher for these outcomes among current than among former smokers. The PAR% for current versus former and never smokers combined was 24.3% for overall mortality, 25.3% for major cardiovascular disease, 30.6% for non-AIDS cancer, and 25.4% for bacterial pneumonia. CONCLUSIONS Smoking contributes to substantial morbidity and mortality in this HIV-infected population. Providers should routinely integrate smoking cessation programs into HIV health care.

Is Frequent CD4+ T-Lymphocyte Count Monitoring Necessary for Persons With Counts ≥300 Cells/µL and HIV-1 Suppression?

Among patients infected with human immunodeficiency virus (HIV), those with HIV-1 RNA <200 copies/mL and CD4 counts ≥300 cells/µL had a 97.1% probability of maintaining durable CD4 ≥200 cells/µL for 4 years. When non-HIV causes of CD4 lymphopenia were excluded, the probability rose to 99.2%. Our data support less frequent CD4 monitoring during viral suppression.

Relationship between HIV coreceptor tropism and disease progression in persons with untreated chronic HIV infection.

Objective:To assess the effect of HIV coreceptor tropism (CRT) on the relative risk of progression to a composite outcome of CD4+ count ≤350 cells per microliter, treatment initiation, or death. Methods:CRT assays were performed after study closure in baseline samples obtained from enrollees in a prospectively monitored cohort of treatment-naive adults with ≥450 CD4+ cells per microliter and ≥1000 HIV-1 RNA copies per milliliter. Results:Dual/mixed (D/M) and R5 CRT were detected in 32 and 282 patients, respectively. The baseline CD4+ count (617 versus 694 cells/μL; P = 0.05) differed in patients with D/M versus R5 CRT. Otherwise, baseline laboratory characteristics were similar.The relative risk of progression to the composite end point was 2.15 (P = 0.002) for D/M versus R5 CRT, 2.07 per 1.0 log10 higher viral load (P < 0.001) and 0.87 per 50 cells per microliter higher CD4+ cell count (P < 0.001). The effect of D/M CRT was also significant in separate analyses of time to initiation of antiretroviral therapy or CD4+ cell count ≤350 cells per microliter. Conclusions:Untreated patients with D/M rather than R5 CRT had a faster rate of disease progression, whether assessed by a composite outcome of time to CD4+ count ≤350 cells per microliter, treatment initiation, or death or by separate analyses of time to CD4+ count ≤350 cells per microliter or treatment initiation.

An Outbreak of Postoperative Gram-Negative Bacterial Endophthalmitis Associated with Contaminated Trypan Blue Ophthalmic Solution

We report 6 cases of postsurgical endophthalmitis due to gram-negative bacteria associated with contaminated trypan blue dye from a compounding pharmacy. Unopened trypan blue syringes yielded Pseudomonas aeruginosa and Burkholderia cepacia complex on culture, with pulsed-field gel electrophoresis patterns indistinguishable from patient isolates. Contamination of compounded medications should be considered when investigating outbreaks of postoperative endophthalmitis.

Long-term follow-up of symptomatic HIV-infected patients originally randomized to early versus later zidovudine treatment: Report of a Veterans Affairs Cooperative Study

Following a 4-year controlled trial comparing early and later zidovudine treatment, we conducted an additional 3-year follow-up. Of the original 338 patients, 275 participated. Clinical outcome measures were AIDS and death. In the early therapy group (n = 170), 67 patients progressed to AIDS compared with 85 in the later therapy group (n = 168); the relative risk (RR) comparing early with later therapy was 0.72% (95% confidence interval [CI] 0.52-0.99; p = 0.044). The early therapy group had 74 deaths compared with 73 in the later therapy (RR = 0.98; 95% CI, 0.71-1.36; p = 0.91). The early group had a peak CD4+ count increase at 1-2 months and a delay of 1 year before CD4+ counts fell below baseline. For patients who received zidovudine for more than the median duration (20.3 months) before their first AIDS diagnosis, the RR for death was 2.08 (95% CI, 1.36-3.19, p = 0.001). Additional factors independently associated with poor prognosis following AIDS were a CD4+ count of < 100 cells/mm3 and increased severity of the first AIDS diagnosis, whereas use of another antiretroviral agent was associated with improved survival. We conclude that early zidovudine therapy delays progression to AIDS but does not affect survival. Patients who progress to AIDS while on prolonged zidovudine monotherapy many benefit from a change to other antiretroviral therapy(ies).

HIV Replication Capacity Is an Independent Predictor of Disease Progression in Persons With Untreated Chronic HIV Infection

Objective:To assess the effect of pol replication capacity (RC) on the hazard ratio of progression to a composite endpoint of time to progression to <350 CD4+ cells per microliter, initiation of therapy, or death. Methods:pol RC assays were performed after study closure in baseline samples obtained from 316 enrollees in a prospectively monitored cohort of treatment-naive adults with ≥450 CD4+ cells per microliter and ≥1000 HIV-1 RNA copies per milliliter. Results:The median RC was 79%. Patients with a lower RC had a lower median viral load (4.0 vs 4.2 Log HIV-1 RNA copies/mL, P = 0.026) and a lower rate of protease inhibitor resistance 2% vs 8%, P = 0.03). Otherwise, baseline demographic and laboratory characteristics were similar. The hazard ratio of progression to the composite endpoint was 0.73 (P = 0.041) for persons with lower RC, 2.07 per 1.0 log10 higher viral load (P < 0.001), and 0.86 per 50 cells per microliter higher CD4+ cell count (P < 0.001). The effect of lower RC was also significant in a separate analysis of time to initiation of therapy (P = 0.04). Conclusions:These results show that untreated patients with lower vs higher RC had a slower rate of progression as assessed by a composite outcome of time to CD4+ count ≤350 cells per microliter, treatment initiation, or death.

Progress realized: Trends in HIV-1 viral load and CD4 cell count in a tertiary-care center from 1999 through 2011

Background HIV-1 RNA and CD4 cell counts are important parameters for HIV care. The objective of this study was to assess the overall trends in HIV-1 viral load and CD4 cell counts within our clinic. Methods Patients with at least one of each test performed by the Infectious Diseases Laboratory from 1999 through 2011 were included in this analysis. By adapting a novel statistical model, log10 HIV-1 RNA means were estimated by month, and log10-transformed HIV-1 RNA means were estimated by calendar year. Geometric means were calculated for CD4 cell counts by month and calendar year. Log10 HIV-1 RNA and CD4 cell count monthly means were also examined with polynomial regression. Results There were 1,814 individuals with approximately 25,000 paired tests over the 13-year observation period. Based on each patients final value of the year, the percentage of patients with viral loads below the lower limit of quantitation rose from 29% in 1999 to 72% in 2011, while the percentage with CD4 counts <200 cells/µL fell from 31% to 11%. On average annually, the mean HIV-1 RNA decreased by 86 copies/mL and the mean CD4 counts increased by 16 cells/µL. For the monthly means, the correlations (R2) from second-order polynomial regressions were 0.944 for log10 HIV-1 RNA and 0.840 for CD4 cell counts. Conclusions Marked improvements in HIV-1 RNA suppression and CD4 cell counts were achieved in a large inner-city population from 1999 through 2011. This success demonstrates that sustained viral control with improved immunologic status can be a realistic goal for most individuals in clinical care.

Four cases of endophthalmitis due to trypan blue

We compare 4 cases of postoperative endophthalmitis due to trypan blue contaminated with Pseudomonas aeruginosa and Burkholderia cepacia and review the literature of gram-negative endophthalmitis. Two cases were due to P. aeruginosa with rapid onset, fulminate course, and loss of vision despite systemic and intravitreal antibiotics. Two cases due to B. cepacia had delayed presentations and were diagnosed on days 23 and 27. Burkholderia cepacia was difficult to treat, requiring multiple courses of antibiotics and ophthalmologic procedures. Outcomes were poor for all 4 patients: 2 required enucleation, 3 had permanent loss of vision, and 1 was left with visual acuity to hand movements. The contrasting clinical presentations and difficulties with diagnosis and treatment of gram-negative endophthalmitis caused by these 2 organisms are compared with other cases in a review of the literature. These cases highlight the serious nature of gram-negative endophthalmitis and the need for better treatment strategies.