Alejandro Sanchez

Early Antiretroviral Therapy Reduces AIDS Progression/ Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. Methods and Findings A5164 was a randomized strategy trial of “early ART” - given within 14 days of starting acute OI treatment versus “deferred ART” - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) ≥50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (pu200a=u200a0.22). However, the early ART arm had fewer AIDS progression/deaths (ORu200a=u200a0.51; 95% CIu200a=u200a0.27–0.94) and a longer time to AIDS progression/death (stratified HRu200a=u200a0.53; 95% CIu200a=u200a0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Conclusions Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications. Trial Registration ClinicalTrials.gov NCT00055120

Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

BACKGROUNDnAntiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known.nnnMETHODSnWe conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks.nnnRESULTSnA total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38).nnnCONCLUSIONSnOverall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.).

Histoplasmosis in Patients With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS): Multicenter Study of Outcomes and Factors Associated With Relapse

AbstractAlthough discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis.Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p < 0.0001) and 5% death (p = 0.28) in the PC group. Relapse occurred in 53% of the nonadherent patients but not in the adherent patients (p < 0.0001). Sixty-seven percent of patients with initial central nervous system (CNS) histoplasmosis relapsed compared to 15% of patients without CNS involvement (p = 0.0004), which may be accounted for by nonadherence. In addition, patients with antigenuria above 2.0 ng/mL at 1-year follow-up were 12.82 times (95% confidence interval, 2.91–55.56) more likely to relapse compared to those with antigenuria below 2.0 ng/mL.Discontinuation of antifungal therapy was safe in adherent patients who completed at least 1 year of antifungal treatment, and had CD4 counts >150 cells/mL, HIV RNA <400 c/mL, Histoplasma antigenuria <2 ng/mL (equivalent to <4.0 units in second-generation method), and no CNS histoplasmosis.

Correspondence of In Vitro and In Vivo Fluconazole Dose-Response Curves for Cryptococcus neoformans

ABSTRACT We conducted in vitro experiments to evaluate the susceptibility of a clinical isolate of Cryptococcus neoformans to a wide range of concentrations of fluconazole. In vitro susceptibility was tested using broth macrodilution methods modified to provide a numeric count of viable organisms. The association between the quantitative in vitro response and fluconazole drug concentrations was estimated using local nonparametric regression. Regression analysis was used to assess the correspondence between the in vitro fluconazole concentration-response curve and the murine dose-response curve observed in our previously reported murine model. The regression model was then used to predict the murine response. There was a strong correspondence between in vitro measures of response to fluconazole alone and the previously reported biologic effects seen in the mouse. In vitro antifungal drug susceptibility testing can reliably predict the murine response to fluconazole.

Correlation of Susceptibility of Cryptococcus neoformans to Amphotericin B with Clinical Outcome

ABSTRACT Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patients quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patients CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.

In Vitro-Clinical Correlations for Amphotericin B Susceptibility in AIDS-Associated Cryptococcal Meningitis

ABSTRACT Reliable measures of antifungal drug susceptibility are needed. We tested the susceptibility of Cryptococcus neoformans from patients treated with amphotericin B. In vitro susceptibility employed a modified broth macrodilution method. We demonstrate a strong correlation between the quantitative measures of in vitro amphotericin B susceptibility and the quantitative response observed in patients.

Emerging fungal pathogens in pulmonary disease

Purpose of review Invasive fungal infections of the lung have been increasing due to the increase of the population most at risk. This review aims to describe some of the emerging fungal pathogens and their complex management. Recent findings With the increase in immunosuppressed populations, physicians are increasingly encountering uncommon fungal pathogens that historically have been difficult to identify and treat. Many of these fungal infections present with similar clinical features and often show similar histopathological changes. Treatment options are more complex because of an increasing number of antifungals that have become available for clinical use. The correct usage of these antifungals in addressing emerging fungal infections is unclear, however. Drawing from in-vitro and in-vivo susceptibility testing and case reports, some deductions may be made for the best empirical treatment of these deadly diseases. In general, the newer triazoles (voriconazole and posiconazole) and the use of combination therapy have shown promise. Summary Invasive fungal infections are on the increase and contribute significantly to overall mortality, particularly among transplant recipients. With the lack of well designed controlled clinical studies, physicians will need to draw from previously described cases and in-vitro susceptibility testing to optimize therapy.

Clinical and Immunologic Predictors of Death After an Acute Opportunistic Infection: Results from ACTG A5164

Abstract Background: In the pre–antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. Objective: To determine clinical and immunological predictors of death after an OI. Methods: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. Results: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. Conclusions: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

Relationship of Acute Phase Reactants and Fat Accumulation during Treatment for Tuberculosis

Background. Tuberculosis causes inflammation and muscle wasting. We investigated how attenuation of inflammation relates to repletion of body composition during treatment in an underserved population. Design. Twenty-four patients (23 to 79 years old) with pulmonary tuberculosis and inflammation (pretreatment albumin = 2.96 ± 0.13u2009g/dL, C-reactive protein [CRP] = 6.71 ± 1.34u2009μg/dL, and beta-2-microglobulin = 1.68 ± 0.10u2009μg/L) were evaluated and had BIA over 24 weeks. Results. Weight increased by 3.02 ± 0.81u2009kg (5.5%; P = 0.007) at week 4 and by 8.59 ± 0.97u2009kg (15.6%; P < 0.0001) at week 24. Repletion of body mass was primarily fat, which increased by 2.09 ± 0.52u2009kg at week 4 and 5.05 ± 0.56u2009kg at week 24 (P = 0.004 and P < 0.0001 versus baseline). Fat-free mass (FFM), body cell mass (BCM), and phase angle did not increase until study week 8. Albumin rose to 3.65 ± 0.14u2009g/dL by week 4 (P < 0.001) and slowly increased thereafter. CRP levels declined by ∼50% at each interval visit. Conclusions. During the initial treatment, acute phase reactants returned towards normal. The predominant accrual of fat mass probably reflects ongoing, low levels of inflammation.

Biomarkers Associated with Death After Initiating Treatment for Tuberculosis and HIV in Patients with Very Low CD4 Cells

Background: The risk of short-term death for treatment naive patients dually infected with Myco-bacterium tuberculosis and HIV may be reduced by early anti-retroviral therapy. Of those dying, mechanisms responsible for fatal outcomes are unclear. We hypothesized that greater malnutrition and/or inflammation when initiating treatment are associated with an increased risk for death. Methods: We utilized a retrospective case-cohort design among participants of the ACTG A5221 study who had baseline CD4 < 50 cells/mm3. The case-cohort sample consisted of 51 randomly selected participants, whose stored plasma was tested for C-reactive protein, cytokines, chemokines, and nutritional markers. Cox proportional hazards models were used to assess the association of nutritional, inflammatory, and immunomodulatory markers for survival. Results: The case-cohort sample was similar to the 282 participants within the parent cohort with CD4 <50 cells/mm3. In the case cohort, 7 (14%) had BMI < 16.5 (kg/m2) and 17 (33%) had BMI 16.5-18.5(kg/m2). Risk of death was increased per 1 IQR width higher of log10 transformed level of C-reactive protein (adjusted hazard ratio (aHR) = 3.42 [95% CI = 1.33-8.80], P = 0.011), inter-feron gamma (aHR = 2.46 [CI = 1.02-5.90], P = 0.044), MCP-3 (3.67 [CI = 1.08-12.42], P = 0.037), and with IL-15 (aHR = 2.75 [CI = 1.08-6.98], P = 0.033) and IL-17 (aHR = 3.99 [CI = -1.06-15.07], P = 0.041). BMI, albumin, hemoglobin, and leptin levels were not associated with risk of death. Conclusions: Unlike patients only infected with M. tuberculosis for whom malnutrition and low BMI increase the risk of death, this relationship was not evident in our dually infected patients. Risk of death was associated with significant increases in markers of global inflammation along with soluble biomarkers of innate and adaptive immunity.