Prior studies have shown improved neurocognition with initiation of antiretroviral treatment (ART) in HIV. We hypothesized that stopping ART would be associated with poorer neurocognitive function.
...Neurocognitive function was assessed as part of ACTG 5170, a multicenter, prospective observational study of HIV-infected subjects who elected to discontinue ART. Eligible subjects had CD4 count >350 cells/mm(3), had HIV RNA viral load <55,000 cp/mL, and were on ART (>or=2 drugs) for >or=6 months. Subjects stopped ART at study entry and were followed for 96 weeks with a neurocognitive examination.
A total of 167 subjects enrolled with a median nadir CD4 of 436 cells/mm(3) and 4.5 median years on ART. Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (all p < 0.001). In the 46 subjects who restarted ART prior to week 96, no significant changes in neurocognitive function were observed.
Subjects with preserved immune function found that neurocognition improved significantly following antiretroviral treatment (ART) discontinuation. The balance between the neurocognitive cost of untreated HIV viremia and the possible toxicities of ART require consideration.
This study provides Class III evidence that discontinuing ART is associated with an improvement in 2 neuropsychological tests (Trail-Making Test A & B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol subtest) for up to 96 weeks. Resuming ART was not associated with a decline in these scores for up to 45 weeks.
Background. Oropharyngeal candidiasis is the most common opportunistic infection among persons infected with human immunodeficiency virus (HIV). Use of some agents is hampered by lack of efficacy, ...emergence of resistance, adverse events, and need for intravenous administration. Posaconazole is an extended-spectrum triazole with potent in vitro activity against Candida species, including Candida albicans, Candida glabrata, and Candida krusei (including fluconazole-resistant strains). Methods. This multicenter, randomized, evaluator-blinded study of subjects with HIV infection and oropharyngeal candidiasis compared efficacy of posaconazole with that of fluconazole. Subjects received either 200 mg of posaconazole or fluconazole oral suspension on day 1, followed by 100 mg/day for 13 days. The primary study end point—clinical success (cure or improvement) on day 14—was evaluated for 329 subjects. Durability of clinical success was evaluated on day 42. Results. Three hundred fifty subjects received posaconazole (n = 178) or fluconazole (n = 172). Clinical success occurred in 155 (91.7%) of 169 posaconazole recipients and in 148 (92.5%) of 160 fluconazole recipients (95% confidence interval, -6.61% to 5.04%), indicating that posaconazole was not inferior to fluconazole. On day 14, mycological success was 68% in both arms, but by day 42, significantly more posaconazole recipients than fluconazole recipients continued to have mycological success (40.6% vs. 26.4%; P = .038). Fewer posaconazole recipients than fluconazole recipients experienced clinical relapse (31.5% vs. 38.2%). Adverse events were similar between treatment arms. Conclusions. Results demonstrate that posaconazole was as effective as fluconazole in producing a successful clinical outcome. However, posaconazole was more effective in sustaining clinical success after treatment was stopped.
Focal neurological disease in patients with acquired immunodeficiency syndrome may be caused by various opportunistic pathogens and malignancies, including Toxoplasma gondii, progressive multifocal ...leukoencephalopathy (PML), cytomegalovirus (CMV), and Epstein-Barr virus-related primary central nervous system (CNS) lymphoma. Diagnosis may be difficult, because the findings of lumbar puncture, computed tomography (CT), and magnetic resonance imaging are relatively nonspecific. Newer techniques have led to improved diagnostic accuracy of these conditions. Polymerase chain reaction (PCR) of cerebrospinal fluid specimens is useful for diagnosis of PML, CNS lymphoma, and CMV encephalitis. Recent studies have indicated the diagnostic utility of new neuroimaging techniques, such as single-photon emission CT and positron emission tomography. The combination of PCR and neuroimaging techniques may obviate the need for brain biopsy in selected cases. However, stereotactic brain biopsy, which is associated with relatively low morbidity rates, remains the reference standard for diagnosis. Highly active antiretroviral therapy has improved the prognosis of several focal CNS processes, most notably toxoplasmosis, PML, and CMV encephalitis.
Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the ...interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.
In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo.
Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval CI, 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94).
In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).
Daptomycin, a new cyclic lipopeptide, was recently approved for the treatment of infections by gram-positive organisms, including infections with methicillin-resistant Staphylococcus aureus (MRSA). A ...patient infected with infected with MRSA developed resistance to daptomycin after prolonged exposure, which resulted in clinical failure. Clinicians should be aware of the possibility of daptomycin resistance and should consider routine testing for daptomycin susceptibility.
We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus–infected patients after response ...to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of <4.1 units, and CD4+ T cell count of >150 cells/mm3 were required for eligibility. Thirty-two subjects were enrolled; the median CD4+ T cell count at study entry was 289 cells/mm3. No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4+ T cell count at final study visit was 338 cells/mm3. Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy.
Background. We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)–infected subjects with oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) ...who were clinically refractory to treatment with oral fluconazole or itraconazole. Methods. Subjects with confirmed OPC or EC who did not improve after receiving standard courses of fluconazole or itraconazole treatment were eligible for study enrollment. Subjects received either oral posaconazole (400 mg twice daily) for 3 days followed by oral posaconazole (400 mg once daily) for 25 days (regimen A; 103 patients) or oral posaconazole (400 mg twice daily) for 28 days (regimen B; 96 patients). The primary end point was cure or improvement after 28 days. Primary efficacy analyses were performed on the subset of treated subjects with refractory disease (e.g., baseline culture positive for fluconazole- or itraconazole-resistant Candida species or persistent or progressive clinical signs or symptoms consistent with treatment failure). Results. Of the modified intent-to-treat population, 132 (75%) of 176 subjects achieved a clinical response to posaconazole treatment. Clinical response rates were similar between regimen A recipients (75.3%) and regimen B recipients (74.7%). Clinical responses occurred in 67 (73%) of 92 subjects with baseline isolates resistant to fluconazole, 49 (74%) of 66 subjects with baseline isolates resistant to itraconazole, and 42 (74%) of 57 subjects with isolates resistant to both. Clinical response was achieved in 32 (74.4%) of 43 subjects with endoscopically documented EC. The most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%). Eight subjects (4%) discontinued therapy as a result of a treatment-related adverse event. Conclusions. Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azole-refractory OPC and/or EC.
We conducted a retrospective chart review of human immunodeficiency virus (HIV)-infected patients who died in 1995 and in 1999-2000. We found an increase in the proportion of patients who died from ...an illness that was not related to acquired immunodeficiency syndrome (AIDS). Although there was a decrease in the prevalence of AIDS-defining illnesses, >85% of patients died with CD4 counts of <200 cells/μL. The leading cause of death was Pneumocystis carinii pneumonia (PCP). Nonadherence to therapy and new diagnosis of HIV infection were the leading reasons why patients were not receiving antiretroviral therapy. The leading causes of non-AIDS-related deaths in 1999-2000 were non-AIDS-defining infections and end-stage liver disease. At our hospital, PCP remains an important cause of death in the highly active antiretroviral therapy (HAART) era, possibly because >50% of HIV-infected patients who died were not receiving HAART. AIDS-defining illnesses continue to be a major cause of mortality in the HAART era in populations where access to care and adherence to HAART is limited.
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