Ann C. Collier

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

Treatment of Human Immunodeficiency Virus Infection with Saquinavir, Zidovudine, and Zalcitabine

BACKGROUND In patients with human immunodeficiency virus (HIV) infection, combined treatment with several agents may increase the effectiveness of antiviral therapy. We studied the safety and efficacy of saquinavir, an HIV-protease inhibitor, given with one or two nucleoside antiretroviral agents, as compared with the safety and efficacy of a combination of two nucleosides alone. METHODS In this double-blind trial, patients with HIV infection were randomly assigned to receive either saquinavir (1800 mg per day) plus both zidovudine (600 mg per day) and zalcitabine (2.25 mg per day) or zidovudine plus either saquinavir or zalcitabine. The 302 patients enrolled had CD4+ counts of 50 to 300 cells per cubic millimeter and had previously received zidovudine for a median of 27 months. The study lasted 24 weeks, with an optional double-blind extension period of an additional 12 to 32 weeks. RESULTS Ninety-six percent of the patients completed the 24-week study. In all three treatment groups, CD4+ cell counts rose at first and then fell gradually. The normalized area under the curve for the CD4+ count was greater with the three-drug combination than with either saquinavir and zidovudine (P=0.017) or zalcitabine and zidovudine (P<0.001). There were significantly greater reductions in plasma HIV with the three-drug combination than with the other regimens when peripheral-blood mononuclear cells were cultured for HIV and HIV RNA was assessed, and there were greater decreases in serum neopterin and beta2-microglobulin levels. There were no major differences in toxic effects among the three treatments. CONCLUSIONS Treatment with saquinavir, zalcitabine, and zidovudine was well tolerated. This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of activation markers in serum more than did treatment with zidovudine and either saquinavir or zalcitabine. Studies are warranted to evaluate whether the three-drug combination will reduce morbidity and mortality.

Clinical and Epidemiologic Features of Primary HIV Infection

Primary infection with the human immunodeficiency virus (HIV) ranges from asymptomatic seroconversion to a severe symptomatic illness resembling infectious mononucleosis that can result in hospitalization [1]. However, most reports of primary HIV infection have characterized the events surrounding acquisition of HIV in only a few patients, and most investigators have obtained this information many months after HIV has been acquired. In this report, we summarize the events leading to the acquisition of HIV and the initial clinical and diagnostic evaluation of 46 patients with primary HIV infection. Methods Study Design Patients were recruited into an institutional review board-approved protocol for the study of primary HIV infection. Eligible participants were documented to be 1) simultaneously positive for HIV p24 antigen (or plasma HIV RNA) and negative for HIV antibody (measured by an enzyme immunoassay [EIA] for HIV) at recruitment; 2) serologically (that is, measured by HIV EIA plus Western blot assay) positive at recruitment; or 3) serologically positive at recruitment and serologically negative within the 12 months before study entry, with a documented retroviral syndrome developing 3 months before study entry. We placed no restrictions on sex, age, or race. All enrolled patients who had HIV seroconversion provided written documentation of a previously negative HIV EIA test result from a laboratory proficient in HIV antibody testing. Between September 1993 and January 1995, 60 persons were referred to the study clinic to be screened for primary HIV infection; 46 met the inclusion criteria. The 14 excluded persons did not provide written documentation of previous negative HIV antibody test results or of recent seroconversion. At the enrollment visit, a standardized 160-item questionnaire was administered in private to each patient to collect demographic information, recent and earlier sexual history, and details of all recent medical illnesses. History of sexual contact was corroborated on subsequent visits. Recent medical records were also reviewed, and each patient had a complete physical examination. Any stored serum or plasma samples available from previous HIV antibody testing or a recent illness were retrieved and tested for p24 antigen, plasma HIV RNA, and antibodies against HIV to determine whether the illness associated with the serum sample had been caused by HIV seroconversion. No patient received antiretroviral therapy before or during the initial evaluation period. All patients were asked to have lumbar puncture to obtain cerebrospinal fluid specimens. Twenty-four of the 46 patients agreed to have lumbar puncture. Laboratory Analysis All laboratory studies were done at the University of Washington. Laboratories at the university are certified by the American College of Pathology and the AIDS (acquired immunodeficiency syndrome) Clinical Trials Group for the HIV antibody test, the p24 antigen test, and HIV RNA polymerase chain reaction assays. Enzyme immunoassays for HIV were done according to the manufacturers instructions (Genetic Systems Corp., Seattle, Washington). All positive EIA results were confirmed by Western blot assay (Epitope, Inc., Beaverton, Oregon). Levels of HIV p24 antigen were assayed by EIA according to the manufacturers directions (Abbott Laboratories, Chicago, Illinois); p24 antigen levels less than 20 pg/mL were considered to represent a negative result. Plasma HIV RNA was detected using the Chiron (Emeryville, California) branched-chain DNA assay. The lower limit of detection for this assay is 10 103 DNA copies/mL of plasma [2, 3]. Quantitative co-cultures of peripheral blood mononuclear cells and standard HIV type 1 (HIV-1) cultures of cerebrospinal fluid and plasma were done at the University of Washington Retrovirology Laboratory using previously published methods [4, 5]. T-cell subsets were measured by the Hematopathology Laboratory of the University of Washington using flow cytometry. Statistical Analysis Differences in demographic characteristics and sexual contact history were evaluated using the Fisher exact test or the Mann-Whitney test, as specified. For patients with symptomatic illness, we used the date of symptom onset as the date of HIV acquisition. For patients who were HIV negative on EIA within the 6 months before study entry and who had no history of symptoms, the estimated acquisition date was established as the date midway between the most recent negative and the subsequent positive HIV antibody test result. One author assigned the acquisition date for all patients. Results Patients We enrolled 46 patients during a 28-month period. Patients were referred because they were at risk for HIV infection and developed symptoms of a retroviral illness or because they were found to be HIV-positive on routine testing and had documented evidence of a recent negative test. Patients were recruited from the University of Washington HIV clinics (43%), regional AIDS prevention programs (15%), King County Jail (12%), and local community physicians (30%). Forty-three of the 46 patients (93%) were men. The median age was 30 years, and 13 of 46 patients (28%) were younger than 25 years of age. Forty-two of the 43 men had had sex with men as a risk factor for HIV acquisition; the other male patient reported only heterosexual contact. Four patients (3 men and 1 woman) reported having used injection drugs. Our cohort was similar to persons reported to have HIV-1 infection in King County, Washington (Table 1). Table 1. Demographic Characteristics of Patients with Primary HIV Infection Compared with the 1995 Demographic Characteristics of Persons with Reported Cases of AIDS in King County, Washington* In 17 of 46 patients (37%), either HIV-1 p24 antigen or HIV RNA was detected when the HIV EIA result was negative. The remaining 29 patients (63%) were identified with a new positive result on an HIV Western blot assay and a previous negative result on HIV EIA paired serologic assays. These 29 patients included persons who were tested because they were at high risk and thus had routinely obtained HIV serologic testing, persons who were tested for recent symptoms consistent with primary HIV infection, and persons who were entering a new personal relationship and wanted to know their HIV serologic status. In these 29 patients, the median time from the last documented negative test result was 5 months (range, 1 to 12 months), and the median time from symptom onset to study entry was 80 days (range 2 to 178 days). No differences were noted between the demographic characteristics of the 17 patients identified as positive for HIV p24 antigen or for HIV RNA at enrollment and the demographic characteristics of the 29 patients identified through paired serologic testing. Clinical Presentation Forty-one patients (89%) reported symptoms associated with HIV seroconversion. Sixteen of 17 patients who were positive for HIV p24 antigen or HIV RNA or were negative for HIV EIA antibody at study entry had signs or symptoms suggestive of an acute retroviral syndrome; 15 of these 16 patients (94%) sought medical assistance, and 12 of these 15 were eventually tested for HIV infection during their illness. Of the remaining 29 patients, 25 (86%) also reported symptoms consistent with an acute retroviral syndrome during the interval between their previously negative antibody test result and study entry (Table 2). Twenty-two of these 25 (88%) sought medical care for these symptoms: Nine had HIV testing at the initial medical encounter, and 5 others referred themselves for testing shortly after the illness developed. Three of 46 patients (6%) reported that they had intentionally engaged in high-risk sexual behavior in attempts to become infected with HIV. Table 2. Clinical Presentation of HIV Seroconversion* Twenty-three patients were participating in routine surveillance programs in which HIV testing was done every 6 months. Twenty of these 23 (87%) reported symptoms consistent with an acute retroviral syndrome, and 19 of the 20 (95%) had medical evaluation for these symptoms (48% went to their own primary care provider, 31% went to an emergency department, and 21% went to a walk-in clinic). A diagnosis of primary HIV infection was considered at these medical encounters in only 5 of these 19 patients (26%). The five most common symptoms reported during primary HIV infection were fever, sore throat, fatigue, weight loss, and myalgia (Figure 1, top). The median maximal temperature reported was 38.9 C (range, 39 C to 40.5 C), and the median weight loss was 5 kg (range, 1.4 to 10 kg). Abnormalities on physical examination for symptoms of primary HIV infection were found in 23 of 35 patients (66%) seeking medical help. These abnormalities included postural hypotension, oral ulceration, exudative pharyngitis, thrush, genital or rectal ulceration, adenopathy, and signs of neuropathy. Signs and symptoms of aseptic meningitis (fever, headache, photophobia, and stiff neck) were noted in 10 of the 41 patients (24%) presenting for medical consultation. The median duration of symptoms of the acute retroviral illness was 14 days (Figure 1, bottom). Seven of the 41 patients (17%) with symptomatic illness were hospitalized. Frequency of hospitalization was the only significant difference noted in the clinical presentation of patients who were positive for p24 antigen (or for HIV RNA) and had negative EIA results compared with patients who were identified by serial testing: 29% compared with 8%. Figure 1. Top. Bottom. Virologic Studies at Study Entry The time from seroconversion to study entry was a significant factor in the ability to detect HIV-1 RNA in plasma (Table 3). Of 16 patients enrolled within 60 days of HIV acquisition (median, 28 days), 14 had HIV RNA detected in plasma (median titer, 116 103 RNA copies/mL [range, <10 to 553 103 RNA copies/mL]). Only 1 of these 14 patients had HIV p24 antigenemia. In the

Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System

OBJECTIVE To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. DESIGN Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. RESULTS The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. CONCLUSIONS Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.

Plasma Viremia in Human Immunodeficiency Virus Infection

To determine which markers of human immunodeficiency virus type 1 (HIV) replication correlate most closely with progressive disease, we compared the following: (1) the frequency of isolation of HIV from peripheral-blood mononuclear cells (PBMC), (2) the frequency of isolation of the virus from cell-free plasma (plasma viremia), (3) the presence and titer of p24 antigen in plasma, and (4) the presence and titer of antibody to p24 antigen. We studied 213 persons who were positive for HIV antibody and 71 who were negative. HIV was isolated from PBMC from 207 of the 213 antibody-positive patients (97 percent), regardless of the clinical stage of the infection. Plasma viremia, in contrast, was correlated with the clinical stage of the infection. It was detected in 11 of 48 patients (23 percent) with asymptomatic infection, 32 of 71 (45 percent) in Class IVa of the Centers for Disease Control (those with AIDS-related complex), and 75 of 92 (82 percent) in Class IVc (those with AIDS) (P less than 0.01). Plasma HIV titers ranged from 10(0) to 10(4.3) and rose from a mean of 10(1.4) in asymptomatic patients to 10(2.5) in those with AIDS (P less than 0.02). Only 45 percent of patients with plasma viremia had HIV p24 antigen in either serum or plasma, and no correlation was found between the amount of p24 antigen in plasma and the plasma HIV titers. Follow-up tests indicated that plasma viremia was associated with a more marked decline in the CD4-lymphocyte cell count and the development of symptomatic disease (P = 0.034). We conclude that plasma viremia is a more sensitive virologic marker of the clinical stage of HIV infection and viral replication than the presence of p24 antigen or antibody in plasma. Not only whole blood but cell-free plasma from HIV-infected patients should be considered potentially infectious.

The prevalence and incidence of neurocognitive impairment in the HAART era.

Objectives:HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial. Design:A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study. Methods:We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study. Results:A history of immunosuppression (nadir CD4 cell count < 200 cells/μl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment. Conclusion:The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Invasion of the Central Nervous System by Treponema pallidum: Implications for Diagnosis and Treatment

STUDY OBJECTIVES To determine the prevalence of Treponema pallidum in cerebrospinal fluid (CSF) of patients with syphilis, to determine the effect of concurrent HIV infection on central nervous system involvement by T. pallidum, and to examine the efficacy of conventional therapy for asymptomatic neurologic involvement. PATIENTS Fifty-eight patients with untreated syphilis who consented to lumbar puncture, representing approximately 10% of new cases of syphilis during the study period. INTERVENTIONS Lumbar puncture was done on all patients. Rabbit inoculation was used to test cerebrospinal fluid for viable T. pallidum. Patients with normal fluid received recommended benzathine penicillin therapy according to the stage of syphilis; patients with CSF abnormalities were offered 10-day therapy for neurosyphilis. RESULTS Treponema pallidum was isolated from the CSF of 12 (30%) of 40 patients (95% CI, 17 to 46) with untreated primary and secondary syphilis; isolation of T. pallidum was significantly associated (P = 0.008) with the presence of two or more abnormal laboratory variables (among leukocyte count, protein concentration, and CSF-Venereal Disease Research Laboratory [VDRL] test). Two (67%) of 3 early latent (CI, 13 to 100) and 3 (20%) of 15 late latent syphilis patients (CI, 5 to 47) also had reactive CSF-VDRL tests and elevated cell and protein levels, although T. pallidum was not isolated. Concurrent infection with the human immunodeficiency virus (HIV) was not associated with isolation of T. pallidum, increased number of CSF abnormalities, or reactive CSF serologic tests for syphilis, although CSF pleocytosis was commoner in subjects infected with HIV. Treatment with conventional benzathine penicillin G (2.4 mIU) failed to cure 3 of 4 patients with secondary syphilis from whom T. pallidum was isolated before therapy; all 3 patients in whom treatment failed were HIV seropositive when treated or seroconverted during follow-up. CONCLUSIONS Central nervous system invasion by T. pallidum is common in early syphilis, and is apparently independent of HIV infection. Examination of the CSF may be beneficial in patients with early syphilis, and therapy should be guided by knowledge of central nervous system involvement. Conventional benzathine penicillin G therapy may have reduced efficacy in patients with early syphilis who are also infected with HIV.

Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection

AMD3100 is a CXCR4 receptor inhibitor with anti–HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 μg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non–SI (45%), or not tested (25%). One patient (5 μg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 μg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-μg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1–11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9–3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 μg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.