Constance A. Benson

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

CONTEXT Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adults with HIV infection. OBJECTIVES To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. DATA SOURCES AND STUDY SELECTION A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. DATA EXTRACTION AND SYNTHESIS New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. CONCLUSIONS Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count < or = 500/microL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count > 500/microL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.

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.

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

Objective: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV‐1 infection and potent antiretroviral therapy, but limited data ate available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. Participants: A 12‐member panel representing international expertise in HIV‐1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society‐USA, a not‐for‐profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society‐USA; the panel members are not compensated for their participation. Evidence: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. Process: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Conclusions: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV‐1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long‐term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long‐term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the riskbenefit ratio of antiretroviral therapies.

Clarithromycin Therapy for Bacteremic Mycobacterium avium Complex Disease: A Randomized, Double-Blind, Dose-Ranging Study in Patients with AIDS

Disseminated infections with Mycobacterium avium complex are increasingly common in advanced human immunodeficiency virus (HIV) disease and cause substantial morbidity [1, 2]. In persons with HIV infection and CD4 lymphocyte counts less than 100 cells/mm3, the probability of developing M. avium complex disease or bacteremia is 10% to 20% per year [3, 4]. Bacteremia involving M. avium complex produces a wide array of clinical signs and symptoms, including wasting, fever, and night sweats, and is associated with decreased survival [3, 5, 6]. Treatment of disseminated M. avium complex bacteremia with conventional antimycobacterial agents, such as isoniazid, rifampin or rifabutin, ethambutol, and clofazimine, has been disappointing. Relatively few patients respond clinically, and continuous bacteremia persists in most patients despite treatment [7-9]. Combination therapy with four to five agents, including amikacin and fluoroquinolones, has resulted in diminution of M. avium complex bacteremia and alleviation of symptoms in several small studies, although toxicity with combination regimens was substantial [10-13]. Recently, several new macrolide antibiotics have been identified that possess enhanced antimycobacterial activity in vitro [14]. Clarithromycin and azithromycin have been shown in pilot studies [15, 16] to decrease the quantity of M. avium complex organisms in the blood of patients with the acquired immunodeficiency syndrome (AIDS) who were treated with these agents for short periods of time. To further characterize the activity of clarithromycin as a single agent in the treatment of disseminated M. avium complex disease in patients with HIV infection, we did a randomized, double-blind study of three different doses of clarithromycin monotherapy. Because the optimal duration of therapy for M. avium complex disease in patients with AIDS was not known and because the emergence of drug-resistant organisms was of concern, our study was limited to 12 weeks. Patients having a clinical and bacteriologic response at the completion of study were permitted to extend their therapy for up to 1 year with the option of adding other antimycobacterial agents. Methods Patients Patients were eligible for enrollment if they had HIV infection and a blood culture that grew M. avium complex within 60 days before entry. Patients could not have received any antimycobacterial agents for at least 4 weeks before entry into the study; those with a history of severe allergic reactions to erythromycin were excluded. Patients were enrolled at six centers, three within the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG) and three sites funded by Abbott Laboratories. Written informed consent was obtained from all study participants. Enrollment began 1 May 1991 and was completed by 30 November 1991. Patients were randomly assigned to treatment with one of three doses of clarithromycin (Biaxin, Abbott Laboratories, North Chicago, Illinois): 500 mg twice daily, 1000 mg twice daily, or 2000 mg twice daily. Neither patients nor study staff were aware of the dose group to which patients were assigned. Randomization was done in blocks of six and was stratified by site of enrollment. Because the safety of 2000 mg of clarithromycin twice daily in patients with HIV infection was not established when the study began, the first group of 36 patients were randomly assigned to receive 500 mg or 1000 mg twice daily. A 2:1 randomization scheme was used, with two patients assigned to the 500-mg group for each patient assigned to the 1000-mg group. After the start of the study, the safety of 2000 mg of clarithromycin twice daily was shown in a phase 1 trial [17], and the second group of 36 patients were randomly assigned in a 2:1 manner to receive clarithromycin at 2000 mg or 1000 mg twice daily. Thus, after the first 72 patients were enrolled, 24 had been randomly assigned to each dose group. The remainder of the patients were randomly assigned 1:1:1 to the three dose groups. For each dose, patients took four capsulesof which one, two, or four were clarithromycin at 500 mgand the remainder were identical-appearing placebos. Patients were evaluated weekly for 2 weeks, then biweekly through week 12. At each study visit, an interval history was taken, a targeted physical examination was done, and blood was collected for culture and other monitoring tests. After 12 weeks of therapy, patients having a clinical or bacteriologic response were permitted to extend their therapy for up to 1 year, with the option to add other antimycobacterial agents at the discretion of the investigator. Mycobacteriologic Analyses Quantitative blood cultures for mycobacteria were done twice before initiating study therapy and every 2 weeks for the 12 weeks of the study. Cultures were done in the Mycobacteriology Clinical Reference Laboratory at the National Jewish Center for Immunology and Respiratory Medicine in Denver, Colorado, by methods previously reported [18]. In brief, 5 to 8 mL of blood was obtained in previously labeled vacutainer tubes containing 1.7 mL of sodium polyanetholsulfate solution as an anticoagulant. Specimens were shipped at ambient temperature by overnight mail to Denver; shipping of mycobacterial cultures in this manner does not affect viability or quantitative results [19]. After receipt in the laboratory, cultures were mixed with 20 mL of a lysing solution that contained 0.45% sodium deoxycholate and 0.09% sodium polyanetholsulfate. After manual mixing, tubes were centrifuged at 3500 g for 30 minutes in a refrigerated centrifuge, and the supernatant was decanted. The pellet was resuspended, and 0.2% bovine albumin was added to yield a final volume of 2.5 mL. The suspension was inoculated onto two 7H11 agar plates, with 0.5 mL distributed on each plate. A third 7H11 agar plate was inoculated with 0.5 mL of the suspension diluted to 1:100. The plates were then incubated at 37 C in the presence of 5% CO2. The remaining 1.0 mL of suspension was inoculated into liquid 7H12 medium in a BACTEC vial (Becton Dickinson Diagnostic Instrument Systems, Sparks, Maryland), which was incubated at 37 C. Growth in the BACTEC vial was monitored radiometrically daily, and results were reported as positive if the growth index was more than 20. Cultures were considered negative if no growth was observed within 2 weeks in BACTEC. All culture-positive vials were incubated until the growth index was more than 500 to permit speciation and drug susceptibility testing. Speciation was done using hybridized DNA-RNA probes for M. avium and M. intracellulare (AccuProbe, Gen-Probe, San Diego, California). Quantitative colony counts were determined by counting the number of colonies of mycobacteria on the agar plates, followed by a calculation that took into account the concentration coefficient and the initial volume of each blood specimen. If colonies were too numerous to count on duplicate plates, colonies on the plate inoculated with a diluted 1:100 sample were counted. Susceptibility testing of isolates to clarithromycin was done in 7H12 broth at pH 7.4 by the dilution method of Heifets as previously described [18, 20]. Because peak serum concentrations of clarithromycin are 4 to 10 g/mL with drug doses used in this study, we selected a minimal inhibitory concentration of 4 g/mL as the cut-point for susceptibility and selected more than 32 g/mL as the cut-point for resistance. Statistical Analyses Analyses were done to compare baseline characteristics among groups and to compare treatment outcomes within and among groups. Differences in categorical variables were assessed with the continuity-corrected chi-square test. Normally distributed continuous variables within groups were compared with the paired t-test, and skewed variables were compared with the Wilcoxon rank-sum test. Initial analyses were on an intent-to-treat basis, and all randomly assigned patients were included in safety and survival analyses. Bacteriologic analyses were done on all patients with a positive baseline culture and at least one follow-up culture. Median values for colony-forming units (CFUs) of M. avium complex/mL of blood at baseline were compared with follow-up values within and among groups using the Kruskal-Wallis test for three groups. The time to achieve cultures that were negative for M. avium complex (sterilization) in blood was estimated using the product-limit method, with differences assessed by the log-rank test. Survival was also estimated by the product-limit method. To assess the effect of baseline characteristics and treatment on survival, Cox proportional-hazards analysis was done. Results Between 1 May and 30 November 1991, 154 patients were enrolled in the study, 108 at the three ACTG sites and 46 at the other sites. Baseline characteristics of the study population are shown in Table 1. Baseline demographic characteristics were similar. Mean ages of patients in the three groups ranged from 34 to 38 years, and most patients were men. Thirty-one percent of patients enrolled were members of racial or ethnic minorities. Mean weights of participants were 60 to 62 kg. The mean baseline Karnofsky performance score was lower in patients assigned to 1000 mg of clarithromycin twice daily than in patients assigned to 500 mg or 2000 mg twice daily. The median time from diagnosis of M. avium complex infection to enrollment was 84 days for patients assigned to 500 mg twice daily, 64 days for patients assigned to 1000 mg twice daily, and 59 days for patients assigned to 2000 mg twice daily. Table 1. Baseline Demographic and Clinical Characteristics of Patients Treated with Clarithromycin* Baseline laboratory values of patients in the study are shown in Table 2. All patients were moderately anemic. Of note, serum lactate dehydrogenase and alkaline phosphatase levels were increased across all groups, with no statistical differences among groups. Patients were prof

ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-Week results

ObjectiveTo evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals. DesignProspective, randomized, double-blind, multicenter. MethodsEligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68). ResultsMean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 × 106/l and 310 × 106/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50–100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound. ConclusionsABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society–USA Panel

IMPORTANCE New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. OBJECTIVE To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. EVIDENCE REVIEW A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. FINDINGS Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure. CONCLUSIONS AND RELEVANCE Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.

Treating Opportunistic Infections among HIV- Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America

The National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, and CDC have developed guidelines for treatment of opportunistic infections (OIs) among adults and adolescents infected with human immunodeficiency virus (HIV). These guidelines are intended for clinicians and other health-care providers who care for HIV-infected adults and adolescents, including pregnant women; they complement companion guidelines for treatment of OIs among HIV-infected children and previously published guidelines for prevention of OIs in these populations. They include evidence-based guidelines for treatment of 28 OIs caused by protozoa, bacteria, fungi, and viruses, including certain OIs endemic in other parts of the world but that might be observed in patients in the United States. Each OI section includes information on epidemiology, clinical manifestations, diagnosis, treatment recommendations, monitoring and adverse events, management of treatment failure, prevention of recurrence, and special considerations in pregnancy. Tables address drugs and doses, drug toxicities, drug interactions, adjustment of drug doses in persons with reduced renal function, and data about use of drugs in pregnant women.

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1: A Randomized Trial

BACKGROUND Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS Antiretroviral-naive patients. INTERVENTION Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine. MEASUREMENTS Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE National Institutes of Health.

Inflammation and Mortality in HIV-Infected Adults: Analysis of the FRAM Study Cohort

Objective: To determine the association of inflammatory markers, fibrinogen, and C-reactive protein (CRP), with 5-year mortality risk. Methods: Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios after adjustment for demographic, cardiovascular, and HIV-related factors. Results: Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile (>406 mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile (<319 mg/dL). Those with high CRP (>3 mg/L) had 2.7-fold higher adjusted odds of death than those with CRP <1 mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [odds ratio (95% confidence intervals)] per 100 mg/dL increase in fibrinogen: 1.93 (1.57 to 2.37); 1.43 (1.14 to 1.79); 1.43 (1.14 to 1.81); and 1.30 (1.04 to 1.63) for CD4 <200, 200-350, >350 to 500, and >500 cells per microliter, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup. Conclusions: Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500 cells per microliter, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.

Late Presentation for Human Immunodeficiency Virus Care in the United States and Canada

BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4(+) T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count > or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.