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The evolutionary success of primate lentiviruses reflects their high capacity to mutate and adapt to new host species, immune responses within individual hosts, and, in recent years, antiviral drugs. APOBEC3G (A3G) and APOBEC3F (A3F) are host cell DNA-editing enzymes that induce extensive HIV-1 mutation that severely attenuates viral replication. The HIV-1 virion infectivity factor (Vif), expressed in vivo, counteracts the antiviral activity of A3G and A3F by inducing their degradation. Other APOBECs may contribute more to viral diversity by inducing less extensive mutations allowing viral replication to persist. Here we show that in APOBEC3C (A3C)-expressing cells infected with the patient-derived HIV-1 molecular clones 210WW, 210WM, 210MW, and 210MM, and the lab-adapted molecular clone LAI, viral G-to-A mutations were detected in the presence of Vif expression. Mutations occurred primarily in the GA context and were relatively infrequent, thereby allowing for spreading infection. The mutations were absent in cells lacking A3C but were induced after transient expression of A3C in the infected target cell. Inhibiting endogenous A3C by RNA interference in Magi cells prevented the viral mutations. Thus, A3C is necessary and sufficient for G-to-A mutations in some HIV-1 strains. A3C-induced mutations occur at levels that allow replication to persist and may therefore contribute to viral diversity. Developing drugs that inhibit A3C may be a novel strategy for delaying viral escape from immune or antiretroviral inhibition.

Background: The primary objective of this study was to determine the prevalence of oral herpes simplex virus (HSV) as detected by polymerase chain reaction, in pediatric oncology patients with febrile neutropenia. Our secondary objectives were to describe the association between oral HSV and prolonged fever, neutropenia, mucositis, and response to initial antimicrobial therapy., Methods: In this prospective cohort study, we obtained a mouth swab and blood specimen from oncology patients with febrile neutropenia, and tested them for HSV by polymerase chain reaction. Prolonged fever was defined as the presence of fever 48 hours after initiation of broad-spectrum antibiotic therapy., Results: Of the 75 oral and blood specimens obtained, only 7 oral swabs (9%) and 2 blood samples (3%) were positive for HSV. Oral HSV was not associated with prolonged fever or neutropenia. However, oral HSV was associated with longer median duration of mucositis (8 days; interquartile range, 0-12 days) compared with negative episodes (0 days; interquartile range, 0-2.5 days); P = 0.005. Oral HSV also was associated with inferior successful response to initial antimicrobial therapy (1 of 7, 14.3%) compared with negative episodes (51 of 67, 76.1%); P = 0.002., Conclusions: The prevalence of HSV infection in pediatric oncology patients with febrile neutropenia was low and was not associated with prolonged fever. However, oral HSV was associated with prolonged mucositis and poorer response to initial therapy. It is unknown whether early intervention with acyclovir can alter these associations.

Human APOBEC3G (A3G), a deoxycytidine deaminase, is a broadly acting antiretroviral factor expressed in a variety of cells. Mitogen activation of CD4 T cells enhances A3G expression and leads to recruitment of low molecular mass (LMM) A3G, which functions as a post-entry human immunodeficiency virus (HIV) restriction factor, into enzymatically inactive, high molecular mass (HMM) RNA-protein complexes that include Staufen RNA-transporting granules. We now report that interleukin-2 (IL-2), IL-15 and, to a lesser extent, IL-7 enhance the expression of A3G in peripheral blood lymphocytes and that this effect is blocked by inhibitors of the JAK and MAPK signaling pathways. In mixed cultures of CD4+ T cells containing either HMM or LMM A3G, HIV preferentially infected cells containing HMM A3G. A3G shifted into a HMM complex when IL-2, -7, or -15 was added to resting T cells, likely explaining how cytokine treatment renders resting CD4+ T cells permissive to HIV infection. Similarly, poly(I:C)/tumor necrosis factor-alpha-induced maturation of dendritic cells was associated with a sharp increase in A3G expression; however, this induction led to the accumulation of LMM A3G. Together, these results highlight the distinct inductive effects of select cytokines on A3G gene expression and A3G complex assembly that occur in natural cellular targets of HIV infection.

Prior studies have indicated that dehydroepiandrosterone (DHEA) may have immunomodulatory properties as well as positive effects on mood, quality of life, and body composition. Preliminary data suggest that DHEA inhibits expression of human immunodeficiency virus 1 (HIV) in latently infected cells; thus, it might be a potential adjunct to currently available antiretroviral therapy. The objective was to determine DHEA's impact on latent HIV infection, persistent viral replication, immunity, and nonimmune aspects of health restoration. A randomized, double-blind, placebo-controlled 24-week outpatient intervention included 40 subjects with suppressed HIV viremia on a stable antiretroviral regimen. Participants were randomized with equal probability to receive either DHEA or placebo for 12 weeks, followed by open-label DHEA for an additional 12 weeks. Intensive virologic monitoring included plasma viral load assays (lower limits of detection 50 copies/ml and 2.5 copies/ml) and quantitative cultures of replication-competent virus reservoirs in blood cells. A full battery of immunologic measurements was performed. Measurements of hormones, body weight, and body composition were obtained. Quality of life was assessed using validated questionnaires. DHEA was bioavailable as ascertained by increased levels of DHEA, DHEA(S), and androstenedione in recipients' plasma compared to the control group. The titers of infectious HIV culturable from blood trended upward in the DHEA arm although there was no significant change in plasma HIV RNA level. No significant immune effects were observed with DHEA. There appeared to be no benefit with regard to lean muscle mass or bone density in the DHEA recipients. DHEA treatment had a positive impact on overall quality of life. DHEA supplementation in fully suppressed HIV patients was associated with an improvement in quality of life but appeared to have no beneficial antiviral, immunomodulatory, hormonal, or body composition effects, suggesting that it not be routinely used as an adjunctive therapy in this population.

Purpose: Reduced-intensity protocols for pediatric Hodgkin's lymphoma are aimed at preserving excellent relapse-free survival while decreasing the incidence of late effects., Patients and Methods: We retrospectively reviewed the outcome of 123 children treated consecutively for Hodgkin's lymphoma at a single institution. Patients with stages I-IIIB disease received three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ doxorubicin, bleomycin, and vinblastine (ABV) followed by 15 Gy of extended-field irradiation, while those with stage IV disease were treated with six to eight cycles of MOPP/ABV chemotherapy with or without radiotherapy., Results: At a median follow-up of 8.5 years (range, 1.4 to 15.5 years), the estimated 10-year overall survival and event-free survival are 94% (SE, 2.2%) and 88% (SE, 3.1%) respectively. There have been 12 treatment failures and six disease-related deaths. A very large mediastinal mass ( 50% of the maximal thoracic diameter) was associated with a 10-year event-free survival of 50% (SE, 14%) compared with 91% (SE, 4.0%) for smaller masses (P < .001). Late cardiopulmonary toxicity is largely absent, and the incidence of hypothyroidism is 14%. There have been no cases of secondary leukemia and four secondary solid malignancies observed to date., Conclusion: MOPP/ABV and low-dose, extended-field radiotherapy is an effective treatment for pediatric Hodgkin's lymphoma. With median follow-up of 8.5 years, late cardiopulmonary effects and secondary malignancies from this treatment regimen are infrequent. Continued longitudinal observations, particularly for breast cancer in female patients and gonadotoxicity, will determine whether the goal of decreasing treatment-related complications while maintaining excellent survival has been achieved.

Background: Sexually transmitted infections (STI) and unprotected anal intercourse (UAI) have been increasing among men who have sex with men (MSM) in San Francisco. However, HIV incidence has stabilised., Objectives: To describe recent trends in sexual risk behaviour, STI, and HIV incidence among MSM in San Francisco and to assess whether increases in HIV serosorting (that is, selective unprotected sex with partners of the same HIV status) may contribute to preventing further expansion of the epidemic., Methods: The study applies an ecological approach and follows the principles of second generation HIV surveillance. Temporal trends in biological and behavioural measures among MSM were assessed using multiple pre-existing, Data Sources: STI case reporting, prevention outreach programmatic data, and voluntary HIV counselling and testing data., Results: Reported STI cases among MSM rose from 1998 through 2004, although the rate of increase slowed between 2002 and 2004. Rectal gonorrhoea cases increased from 157 to 389 while early syphilis increased from nine to 492. UAI increased overall from 1998 to 2004 (p<0.001) in community based surveys; however, UAI with partners of unknown HIV serostatus decreased overall (p<0.001) among HIV negative MSM, and among HIV positive MSM it declined from 30.7% in 2001 to a low of 21.0% in 2004 (p<0.001). Any UAI, receptive UAI, and insertive UAI with a known HIV positive partner decreased overall from 1998 to 2004 (p<0.001) among MSM seeking anonymous HIV testing and at the STI clinic testing programme. HIV incidence using the serological testing algorithm for recent HIV seroconversion (STARHS) peaked in 1999 at 4.1% at the anonymous testing sites and 4.8% at the STI clinic voluntary testing programme, with rates levelling off through 2004., Conclusions: HIV incidence among MSM appears to have stabilised at a plateau following several years of resurgence. Increases in the selection of sexual partners of concordant HIV serostatus may be contributing to the stabilisation of the epidemic. However, current incidence rates of STI and HIV remain high. Moreover, a strategy of risk reduction by HIV serosorting can be severely limited by imperfect knowledge of one's own and one's partners' serostatus.

Objective: To estimate the rate of acute and recent HIV infections and the prevalence of primary antiretroviral resistance., Design, Setting, and Subjects: A consecutive sample of individuals presenting for HIV testing at the San Francisco municipal sexually transmitted diseased (STD) clinic in 2004 (n = 3789)., Main Outcome Measures: HIV antibody-positive specimens were screened by BED IgG capture enzyme immunoassay to identify recent infections. HIV antibody-negative specimens were screened by nucleic acid amplification testing (NAAT) to detect acute infections. Newly detected infections were genotyped to detect primary antiretroviral resistance., Results: There were 11 acute and 44 recent HIV infections among the total 136 newly detected cases. NAAT increased case identification by 8.08% over standard antibody testing. Acute HIV infections were associated with having a known HIV-positive partner, and a history of hepatitis B, syphilis, and chlamydia. The prevalence of primary antiretroviral resistance was 13.2%, with drug-resistant mutations detected in 17 of 129 cases genotyped. Mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) were present in 11 of 17 cases., Conclusion: The integration of HIV nucleic acid amplification, recent infection, and antiretroviral resistance testing enhanced HIV/STD surveillance. The high proportion of NNRTI mutations detected suggests they may be more common in source partners or more fit for transmission than other forms of drug-resistant HIV-1. Primary antiretroviral resistance monitoring in STD clinic patients may guide the selection of treatment and post-exposure prophylaxis regimens active against viruses being transmitted in the community, and provide health departments with surveillance data in a sentinel population at risk of HIV transmission.

The human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) causes cell cycle arrest in G2. Vpr-expressing cells display the hallmarks of certain forms of DNA damage, specifically activation of the ataxia telangiectasia mutated and Rad3-related kinase, ATR. However, evidence that Vpr function is relevant in vivo or in the context of viral infection is still lacking. In the present study, we demonstrate that HIV-1 infection of primary, human CD4+ lymphocytes causes G2 arrest in a Vpr-dependent manner and that this response requires ATR, as shown by RNA interference. The event leading to ATR activation in CD4+ lymphocytes is the accumulation of replication protein A in nuclear foci, an indication that Vpr likely induces stalling of replication forks. Primary macrophages are refractory to ATR activation by Vpr, a finding that is consistent with the lack of detectable ATR, Rad17, and Chk1 protein expression in these nondividing cells. These observations begin to explain the remarkable resilience of macrophages to HIV-1-induced cytopathicity. To study the in vivo consequences of Vpr function, we isolated CD4+ lymphocytes from HIV-1-infected individuals and interrogated the cell cycle status of anti-p24Gag-immunoreactive cells. We report that infected cells in vivo display an aberrant cell cycle profile whereby a majority of cells have a 4N DNA content, consistent with the onset of G2 arrest.

We sought to determine whether pretreatment low pol replication capacity (polRC) is associated with CD4 T-cell count gains during antiretroviral therapy (ART). Patients were recruited at north American and Australian sites. Viral polRC was measured before starting ART in all subjects. We examined 243 individuals for a median 260 days after initiating ART. Low baseline polRC was associated with greater CD4 T-cell gains independent of virological responses.

Coinfections with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are common globally. HIV infection modifies the course of HBV infection by increasing rates of chronicity, prolonging HBV viremia, and increasing liver-related morbidity. To minimize the emergence of HIV and/or HBV resistance, as well as the emergence of liver enzyme flares, the treatment of both infections should be coordinated. Lamivudine or emtricitabine monotherapy readily selects resistant strains in the YMDD motif of the polymerase gene. Adefovir and tenofovir are fully active in the presence of YMDD mutations [corrected] If HBV treatment can be deferred until combination antiretroviral therapy for HIV infection is needed, the combination of tenofovir plus lamivudine or emtricitabine provides potent HBV therapy and a solid backbone for HIV combination antiretroviral therapy, and it likely decreases the emergence of HBV resistance.

Background: HIV drug resistance surveillance is limited by recruitment and selection bias and by limited information regarding HIV incidence rates, secondary resistance, and treatment prevalence., Methods: A second-generation HIV sentinel surveillance among men who have sex with men (MSM), regardless of prior history of HIV screening, serostatus, or treatment, was conducted in Peru in 2002. Recent HIV infection was estimated using sensitive/less sensitive enzyme immunoassay testing. Genotypic resistance testing was performed., Results: HIV prevalence was 13.9% (456 HIV positive of 3280 participants). HIV incidence was estimated to be 5.1 per 100 person-years (95% confidence interval: 3.1-8.3). Among 143 MSM who were aware of their HIV infection before testing, only 20 (14.0%) were receiving antiretrovirals (ARV). Mutations conferring ARV resistance were found in 12 (3.3%) of 359 treatment-naive and 5 (31.3%) of 16 treatment-experienced participants with successful genotyping. One recently infected man from Lima demonstrated 3-class multidrug resistance. The most frequently observed mutations in treatment-naive, chronically infected persons from Lima were M184V (1.7%), D30N (1.3%), L90M (1.3%), and L10I (1.3%)., Conclusions: The prevalence of ARV resistance among treatment-naive MSM in Peru is low, reflecting limited access to treatment before 2004, and contrasts with the history of ARV treatment in developed countries, where high levels of nucleoside reverse transcriptase inhibitor resistance occurred before introduction of highly active antiretroviral therapy. Linking ARV resistance and HIV sentinel surveillance in developing settings is feasible and should be considered in third-generation HIV sentinel surveillance programs.

Observed declines in drug resistance to nucleoside reverse transcriptase inhibitors among persons recently infected with HIV-1 in monitored subpopulations can be interpreted as a positive sign and lead public health officials to decrease efforts towards HIV prevention. By means of a mathematical model, we identified 3 processes that can account for the observed decline: increase in high-risk behavior, decrease in proportion of acutely infected persons whose conditions are treated, and change in treatment efficacy. These processes, singly or in combination, can lead to increases or decreases in disease and drug-resistance prevalence in the general population. We discuss the most appropriate public health response under each scenario and emphasize how further data collection and analyses are required to more reliably evaluate the observed time trends and the relative importance of forces shaping the epidemic. Our study highlights how drug resistance markers can be used as epidemiologic sentinels to devise public health solutions.

Objectives: To describe the prevalence of specific protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and the relationship between the presence of these mutations and immunologic outcomes following PI/NNRTI initiation among a cohort of HIV-1-infected women., Methods: Viral genotypic resistance testing was done for 366 women enrolled in the Women's Interagency HIV Study at the visit immediately prior to 1st reported use of PI or NNRTI (baseline) and at the visit approximately 1 year after PI/NNRTI initiation. We modeled the changes in CD4+ T-cell counts and HIV RNA levels approximately 1 year after therapy initiation as a function of baseline and follow-up markers, type of antiretroviral therapy used, and resistance mutations., Results: At baseline, 52% of women showed only nucleoside reverse transcriptase inhibitor (NRTI) mutations, 38% showed no mutations, and 10% showed PI or NNRTI mutations. Only 40% of women showed viral response (HIV-1 RNA < or = 80 copies/mL) 1 year after initiating a PI or NNRTI. Among those without a viral response, 54% developed PI or NNRTI mutations. NNRTI (among those with baseline NRTI mutations) and PI resistance mutations were associated with better CD4+ cell count changes (mean increase of 118 cells/mm3 and 64 cells/mm3, respectively, as compared with viral nonresponders with no PI or NNRTI mutations)., Conclusions: In this population-based cohort, virologic failure with PI or NNRTI resistance was common. Viremia with these resistance mutations was associated with preserved CD4+ T-cell count responses, providing evidence of reduced virulence or viral fitness.

Background: The substantial frequency of drug resistance in persons recently infected with HIV implies exposure among HIV-uninfected individuals to HIV-infected persons with drug-resistant virus. Although there is an increasing emphasis on understanding high-risk behavior among HIV-infected patients, little work has focused on those with drug-resistant virus., Methods: We examined antiretroviral-treated patients with drug resistance in the Study of the Consequences of the Protease Inhibitor Era, a clinic-based cohort of HIV-infected adults. Sexual behavior was ascertained by self-administered questionnaire. Genotypic antiretroviral resistance testing was performed on isolates from participants with a plasma HIV RNA level > or =100 copies/mL., Results: Among 279 participants on antiretroviral therapy, 168 (60%) had genotypic resistance to at least 1 drug. In those with drug resistance, 27% of men who have sex with men (MSM) and 11% of heterosexual men and women reported at least 1 episode of unprotected penile-anal or penile-vaginal intercourse in the previous 4 months; 17% of MSM and 6% of heterosexual participants reported unprotected intercourse with an HIV-uninfected or status unknown partner. In a multivariable model of predictors of unprotected anal or vaginal intercourse with an HIV-uninfected or status unknown partner, there was strong evidence for an effect of younger age, depression, and sildenafil use and moderate evidence for frequent alcohol use., Conclusions: Among HIV-infected patients with drug-resistant viremia, there is a substantial prevalence of high-risk sex with HIV-uninfected partners. The presence of definable risk factors for unsafe sex suggests a role for targeted rather than broad intervention, particularly when resources are limited.

Background: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP., Methods: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation., Results: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus., Conclusions: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Background: Many antiretroviral-treated human immunodeficiency virus (HIV)-infected patients experience sustained immunologic and virologic benefit despite the presence of multidrug-resistant HIV. We hypothesized that the use of simplified regimens could maintain treatment benefit while preventing viral evolution and reducing drug-related toxicity and costs., Methods: We conducted a 48-week nonrandomized study of adults with multidrug-resistant HIV type 1 infection. Subjects interrupted protease inhibitor (PI) (n=18), reverse-transcriptase inhibitor (RTI) (n=6), or nonnucleoside RTI (NNRTI) (n=6) treatment., Results: At study entry, subjects had a median reduction in HIV RNA levels of 1.2 log10 copies/mL relative to pretreatment levels. Interruption of PI treatment was associated with stable HIV RNA levels (mean change per week, +0.005 log10 copies/mL; P=.36). PI mutations waned and replicative capacity and HIV RNA levels increased after long-term observation. HIV RNA levels also remained stable in subjects interrupting NNRTI treatment. In contrast, all subjects who interrupted RTI treatment exhibited immediate increases in HIV RNA levels, and most exhibited a subsequent loss of the M184V mutation., Conclusions: These data indicate that nucleoside analogues often exert continued antiviral activity in the setting of drug-resistance mutations and that both nucleoside analogues and PIs can select for drug-resistance mutations that reduce viral fitness. These observations support the evaluation of treatment strategies aimed at maintaining the treatment benefit of therapy while reducing drug exposure.

Objectives: In HIV infection, activated monocytes are enriched in blood and in the perivascular area of the brain, especially in patients with HIV-associated dementia. Although clinical brain disease is uncommon during combination antiretroviral therapy (ART), autopsy series indicate that HIV-infected brain tissue can contain high numbers of monocytes/macrophages despite ART., Design: We assessed activated monocytes in blood and cerebrospinal fluid (CSF) in 76 living patients on and off ART. Plasma lipids were measured because they have been associated with monocyte activation and ART., Methods: A novel quantitative six-color flow cytometric approach was used to identify monocytes in blood and CSF and to evaluate monocyte activation status., Results: The mean percentage and number of activated CD16 monocytes in CSF was highest in individuals on combination ART, especially in those receiving protease inhibitors (PI). CSF viral load was also associated with higher monocyte activation in CSF. The mean calculated low density lipoprotein (LDL)-, oxidized LDL- and total cholesterol in plasma were highest in patients receiving PI., Conclusions: Activated monocytes are enriched in the CSF of persons living with HIV-1 and receiving ART. This finding is consistent with previously reported autopsy series. The mechanisms and long-term clinical consequences of persistent monocyte activation require further study.

Sinus histocytosis with massive lymphadenopathy, or Rosai-Dorfman disease, is a rare histiocytic disorder that typically presents with chronic, self-limiting, cervical lymphadenopathy. We present a case, a diagnostic dilemma for multiple consultation services, of an otherwise well 17-year-old boy without lymphadenopathy who, 8 months after excision of a T9 lytic vertebral lesion and epidural mass that caused cord compression, again presented with cord compression from progressive vertebral disease, recurrent epidural mass, and development of a paraspinal mass and tibial lesion. The excised vertebral and epidural lesions, 2 paraspinal biopsies, and tibial biopsy were interpreted as chronic inflammation until large histiocytes were noted, which were positive for CD68, S100 protein, fascin, and MAC387, and demonstrated characteristic emperipolesis (lymphophagocytosis) that was diagnostic of Rosai-Dorfman disease. This atypical clinical behavior and sites of involvement of multiple bones but not of lymph nodes is unusual and constitutes the aggressive end of the clinical spectrum and a rare cause for cord compression.

Transient decreases in the proportion of individuals newly infected with an HIV-resistant virus (primary resistance) are documented for several cities of North America, including San Francisco. Using a staged SI deterministic model, we identified three potential causes consistent with the history of the epidemic: (1) increase in risky behaviour, (2) reduction in the proportion of HIV-acutely infected individuals undergoing treatment, and (3) replacement of mono- and dual-drug therapies with triple-drug therapies. Although observed patterns resemble scenario 1 most closely, these explanations are not mutually exclusive and may have contributed synergistically to the decline. Under scenario 1 the counterintuitive situation arises where, although the proportion of primary resistance cases decreases transiently, the epidemic worsens because the actual numbers of infected individuals and of drug resistance carriers increases. Our results call for improved efforts to control the epidemic in developed nations, and highlight the usefulness of drug resistant strains as epidemiological markers.

We characterized T cell phenotypes in 74 paired blood and cerebrospinal fluid (CSF) samples of HIV-infected and uninfected persons using four-color flow cytometry. CD4+ and CD8+ T cells subsets were further characterized by identifying activated/resting and memory/naive subsets in CSF and blood using the markers CD38/HLA-DR and CD45RA/CD62L, respectively. With and without HIV-infection, the proportion of CD4+ T cells and memory T cells among T cells in CSF was higher compared to blood. In HIV-infection, activated CD4+ and CD8+ T cells in CSF were more abundant than in uninfected controls. As expected, combination antiretroviral therapy (ART) reduced T cell activation in CSF and blood.

The development of clinical symptoms, and clinical progression among persons infected with HIV-1 is the manifestation of the effects of the pathogenic viral life cycle of HIV-1. Individual variants of HIV-1 vary widely in features that determine viral fitness and virulence. HIV-1 exploits host antiviral responses, the APOBEC3G cytidine deaminase, and the low-fidelity HIV-1 reverse transcriptase, to ensure new variants with novel phenotypic features are continually present for expansion in response to changing conditions in the host, such as immune responses, or antiretroviral therapy. This high-level variance has led to a wide range in observed fitness and virulence, across strains of HIV-1. The HIV-1 pol replication capacity assay (pol RC) measures features of viral fitness, associates with elevated CD4+ T-cell counts, yet is not strongly associated with HIV-1 RNA levels. The biological basis for elevated CD4+ T-cell counts among those carrying a virus of low pol RC may be because of lowered virus infectivity, or restricted tissue replication.

Background: Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms., Methods and Findings: Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1-8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4-8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen., Conclusion: Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted.

In HIV-1-infected subjects, the magnitude of HIV-1 viral load in cerebrospinal fluid (CSF) correlates with the CSF white cell count. To determine whether HIV-1-producing T cells appear in CSF and whether their percentage and number correlate with viral load in CSF, we developed a flow cytometric assay that detects HIV-1-producing T cells by identifying intracellular p24 HIV-1 antigen. We found that most CSF T cells were not HIV-1 producing, even when cell-free viral load in CSF was high. Most activated T cells in CSF were also not HIV-1 producing, but the activated CD38+ CD4 T-cell fraction in CSF was independently associated with the fraction of HIV-1-producing T cells in CSF. We conclude that HIV-1-producing T cells appear in CSF and that their percentage and number correlate with cell-free viral load in CSF, even though the CSF total white cell count remains the best predictor for CSF viral load. In HIV-1 infection, CSF white cell counts seem to contain a large number of uninfected cells. White cell counts and viral load in CSF may result from systemic inflammation and immune activation.

Objectives: Primary, or transmitted, drug resistance is common among treatment naive patients recently infected with HIV-1, and impairs response to anti-retroviral therapy. We previously observed that patients with secondary resistance (developed in response to anti-retroviral treatment) who chose to stop an anti-retroviral regimen experience rapid overgrowth of drug resistant viruses by wild-type virus of higher pol replication capacity. We sought to determine if primary drug resistance would be lost at a rapid rate, and viral pol replication capacity would increase, in the absence of treatment., Methods: We tracked drug resistance phenotype, genotype, viral pol replication capacity (single cycle recombinant assay incorporating a segment of the patient pol gene [pol RC]), plasma HIV-1 RNA, and CD4 T cell counts in the absence of treatment among patients in early HIV-1 infection., Results: Six of 22 patients had evidence of primary drug resistance to at least one class of drug; three resistant to protease inhibitors, three resistant to non-nucleoside reverse transcriptase inhibitors, and four resistant to nucleoside reverse transcriptase inhibitors. All six patients maintained evidence of drug resistance for the period of observation. Among patients with baseline primary drug resistance pol RC did not increase over time., Conclusion: The selection environment of early infection is determined by immune pressure, and stochastic events, not viral pol replication capacity. In contrast to secondary resistant infections that are rapidly overgrown when therapy is stopped, primary drug resistance persists over time. Surveillance and clinical detection of primary resistance is feasible in the first year of infection.

Objective: Sequential acquisition of viral variants, or HIV-1 superinfection, has been proposed to explain the high fractions of recombinant viruses observed in some geographical regions, but only a few cases of superinfection in humans have been reported. Animal models suggest that susceptibility to superinfection may be restricted to a short period of time after initial infection, possibly due to maturation of broad antiviral immune responses., Methods: A mathematical model involving a system of differential equations was developed to identify transmission and superinfection patterns that would lead to the observed global patterns of viral diversity., Results: Requirements for a high prevalence of infections involving recombinant viruses include high viral infectivity, the presence of highly sexually active core groups, and introduction of divergent viruses early in the epidemic spread of HIV-1. Restricted superinfection could explain the persistent predominance of single virus subtypes in regions with well-established HIV-1 epidemics. The rate of recombination within individuals was not strongly related to recombinant fractions in populations., Conclusions: HIV-1 superinfection restricted to early HIV-1 infection could account for the high fraction of recombinant virus infections observed in populations. The relationship between recombination in cellular infections and recombinant fractions in populations is complex and depends on epidemiological factors and biological factors that can be modeled.

Background: Infection with primary drug-resistant human immunodeficiency virus type 1 (HIV-1) has been associated with higher CD4(+) T cell counts in drug-naive patients, suggesting that altered viral pol replication capacity (RC) associated with drug resistance diminishes immune injury in vivo, independent of exposure to drugs., Methods: Virus replication over a single cycle was measured by use of a viral test vector containing patient-derived HIV-1 protease and reverse transcriptase gene segments., Results: Among 191 recently infected patients, pol RC ranged widely, with only 6% of the variance explained by drug-resistance mutations. Patients infected with a virus with a low pol RC (

We report two cases of accidental ingestion of large quantities of 6-mercaptopurine (6-MP) in siblings of patients with acute lymphoblastic leukemia (ALL). These cases reinforce the need for thorough anticipatory guidance to families in order to prevent the incidence of potentially life-threatening accidental ingestions.

Viral fitness, defined as the extent of viral adaptation to the host environment, arises from tissue tropism, immune system evasion, drug resistance, and viral replication capacity. The fitness of wild-type and drug-resistant HIV-1 varies widely, associating with plasma viremia, CD4+ T-cell count, and clinical progression. HIV-1 fitness may be measured in competitive culture assays, single cycle assays, or single cycle assays based on a subgenomic fragment of HIV-1, which has been standardized as the replication capacity assay (pol RC). During virologic failure of antiretroviral therapy, CD4 T-cell counts remain elevated while pol RC declines and remains durably lower because of drug-selected changes in the gag and pol genes. CD4 T-cell sparing also is observed among patients without evidence of drug resistance who carry a low pol RC virus. Reduced HIV-1 replication capacity and virulence may occur because of drug resistance or viral escape from host immune responses.

An HIV-1 infected man who experienced rapid disease progression and poor response to therapy after starting a new sexual relationship with an infected partner is known as the 'Ottawa superinfection case'. Subsequent analysis of viral sequences of protease, reverse transcriptase, Gag p17, and Env V3 provided no evidence for the acquisition of genetically divergent viruses before disease progression or drug resistance during virological failure of combination therapy. Whether HIV-1 superinfection contributes to disease progression or the spread of drug-resistant HIV-1 remains unknown.

Objective: Little is known about the degree to which widespread use of antiretroviral therapy in a community reduces uninfected individuals' risk of acquiring HIV. We estimated the degree to which the probability of HIV infection from an infected partner (the infectivity) declined following the introduction of highly active antiretroviral therapy (HAART) in San Francisco., Design: Homosexual men from the San Francisco Young Men's Health Study, who were initially uninfected with HIV, were asked about sexual practices, and tested for HIV antibodies at each of four follow-up visits during a 6-year period spanning the advent of widespread use of HAART (1994-1999)., Methods: We estimated the infectivity of HIV (per-partnership probability of transmission from an infected partner) using a probabilistic risk model based on observed incident infections and self-reported sexual risk behavior, and tested the hypothesis that infectivity was the same before and after HAART was introduced., Results: A total of 534 homosexual men were evaluated. Decreasing trends in HIV seroincidence were observed despite increases in reported number of unprotected receptive anal intercourse partners. Conservatively assuming a constant prevalence of HIV infection between 1994 and 1999, HIV infectivity decreased from 0.120 prior to widespread use of HAART, to 0.048 after the widespread use of HAART- a decline of 60% (P=0.028)., Conclusions: Use of HAART by infected persons in a community appears to reduce their infectiousness and therefore may provide an important HIV prevention tool.

Evidence for human immunodeficiency virus type 1 (HIV-1) superinfection was sought among 37 HIV-1-positive street-recruited active injection drug users (IDUs) from the San Francisco Bay area. HIV-1 sequences from pairs of samples collected 1 to 12 years apart, spanning a total of 215 years of exposure, were generated at p17 gag, the V3-V5 region of env, and/or the first exon of tat and phylogenetically analyzed. No evidence of HIV-1 superinfection was detected in which a highly divergent HIV-1 variant emerged at a frequency >20% of the serum viral quasispecies. Based on the reported risk behavior of the IDUs and the HIV-1 incidence in uninfected subjects in the same cohort, a total of 3.4 new infections would have been expected if existing infection conferred no protection from superinfection. Adjusted for risk behaviors, the estimated relative risk of superinfection compared with initial infection was therefore 0.0 (95% confidence interval, 0.00, 0.79; P = 0.02), indicating that existing infection conferred a statistically significant level of protection against superinfection with an HIV-1 strain of the same subtype, which was between 21 and 100%.

The problem of relating genotype (as represented by amino acid sequence) to phenotypes is distinguished from standard regression problems by the nature of sequence data. Here we investigate an instance of such a problem where the phenotype of interest is HIV-1 replication capacity and contiguous segments of protease and reverse transcriptase sequence constitutes genotype. A variety of data analytic methods have been proposed in this context. Shortcomings of select techniques are contrasted with the advantages afforded by tree-structured methods. However, tree-structured methods, in turn, have been criticized on grounds of only enjoying modest predictive performance. A number of ensemble approaches (bagging, boosting, random forests) have recently emerged, devised to overcome this deficiency. We evaluate random forests as applied in this setting, and detail why prediction gains obtained in other situations are not realized. Other approaches including logic regression, support vector machines and neural networks are also applied. We interpret results in terms of HIV-1 reverse transcriptase structure and function.

Objective: To determine the effect of treatment interruptions (TI) on the evolution and persistence of drug-resistant viruses in chronically HIV-1-infected suppressed patients., Methods: The emergence of viral resistance to combination antiretroviral therapy was monitored in 11 suppressed chronically HIV-1-infected patients undergoing from one up to four sequential TI (a total of 25 TI), by genotyping of the virus for known mutations in the genes for protease and reverse transcriptase. Resistance assays were performed at the first viral rebound > 100 copies/ml., Results: All subjects achieved resuppression of HIV-1 under the same antiretroviral therapy, regardless of the number of TI. Five of eleven patients showed no development of resistance. In the remaining six patients, the following patterns of mutations associated with viral resistance were found: one mutation (K70R), which was observed in one patient during the 1st TI and persisted during follow-up; two mutations (L90M, M184V), which were observed in four patients during the 1st TI and were intermittently present or lost following extended TI, treatment reinitiation and/or during subsequent TI; and evolution of two mutations (M184V, K219E) observed in two patients. These two mutations were not present during the 1st TI and were subsequently lost following therapy reinitiation or during the next TI., Conclusions: Detection of drug resistance during TI by virus genotyping assays does not predict failure to resuppress after antiretroviral therapy reinitiation nor persistence of a resistant viral population during extended interruptions or subsequent TI.

Objectives: To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence., Methods: Adherence was measured with unannounced pill counts performed at the participant's usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2., Results: High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92-100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79-100%)., Conclusion: Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.

Human immunodeficiency virus (HIV)-specific CD8(+) T-lymphocyte pressure can lead to the development of viral escape mutants, with consequent loss of immune control. Antiretroviral drugs also exert selection pressures on HIV, leading to the emergence of drug resistance mutations and increased levels of viral replication. We have determined a minimal epitope of HIV protease, amino acids 76 to 84, towards which a CD8(+) T-lymphocyte response is directed. This epitope, which is HLA-A2 restricted, includes two amino acids that commonly mutate (V82A and I84V) in the face of protease inhibitor therapy. Among 29 HIV-infected patients who were treated with protease inhibitors and who had developed resistance to these drugs, we show that the wild-type PR82V(76-84) epitope is commonly recognized by cytotoxic T lymphocytes (CTL) in HLA-A2-positive patients and that the CTL directed to this epitope are of high avidity. In contrast, the mutant PR82A(76-84) epitope is generally not recognized by wild-type-specific CTL, or when recognized it is of low to moderate avidity, suggesting that the protease inhibitor-selected V82A mutation acts both as a CTL and protease inhibitor escape mutant. Paradoxically, the absence of a mutation at position 82 was associated with the presence of a high-avidity CD8(+) T-cell response to the wild-type virus sequence. Our results indicate that both HIV type 1-specific CD8(+) T cells and antiretroviral drugs provide complex pressures on the same amino acid sequence of the HIV protease gene and, thus, can influence viral sequence evolution.

Background: The Viral Activation Transfusion Study was a prospective, randomized, double-blind comparison of transfusion with WBC-reduced versus non-WBC-reduced RBCs to HIV+ patients. The primary study characterized the effect of transfusion on HIV and CMV activation by monitoring viral load changes. The present study analyzed HBV, HCV, HTLV-I and -II, and human herpes virus-8 (HHV-8) viral load before and after transfusion to evaluate the further hypothesis that global immune stimulation following allogeneic RBC transfusion results in activation and increased viral proliferation of chronic viral infections other than HIV and CMV., Study Design and Methods: Baseline samples from 519 to 523 subjects were screened for HBV, HCV, HTLV-I and -II, and HHV-8 infection, and baseline, serial weekly, and quarterly blood samples from infected subjects in the non-WBC-reduced arm were evaluated for changes from baseline in viral nucleic acid and ALT levels., Results: Seroprevalence of HBV, HCV, HTLV-I and -II, and HHV-8 was 68, 25, 5, and 30 percent, respectively. No significant induction of HBV, HCV, HHV-8, or HTLV-I and -II viral replication following allogeneic transfusion of non-WBC-reduced blood was observed. A significant, albeit small, association was observed between transfusion and ALT., Conclusions: Based on these results and our previous finding that no adverse effect on HIV and CMV viral load and disease progression results from allogeneic transfusion, no evidence is found to support the selective use of WBC-reduced blood components for HIV-infected patients.

Drug resistance and poor virological responses are associated with well-characterized mutations in the viral reading frames that encode the proteins that are targeted by currently available antiretroviral drugs. An integrated system was developed that includes target gene amplification, DNA sequencing chemistry (TRUGENE HIV-1 Genotyping Kit), and hardware and interpretative software (the OpenGene DNA Sequencing System) for detection of mutations in the human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase sequences. The integrated system incorporates reverse transcription-PCR from extracted HIV-1 RNA, a coupled amplification and sequencing step (CLIP), polyacrylamide gel electrophoresis, semiautomated analysis of data, and generation of an interpretative report. To assess the accuracy and robustness of the assay system, 270 coded plasma specimens derived from nine patients were sent to six laboratories for blinded analysis. All specimens contained HIV-1 subtype B viruses. Results of 270 independent assays were compared to "gold standard" consensus sequences of the virus populations determined by sequence analysis of 16 to 20 clones of viral DNA amplicons derived from two independent PCRs using primers not used in the kit. The accuracy of the integrated system for nucleotide base identification was 98.7%, and the accuracy for codon identification at 54 sites associated with drug resistance was 97.6%. In a separate analysis of plasma spiked with infectious molecular clones, the assay reproducibly detected all 72 different drug resistance mutations that were evaluated. There were no significant differences in accuracy between laboratories, between technologists, between kit lots, or between days. This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories.

The TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System are designed to sequence the protease (PR)- and reverse transcriptase (RT)-coding regions of human immunodeficiency virus type 1 (HIV-1) pol. Studies were undertaken to determine the accuracy of this assay system in detecting resistance-associated mutations and to determine the effects of RNA extraction methods, anticoagulants, specimen handling, and potentially interfering substances. Samples were plasma obtained from HIV-infected subjects or seronegative plasma to which viruses derived from wild-type and mutant infectious molecular clones (IMC) of HIV-1 were added. Extraction methods tested included standard and UltraSensitive AMPLICOR HIV-1 MONITOR, QIAGEN viral RNA extraction mini kit, and QIAGEN Ultra HIV extraction kit, and NASBA manual HIV-1 quantitative NucliSens. Sequence data from test sites were compared to a "gold standard" reference sequence to determine the percent agreement. Comparisons between test and reference sequences at the nucleotide level showed 97.5 to 100% agreement. Similar results were obtained regardless of extraction method, regardless of use of EDTA or acid citrate dextrose as anticoagulant, and despite the presence of triglycerides, bilirubin, hemoglobin, antiretroviral drugs, HIV-2, hepatitis C virus (HCV), HBV, cytomegalovirus, human T-cell leukemia virus type 1 (HTLV-1), or HTLV-2. Samples with HIV-1 RNA titers of >or=1,000 copies/ml gave consistent results. The TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System consistently generate highly accurate sequence data when tested with IMC-derived HIV and patient samples.

We developed fluorescence-linked antigen quantification (FLAQ) assays for HIV-1 and SIV antigen quantitation. The assays utilize polystyrene microspheres coated with monoclonal antibodies against HIV-1 Gag p24 or SIV Gag p27, which are incubated with unknown samples, flourochrome-conjugated detector antibody, and lysing agent. The fluorescence of individual microspheres is measured using flow cytometry. The speed, simplicity, and wide dynamic range of FIAQ assays makes them superior to enzyme-linked immunosorbent assays for many applications performed in research laboratories.

Objective: Among treated patients with drug-resistant viremia, structured treatment interruptions often result in the re-emergence of drug-susceptible HIV-1. Theoretically, this may allow for a more durable response to salvage therapy. We therefore studied the long-term treatment outcome to antiretroviral therapy in a cohort of patients who had previously interrupted therapy, focusing on the determinants of treatment success versus failure., Design: A prospective observational study of the response to antiretroviral therapy in patients resuming therapy after a treatment interruption. Virological and immunological studies were performed every month for 3 months and then every 3 months., Results: Twenty-four patients underwent a structured treatment interruption and resumed therapy after a variable period of time (median 20 weeks). The median duration of treatment after the treatment interruption was 109 weeks. A transient virological response was observed in all patients who resumed a regimen containing no drug to which their pre-interruption virus was fully susceptible. Virus isolated during virological failure was genotypically and phenotypically identical to the pre-interruption virus, exhibited reduced replicative capacity, and replicated at levels similar to the pre-interruption baseline. In contrast, durable viral suppression (< 200 copies/ml) was observed in patients who initiated a regimen containing only one drug to which their pre-interruption virus was fully susceptible. Despite viral suppression, the pre-interruption drug-resistant virus population remained detectable in two patients., Conclusion: Although drug-resistant HIV-1 persists at low levels during and after the interruption of therapy, durable suppression of this virus population may be achieved with a combination regimen containing only one fully active agent.

We report the emergence of drug-resistant viral mutations in chronically HIV-infected individual undergoing structured treatment interruptions (STI). THe protease mutations K101E and K103N were detected at the end of the second or third STI. We concluded that the repeated abrupt termination and resumption of certain antiretroviral drug regimens during STI therapy may lead to the development of drug resistance in chronically HIV-infected individuals.

Continued use of antiretroviral therapy despite the emergence of drug-resistant human immunodeficiency virus (HIV) has been associated with the durable maintenance of plasma HIV RNA levels below pretherapy levels. The factors that may account for this partial control of viral replication were assessed in a longitudinal observational study of 20 HIV-infected adults who remained on a stable protease inhibitor-based regimen despite ongoing viral replication (plasma HIV RNA levels consistently >500 copies/ml). Longitudinal plasma samples (n = 248) were assayed for drug susceptibility and viral replication capacity (measured by using a single-cycle recombinant-virus assay). The initial treatment-mediated decrease in plasma viremia was directly proportional to the reduction in replicative capacity (P = 0.01). Early virologic rebound was associated the emergence of a virus population exhibiting increased protease inhibitor phenotypic resistance, while replicative capacity remained low. During long-term virologic failure, plasma HIV RNA levels often remained stable or increased slowly, while phenotypic resistance continued to increase and replicative capacity decreased slowly. The emergence of primary genotypic mutations within protease (particularly V82A, I84V, and L90M) was temporally associated with increasing phenotypic resistance and decreasing replicative capacity, while the emergence of secondary mutations within protease was associated with more-gradual changes in both phenotypic resistance and replicative capacity. We conclude that HIV may be constrained in its ability to become both highly resistant and highly fit and that this may contribute to the continued partial suppression of plasma HIV RNA levels that is observed in some patients with drug-resistant viremia.

Postmortem neuropathologic reports for a consecutive series of 436 HIV-seropositive patients who died between 1985 and 1999 were matched with clinical data for 371 of them. Cases were divided into four groups depending on the date of death. The chosen time periods reflected the type of antiretroviral therapy available: before 1987 (before zidovudine); 1987-1992, the period of monotherapy (nucleoside analog reverse transcriptase inhibitors [NRTIs]); 1993-1995, the era of the use of dual NRTI combinations; and 1996-1999, the era of highly active antiretroviral therapy (HAART) containing protease inhibitors. Fifty-seven percent of our cases in this group had been prescribed HAART. In our study population, accessibility to the latest antiretroviral therapy was widespread. The total number of HIV autopsies declined after the advent of combination therapy. The prevalence of opportunistic infections-cytomegalovirus, toxoplasmosis, cryptococcosis, and central nervous system lymphoma-decreased over time. Cerebral tuberculosis, aspergillosis, herpes, and progressive multifocal leukoencephalopathy showed a downward trend, but the numbers were too low for statistical analyses. The incidence of HIV encephalopathy increased over time (p =.014). The rising prevalence of HIV encephalopathy at time of death may reflect a longer survival time after initial HIV infection in the HAART era. Although combination therapies decrease overall mortality and prevalence of CNS opportunistic infections, these therapies may be less active in preventing direct HIV-1 effects on the brain.

Background: Fotemustine is a nitrosourea with theoretic and preclinical advantages over the original analogs, carmustine and lomustine, in the treatment of brain tumors. This is the first pediatric Phase I study of fotemustine., Methods: Patients younger than 21 with recurrent/resistant brain tumors were enrolled in a conventional Phase I study. Fotemustine was administered intravenously every 3 weeks at increasing dose levels starting at 100 mg/m(2). Toxicity and response data were monitored closely., Results: Fifteen evaluable patients entered the study and received a total of 45 courses of fotemustine (dose range, 100-175 mg/m(2)). Myelosuppression was observed, with the dose-limiting toxicity being Grade 4 neutropenia and thrombocytopenia. Toxicity was delayed and cumulative. The maximum tolerated dose was 150 mg/m(2) every 3 weeks. There were three documented radiologic responses (20% of patients) comprising one partial response and two minor responses in patients with a sarcoma, medulloblastoma, and ependymoma, respectively., Conclusions: Fotemustine administered at a dose of 150 mg/m(2) every 3 weeks is well tolerated in children and has antitumor activity in several brain tumors. This is the first dedicated Phase I study of a single agent nitrosourea in a pediatric population. More comparative studies should be undertaken to define the optimum nitrosourea analog for use in children with brain tumors., (Copyright 2002 American Cancer Society.)