Potentially preventable tuberculosis among HIV-infected persons in the era of highly active antiretroviral treatment.

OBJECTIVE: To characterize the proportion of tuberculosis (TB) cases that could have been prevented among human immunodeficiency virus (HIV) infected persons receiving care in the era of highly active antiretroviral treatment (HAART). DESIGN: We conducted an observational cohort study among HIV-infected patients with >or=2 out-patient visits at the Comprehensive Care Center, Nashville, Tennessee, USA, between 1 January 1998 and 31 December 2005. METHODS: A potentially preventable TB case was defined as a case in which the patient received no screening tuberculin skin test (TST) prior to TB diagnosis or a case in which a patient with a positive screening TST did not complete treatment for latent infection. RESULTS: Of 3601 HIV-infected persons in care (13 905 person-years [p-y] of follow-up), 29 developed TB (230/100,000 p-y). Of the 29, 20 (69%) had not had TST performed as part of routine screening. Of the nine patients screened, four had a positive test, three of whom completed treatment for latent TB infection. Of 29 TB cases, 21 (72%) were therefore potentially preventable. CONCLUSIONS: Most TB cases in this cohort were potentially preventable had the patients undergone a screening TST followed by treatment of latent infection if they had a positive TST.

Two phases of HIV RNA decay in CSF during initial days of multidrug therapy.

BACKGROUND: Defining cellular and tissue sources of HIV-1 in CSF is important for understanding disease pathogenesis and optimal therapies for HIV infection in the brain. OBJECTIVE: To identify the time of maximal viral decay in CSF during the initial days of antiretroviral therapy. METHODS: Serial CSF and plasma data were available from four adults who underwent ultraintensive CSF sampling for 48 hours at baseline and again beginning 72 hours after starting antiretroviral therapy. Regression lines were generated using HIV-1 RNA data from 17 on-treatment serial CSF samples obtained at 3-hour intervals. Viral RNA was quantified by Nuclisens and Amplicor HIV-1 Monitor assays. RESULTS: Extrapolation of regression lines intersected baseline below actual baseline CSF HIV-1 RNA concentrations, indicating that virus decayed most rapidly on days 1 through 3 with half-lives of no more than 0.9 to 2.8 days. Half-lives on days 4 and 5 ranged from 1.3 to 4.9 days. Plasma data also showed early rapid decay. CONCLUSIONS: Multiple phases of viral decay suggest that virus in CSF originates from at least two sources during untreated, asymptomatic HIV-1 infection. The short half-life indicates that the primary source is CD4+ T cells. Sampling during days 1 through 3 and different stages of disease will better define sources of virus.

Thymidine analog and multinucleoside resistance mutations are associated with decreased phenotypic susceptibility to stavudine in HIV type 1 isolated from zidovudine-naive patients experiencing viremia on stavudine-containing regimens.

Studies have demonstrated that HIV-1 isolated from subjects experiencing virologic failure on stavudine (d4T)-containing regimens often contains thymidine analog mutations (TAMs), consisting of reverse transcriptase (RT) mutations M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, previously associated only with zidovudine (ZDV) resistance. In clinical study NZT40012, HIV-1 was isolated from 86 ZDV-naive subjects experiencing viremia on d4T-based therapies (plasma HIV-1 RNA > or =1000 copies/ml) and analyzed to examine the association between RT mutations and phenotypic resistance to d4T. Resistance-associated mutations were analyzed from HIV-1 isolated from 85 subjects. Of these, 24 samples (28%) had TAMs, and 30 samples (35%) had either TAMs and/or the Q151M multinucleoside resistance (MNR) mutation. Phenotypic susceptibility to d4T was determined by two commercially available methods. Statistically significant increases (p < 0.001) in phenotypic fold resistance to d4T were observed in virus with at least one TAM or MNR mutation. However, the mean increases in phenotypic resistance were 4-fold for the Antivirogram assay and 3-fold for the Phenosense HIV assay, only slightly above the levels used to designate decreased susceptibility to d4T. Subjects can experience viremia on d4T-containing regimens with virus exhibiting only small increases in IC(50), suggesting that relatively small changes in viral susceptibility to d4T may influence drug efficacy.

Zidovudine and stavudine sequencing in HIV treatment planning: findings from the CHORUS HIV cohort.

BACKGROUND: Optimal sequencing of zidovudine and stavudine in antiretroviral therapy has not been elucidated. OBJECTIVE: To examine the impact of the sequence of therapeutic regimens containing zidovudine and stavudine on HIV-1 RNA and CD4 lymphocyte counts over 12 months. DESIGN: Observational, multicenter, longitudinal cohort study. SETTING: Four large outpatient, HIV practices participating in the community-based Collaborations in HIV Outcomes Research-U.S. (CHORUS) cohort study. PARTICIPANTS: 940 HIV-infected patients. METHODS: Comparison of HIV-1 RNA and CD4 lymphocyte responses in patients sequenced from zidovudine to stavudine or from stavudine to zidovudine using repeated measures regression models fit to outcomes by application of generalized estimating equation (GEE) methodology. RESULTS: Patients treated with zidovudine prior to stavudine (n = 834) achieved a greater mean drop from baseline HIV-1 RNA (p = .01) and higher proportion of undetectable HIV-1 RNA results (p = .05) over 12 months than those sequenced from stavudine to zidovudine (n = 106). CD4+ lymphocyte increases did not differ between the groups (p = .6). CONCLUSIONS: Prior zidovudine therapy was not associated with long-term attenuation of HIV-1 RNA or CD4 response to subsequent stavudine-containing regimens. Zidovudine before stavudine may have benefit in a strategic long-term therapeutic plan.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma.

Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.

Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial.

PURPOSE: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4 + T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and high-dose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL-2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). METHOD: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4 + T cell counts less than 300 cells/microL at screening and a stable HIV viral load received low-dose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). RESULTS: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/microL in the IL-2 group compared to 19.93 cells/microL in the control group (p <.001). Additionally, IL-2-treated patients experienced a statistically significant increase in the mean percentage of CD4 + T cells (3.52% increase) when compared to control patients (1.33% increase) (p <.001). The expanded CD4 + T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p <.001 for between-group difference). In addition, a higher proportion of IL-2-treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p =.08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. CONCLUSION: Daily, low-dose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells.

Factors that predict incomplete virological response to protease inhibitor-based antiretroviral therapy.

Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.

Randomized, double-blind, placebo-controlled trial of the immune modulator WF10 in patients with advanced AIDS.

A randomized, double-blind trial compared treatment with the immune modulator WF10 (ten patients) and placebo (nine patients) administered in cycles over 3 months among individuals with advanced AIDS. There were no notable clinical adverse events; changes in hematologic and chemistry values were comparable in the two groups. In both groups, median HIV-RNA PCR values remained stable. Immunologic variables showed a consistent tendency to increase in the WF10 group and to decrease in the control group, with significant differences between groups for median WBC, lymphocyte, CD19, and CD35 values. Ten infections occurred in the control group, four of which were Pneumocystis carinii pneumonia (PCP), and three in the WF10 group none of which was PCP. Five patients in the control group were hospitalized during the trial for a total of 53 days; no patients in the WF10 group were hospitalized. Over a subsequent 9-months follow-up, six patients from the control group and one from the WF10 group died. These results indicate that WF10 administration appears safe, may enhance immunologic function, and unlike other macrophage-activating cytokines does not increase HIV expression in this patient population. Further studies of WF10 in larger patient populations are warranted.

Clinical aspects of the interactions between human immunodeficiency virus and the hepatotropic viruses.

The hepatitis viruses A through D are prevalent among patients at risk for human immunodeficiency virus (HIV) infection. The courses of hepatitis B, C, and D are modified by HIV infection. With hepatitis B, increased carriage rates, increased viral replication, and milder liver injury are seen. The degree of HIV-induced immunosuppression does not correlate well with liver injury or amount of hepatitis B viral replication. With progression to AIDS, surface antibody titers can decline, resulting in reactivation of latent hepatitis B virus or reinfection with another subtype. hepatitis B virus may enhance progression to AIDS. Preliminary data suggest that HIV infection can prolong or increase hepatitis C or D viremia and decrease the accuracy of tests for hepatitis C. Interferon may have efficacy against hepatitis C but rarely against hepatitis B in patients who are coinfected with HIV. Zidovudine, ganciclovir, and foscarnet also may be active against these hepatotropic viruses.

Association of '(tropical) ataxic neuropathy' with HTLV-II.

Jamaican Neuropathy of the ataxic type (tropical ataxic neuropathy [TAN] and spastic type (tropical spastic paraparesis [TSP]) have been recognized for over a century in Jamaica. The recent association of TSP with HTLV-I (TSP/HAM) is now well established. We now present evidence for a possible association between a TAN-like illness with HTLV-II in four females aged 34-49. All presented with ataxic gait and all four have prominent mental changes. Three of the four also have minor motor deficits with urinary frequency and two have nocturnal leg cramps. All have serum antibody and all had PCR evidence of HTLV-II infection. Antibody to HTLV-II is present in CSF from two subjects. The distinctive picture of prominent ataxia and altered mental status in these subjects contrasts with a predominantly myelopathic picture seen in TSP/HAM.

Oral candidiasis as a marker of acute retroviral illness.

All reported clinical characteristics of acute retroviral illness with the human immunodeficiency virus (HIV) are nonspecific. Signs and symptoms described are associated with a variety of acute infections. We report the cases of three patients in whom the acute retroviral illness was characterized by transient oral candidiasis and unexplained high lactate dehydrogenase values, with or without transient pulmonary infiltrate, in the context of an acute febrile illness. The clinical findings correlated with a severe reduction in the number of CD4 cells. We believe that thrush could be a marker of acute retroviral infection, as it is not a feature of any other heterophil-negative mononucleosis-like syndrome. We propose that in any patient having transient thrush and acute viral syndrome, the possibility of HIV infection should be aggressively pursued serologically, regardless of the patient's HIV risk status, provided that the usual causes of candidiasis (eg, diabetes mellitus, antibiotic use, and dentures) can be excluded.

The role of HTLV in HIV-1 neurologic disease.

We performed a serologic survey for antibodies to HTLV-I/II in the course of a longitudinal study of the neurologic complications of HIV-1 infection. Nine (3.7%) of 242 HIV-1 seropositive subjects and none of 60 HIV-1 seronegative control subjects had antibodies to HTLV-I/II by ELISA. Western blot and polymerase chain reaction confirmed the presence of HTLV-I in 2 subjects and HTLV-II infection in 2 others. Both HIV-1/HTLV-I coinfected subjects and 1 HIV-1/HTLV-II coinfected subject had a slowly progressive myelopathy clinically identical tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). The presence of a myelopathy resembling TSP/HAM in the coinfected subjects suggests that HIV-1 may enhance the expression of neurologic disease caused by HTLV. Patients with a progressive myelopathy occurring in association with HIV-1 infection should be serologically tested for the presence of HTLV. Establishing dual infection has therapeutic and prognostic import as 1 of the HIV-1/HTLV-I subjects substantially improved with corticosteroids and the HIV-1/HTLV-II subject with myelopathy had a marked improvement in the absence of therapeutic intervention.

Tropical spastic paraparesis-like illness occurring in a patient dually infected with HIV-1 and HTLV-II.

We describe a 34-year-old man from southern Florida with a history of intravenous drug use, dually infected with human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type II (HTLV-II), who developed a myelopathy clinically indistinguishable from HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This myelopathy was characterized by spastic lower extremity weakness, distal paresthesias, sensory loss with a discrete thoracic level to pinprick, back pain, impotence, and sphincter disturbances. Nerve conduction studies revealed an associated mixed axonal and demyelinative neuropathy. Despite a lack of response to 10 months of zidovudine therapy, the myeloneuropathy improved dramatically 2 years after its onset in the absence of any therapeutic intervention.

Native valve endocarditis due to Pseudallescheria boydii in a patient with AIDS: case report and review.

A 53-year-old man with AIDS developed mitral valve endocarditis due to infection with the fungus Pseudallescheria boydii. A limited number of cases of prosthetic valve endocarditis caused by this organism have been described. We report a unique case of pseudallescheria infection of a native valve and describe this disease in a patient with AIDS.