Relative social standing and suicide ideation among Kenyan males: the interpersonal theory of suicide in context.

PURPOSE: The purpose of this study is to investigate the association between subjective social status and suicide ideation in a sample of young Kenyan men (age 18-34 years). Situating insights from the interpersonal theory of suicide within social determinants of health framework, we consider whether lower subjective social status predicts lower collective self-esteem (CSE), hopelessness, less meaning in life and more loneliness, and whether these characteristics mediate associations between subjective social status and suicide ideation. METHOD: A community-based, semi-rural sample (n = 532) of young men, aged 18-34 years, was collected using a standardized questionnaire. The survey questionnaire included the following validated scale items: the short form of the Social and Emotional Loneliness Scale for Adults, CSE, Herth Hope Index, the Meaning in Life Questionnaire, and the Modified Scale for Suicide Ideation. Regression and mediation analyses were used to test hypotheses. RESULTS: Nearly 12% of respondents reported suicide ideation. Suicide ideation was significantly more common among survey respondents who reported lower subjective social standing. In the first of two mediation models, we found that lower CSE and more loneliness mediate the association between lower subjective social status and suicide ideation. In the second model, we found that respondents with lower CSE and more loneliness expressed lower hope and meaning in life, which also mediated pathways to suicide ideation. CONCLUSIONS: Findings show a novel synthesis of social determinants literature with the interpersonal theory of suicide. Suicide ideation, along with other mental and social outcomes, may figure more prominently than previously appreciated in the benefits of socio-economic equality. Those who do not participate equally in socio-economic development may be at greater risk of engaging in suicide ideation and behaviors. Suicide prevention research and programmatic responses should adopt a health equity perspective to ensure that prevention is targeted where people are more likely to engage in suicide ideation.

A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression.

This phase I clinical trial assessed the safety and immunogenicity of a native outer membrane vesicle (NOMV) vaccine prepared from an lpxL1(-) synX(-) mutant of strain 8570(B:4:P1.19,15:L8-5) of Neisseria meningitidis. Additional mutations enhance the expression of factor H binding protein variant 1 (fHbp v.1), stabilize expression of OpcA and introduce a second PorA (P1.22,14). Thirty-six volunteers were assigned to one of four dose groups (10, 25, 50 and 75 mcg, based on protein content) to receive three intramuscular injections at six week intervals with aluminum hydroxide adjuvant. Specific local and systemic adverse events were solicited by diary and at visits on days 2, 7, and 14 after each vaccination. Blood chemistries, complete blood count, and coagulation studies were measured on each vaccination day and again 2 and 14 days later. Blood for ELISA and serum bactericidal assays was drawn two and six weeks after each vaccination. The proportion of volunteers who developed a fourfold or greater increase in bactericidal activity to the wild type parent of the vaccine strain at two weeks after the third dose was 27 out of 34 (0.79, 95% C.I. 0.65-0.93). Against four other group B strains the response rate ranged from 41% to 82% indicating a good cross reactive antibody response. Depletion assays show contributions to bactericidal activity from antibodies to lipooligosaccharide (LOS), fHbp v.1 and OpcA.

Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030.

PURPOSE: To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia. METHODS: Subjects (N = 338) were HIV-infected with CD4+ count <100 cells/mm3, plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2). RESULTS: Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. During Step 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months. CONCLUSIONS: We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population.

Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response.

As therapy for human immunodeficiency virus (HIV) infection evolves, optimizing hepatitis B virus (HBV) treatment and identifying factors that impact its response in the HIV/HBV-coinfected population is critical. We identified retrospectively 45 HBV/HIV-coinfected patients with detectable HBV DNA by the Bayer VERSANT HBV 3.0 bDNA assay (limit of quantification 2000 copies/mL) at baseline and/or year 1 of therapy. Patients were divided into three groups based on the active HBV agent in their antiretroviral regimen: group 1 (n = 15) received lamivudine; group 2 (n = 10), lamivudine plus tenofovir and group 3 (n = 20), lamivudine followed by lamivudine plus tenofovir. HBV genotypes and resistance profiles were determined by the Bayer Trugene HBV 1.0 assay. More patients in group 2 achieved HBV DNA suppression below 2000 copies/mL (80%), loss of HBe antigen (HBeAg) (40%) and loss of HBeAg and gain of anti-HBe (20%) than did patients in group 1 or 3. More patients with HBV genotype A, achieved HBV DNA suppression <2000 copies/mL than did patients with non-A genotypes [74% (26/35) vs 20% (2/10)], respectively (P = 0.003). Risk for virological nonresponse was significant in those with non-A genotypes [odds ratio (OR) 11.1; 95% CI: 2.0-50], previous HIV therapy (OR 6.5; 95% CI: 1.2-35) and <90% compliance (OR 3.7; 95% CI: 0.99-14.3). Simultaneous therapy with lamivudine/tenofovir suppresses HBV DNA more effectively than lamivudine or tenofovir added to lamivudine. More patients infected with HBV genotype A responded than the non-A patients, regardless of therapeutic regimen, compliance or prior HIV therapy.

Role of sequencing in therapy selection.

The goals of sequencing antiretroviral agents are to preserve as many treatment options as possible, minimize drug toxicity, and prolong suppression of HIV. There are numerous options for sequencing antiretroviral agents when treatment fails. The most common reasons for treatment failure are the emergence of resistance and poor adherence. Data indicate that protease inhibitor therapy enhanced by ritonavir may delay the development of resistance longer than nonboosted protease inhibitor therapy. The results of using efavirenz or abacavir to simplify protease inhibitor treatment regimens for HIV-suppressed patients are promising. Although resistance to nonnucleoside reverse transcriptase inhibitors is a serious problem, sequencing them after zidovudine or abacavir therapy may be effective because of the hypersusceptibility to nonnucleoside reverse transcriptase inhibitors exhibited by viral populations in many nucleoside reverse transcriptase inhibitor-experienced patients. New antiretrovirals with greater tolerability, higher genetic barriers, and less cross-resistance than existing agents are needed to achieve further dramatic advances in treating HIV infection.

Evidence for increased T cell turnover and decreased thymic output in HIV infection.

The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO-CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.

Protease inhibitor therapy is associated with markedly prolonged time to relapse and improved survival in AIDS patients with cytomegalovirus retinitis.

Prior to the use of highly active antiretroviral therapy (HAART), cytomegalovirus retinitis (CMV-R) in AIDS patients was characterized by multiple relapses and decreased survival. Recent data suggest that CMV-R in patients treated with HAART may remain relapse-free for long periods. We performed a study of the effects of HIV protease inhibitors (PIs) on the incidence of relapse and time to death in AIDS patients with CMV-R treated with anti-CMV therapy. Medical records of all AIDS patients with CMV-R at Parkland Memorial Health and Hospital System treated with anti-CMV agents were reviewed for date of diagnosis of CMV-R, date of CMV-R relapse, type and duration of anti-CMV therapy, and duration of PI therapy. Relapse rates in subjects treated with PIs were compared with the relapse rates in those who were not treated with PIs. The primary endpoint was the time to relapse and death as determined by Kaplan-Meier analysis. Multivariate analysis was performed by Cox proportional hazard model. One hundred and nine cases of CMV-R were identified in 75 patients. Median follow-up time was 247 days (range 31-1818 days). There were 0.54 relapses per 1000 patient days in the group treated with PIs compared with 1.83 relapses per 1000 patient days in the non-PI treatment group (relative risk [RR]=0.29, P<0.01). Time to relapse was increased in the PI treatment group compared with the non-PI treatment group (endpoint not reached vs 182 days, P<0.001, log-rank). Similarly, the time to relapse or death was increased in the PI group compared with the non-PI group (543 days vs 103 days, P<0.001, log-rank). Multivariate analysis utilizing the Cox proportional hazards model demonstrated that only PI therapy but not anti-CMV therapy was associated with decreased risk of CMV-R relapse or death. Only 3 patients with an undetectable HIV viral load and one patient with a CD4 count >120 cells/microl had a relapse. We conclude that patients with CMV-R treated with HAART containing a PI have increased time to relapse and have prolonged survival.

Long-term impact of highly active antiretroviral therapy on HIV-related health care costs.

CONTEXT: Highly active antiretroviral therapy (HAART) is associated with decreased opportunistic infections, hospitalization, and HIV-related health care costs over relatively short periods of time. We have previously demonstrated that decreases in total HIV cost are proportional to penetration of protease inhibitor therapy in our clinic. OBJECTIVE: To determine the effects of HAART on HIV health care use and costs over 44 months. SETTING: A comprehensive HIV service within a Veterans Affairs Medical Center. DESIGN: A cost-effectiveness analysis of HAART. MAIN OUTCOME MEASUREMENTS: The mean monthly number of hospital days, infectious diseases clinic visits, emergency room visits, non-HIV-related outpatient visits, inpatient costs, and antiretroviral treatment costs per patient were determined by dividing these during the period from January 1995 through June 1998 into four intervals. Viral load tests were available from October 1996. Cost-effectiveness of HAART was evaluated by determining the costs of achieving an undetectable viral load over time. RESULTS: Mean monthly hospitalization and associated inpatient costs decreased and remained low 2 years after the introduction of protease inhibitors (37 hospital days per 100 patients). Total cost decreased from $1905 per patient per month during the first quarter to $1090 per patient per month in the third quarter but increased to $1391 per patient per month in the fourth quarter. Antiretroviral treatment costs increased throughout the entire observation period from $79 per patient per month to $518 per patient per month. Hospitalization costs decreased from $1275 per patient per month in the first quarter to less than $500 per patient per month in each of the third and fourth quarters. The percentage of patients with a viral load <500 copies/mL increased from 21% in October 1996 to 47% in June of 1997 (p =.014). The cost of achieving an undetectable viral load decreased from $4438 per patient per month to $2669 per patient per month, but this trend did not reach statistical significance (p =.18). CONCLUSIONS: After an initial decrease, there was an increase in the total monthly cost of caring for HIV patients. Cost increases were primarily due to antiretroviral treatment costs, but these costs were offset by a marked decrease in inpatient-related costs. Increases in costs were not related to antiretroviral treatment failures as measured by the proportion of patients with low or undetectable viral loads. The cost of achieving an undetectable viral load remained stable despite increases in the cost of procuring antiretroviral agents.

Treatment of patients with refractory giardiasis.

Giardia lamblia is one of the most common parasitic infections. Although standard treatments are usually curative, some immunocompromised patients, including patients with acquired immunodeficiency syndrome as well as healthy patients, have giardiasis that is refractory to recommended regimens. We report our experience with 6 patients with giardiasis, for whom therapy with a combination of quinacrine and metronidazole resulted in cures for 5 of the 6 patients.

Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors.

OBJECTIVE: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen. DESIGN: A cross-sectional analysis of antiretroviral susceptibility. SETTING: HIV clinics in six metropolitan areas. PATIENTS: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after > or = 6 months of antiretroviral therapy, including the use of one protease inhibitor for > or = 3 months. MEASUREMENTS: The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive control virus. RESULTS: At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. CONCLUSION: The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial.

CONTEXT: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment. OBJECTIVE: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen. DESIGN AND SETTING: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe. PATIENTS: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy. MAIN OUTCOME MEASURE: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48. RESULTS: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment. CONCLUSIONS: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

Osteonecrosis in HIV: a case-control study.

BACKGROUND: Osteonecrosis (avascular necrosis) has been infrequently reported in HIV-infected patients. It is not known whether HIV itself is an independent risk factor for osteonecrosis. METHODS: We identified 25 patients with osteonecrosis from 1984 to 1999 from a large county teaching hospital and two large practices in Dallas County that specialize in HIV-disease related therapy. A retrospective chart review was performed to evaluate potential risk factors for osteonecrosis. Each case was matched with two controls for HIV positive status and date of osteonecrosis diagnosis. RESULTS: In the study, 22 of 25 (88%) case patients had at least one osteonecrosis risk factor compared with 24 of 50 (48%) controls, p =.003. The most common osteonecrosis risk factors were hyperlipidemia (32%), alcoholism (28%), pancreatitis (16%), corticosteroids (12%), and hypercoaguability (12%). Of the cases, 12% were idiopathic. Multiple joints were involved in 72% of cases. Four of the case patients compared with none of the controls received megesterol acetate before the diagnosis of osteonecrosis, p =.01. No significant differences were found between cases and controls with respect to liver function tests, testosterone levels, triglyceride levels, cholesterol levels, or CD4 cell counts. Saquinavir was independently associated with osteonecrosis, p <.05. However, no differences in overall use of protease inhibitors among cases and controls were noted: 79% versus 76%, respectively. CONCLUSIONS: The increased incidence of osteonecrosis in HIV/AIDS may be due to an increased frequency of risk factors previously associated with osteonecrosis such as hyperlipidemia, corticosteroid use, alcohol abuse, and hypercoaguability. Use of protease inhibitors was not independently associated with osteonecrosis.

A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus.

Two hundred and forty-six patients infected with human immunodeficiency virus (HIV) who also had disseminated Mycobacterium avium complex received either azithromycin 250 mg every day, azithromycin 600 mg every day, or clarithromycin 500 mg twice a day, each combined with ethambutol, for 24 weeks. Samples drawn from patients were cultured and clinically assessed every 3 weeks up to week 12, then monthly thereafter through week 24 of double-blind therapy and every 3 months while on open-label therapy through the conclusion of the trial. The azithromycin 250 mg arm of the study was dropped after an interim analysis showed a lower rate of clearance of bacteremia. At 24 weeks of therapy, the likelihood of patients' developing 2 consecutive negative cultures (46% vs. 56%, P=.24) or 1 negative culture (59% vs. 61%, P=.80) was similar for azithromycin 600 mg (n=68) and clarithromycin (n=57), respectively. The likelihood of relapse was 39% versus 27% (P=.21) on azithromycin compared with clarithromycin, respectively. Of the 6 patients who experienced relapse, none of those randomized to receive azithromycin developed isolates resistant to macrolides, compared with 2 of 3 patients randomized to receive clarithromycin [corrected]. Mortality was similar in patients comprising each arm of the study (69% vs. 63%; hazard, 95.1% confidence interval, 1.1 [0.7, 1.7]). Azithromycin 600 mg, when given in combination with ethambutol, is an effective agent for the treatment of disseminated M. avium disease in patients infected with HIV.

Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites.

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infection have been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

Peripherally inserted central catheters in patients with AIDS are associated with a low infection rate.

We reviewed the medical records of all human immunodeficiency virus (HIV)-infected patients who had a peripherally inserted central catheter (PICC) placed during a 1-year period. Ninety-seven PICCs were inserted in 66 patients for 8337 catheter-days. Eighty of 97 catheters were used primarily to treat cytomegalovirus disease. The mean time to any complication was 150 days. The total complication rate was 6.1 per 1000 catheter-days. The total infection rate was 1. 3 per 1000 catheter-days, and the serious infection rate was 0.8 per 1000 catheter-days. The mean time to a serious infection was 310 days. The noninfectious complication rate was 4.6 per 1000 catheter-days. PICCs were associated with a low infection rate and a moderate mechanical complication rate, which compare favorably with historical rates seen in AIDS patients with other types of central venous access devices. PICCs are a reasonable alternative to other central venous access devices in patients with HIV or AIDS.

Efficacy of nelfinavir in patients switched from ritonavir/saquinavir combination antiretroviral therapy.

UNLABELLED: Based on available data and expert opinion, the IAS-USA treatment guidelines recommend "selective substitution" of the medication thought most likely to be causing a side effect for one that should have a different side effect profile. PURPOSE: This study evaluates the short-term virological efficacy of selective substitution with nelfinavir-nucleoside combination therapy in individuals with plasma viral RNA below 400 copies/mL. METHOD: This study involved a retrospective chart review at five large urban HIV Clinical practice settings and included 19 patients taking combination therapy including ritonavir with saquinavir. We performed selective substitution with a nelfinavir combination. Our main outcome measure was plasma HIV-1 RNA (Amplicor) obtained during the period between weeks 12 to 18. RESULTS: We identified 19 HIV-1-infected individuals with evidence of viral suppression as defined by a viral load below 400 copies/mL while taking dual nucleoside reverse transcriptase inhibitors with ritonavir/saquinavir. Reasons for switching included adverse effects (37%) or preference for nelfinavir due to the possibility of a better defined salvage regimen (63%). We defined a composite viral endpoint indicative of continued viral suppression using the first 12 to 18 weeks following the medication change. We found that 73% maintained undetectable viral loads (plasma HIV RNA below 400 copies/mL) during this period. CONCLUSION: These data suggest that any medication adjustment should be made cautiously, as there may be some potential risk in a substitution. Selective substitution of a medication that has undesirable side effects or other characteristics should be considered when the possible risks of the loss of viral suppression are outweighed by the potential benefits of that substitution.

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.

Reduced antiretroviral drug susceptibility among patients with primary HIV infection.

CONTEXT: The transmission of drug-resistant human immunodeficiency virus (HIV) has been documented, but the prevalence of such transmission is unknown. OBJECTIVE: To assess the spectrum and frequency of antiretroviral susceptibility among subjects with primary HIV infection. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 141 subjects identified from clinical research centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV seroconversion within the preceding 12 months and no more than 7 days' prior antiretroviral (ARV) therapy. MAIN OUTCOME MEASURES: Phenotypic and genotypic ARV susceptibility of HIV from plasma samples. RESULTS: The transmission of drug-resistant HIV as assessed by a greater than 10-fold reduction in ARV susceptibility to 1 or more drugs was observed in 3 (2%) of 141 subjects, including to a nonnucleoside reverse transcriptase inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor and a protease inhibitor in 2 patients. Population-based sequence analysis of these 3 samples identified multidrug-resistance mutations in reverse transcriptase (M184V, T215Y, K219K/R) and protease (L101/V, K20R, M361, M46I, G48V, L63P, A71T, V771, V82T, 184V, L90M) in the 2 latter patient samples, along with numerous polymorphisms. A reduction in susceptibility of greater than 2.5- to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients (26%). Sequence analysis of these 36 samples identified well-characterized drug resistance mutation in reverse transcriptase and protease in only 1 of these patients. CONCLUSIONS: Reductions in drug susceptibility of more than 10-fold were rare among this cohort of recently HIV-infected subjects and were distributed among each of the 3 major classes of ARV drugs tested. Reductions in susceptibility of more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance were highly prevalent among newly infected patients. Resistance testing may be warranted to monitor the frequency of drug resistance over time and to assess the potential for geographic variability.

Protease inhibitor-based therapy is associated with decreased HIV-related health care costs in men treated at a Veterans Administration hospital.

BACKGROUND: Protease inhibitor (PI) therapy for HIV infection is associated with decreased rates of opportunistic infections and death. Statistical models predict that decreased complications will be associated with decreased hospitalization costs. A recent report suggested that the decrease in the HIV hospitalization costs were offset by increases in demand for outpatient services. We performed a study of hospital use and HIV-associated health care costs in our center to determine the following: whether PI therapy is associated with decreased inpatient use; whether PI therapy is associated with decreased outpatient use and costs; whether decreased HIV health care costs are associated with increased use of nucleoside analogues. METHODS: The Dallas Veteran Affairs Medical Center provides comprehensive inpatient and outpatient HIV care and thus can evaluate the relation between inpatient and outpatient costs. The mean monthly number of hospital days, Infectious Diseases clinic visits, emergency department visits, other outpatient clinic visits, inpatient costs, outpatient costs, and PI costs were determined from January 1, 1995 through July 31, 1997. This time period was then divided into three intervals. Comparisons of PI use and HIV-related health care costs were during the three intervals was performed using analysis of variance (ANOVA). Significant differences between the baseline characteristics were further analyzed through multiple linear regression. RESULTS: A decrease in hospital days, and all outpatient visits including emergency visits, and HIV clinic visits was determined. No difference was found in the rate of use of other outpatient services. The per patient costs of HIV care decreased from a monthly average of $1905 U.S. in the first interval to $1122 U.S. in the last interval (p < .01). Linear regression demonstrated an inverse relation between PI use and total HIV costs (B=-0.67, p=.00, adjusted R2=0.52) but no relation between nucleoside use, stage of disease or financial class. CONCLUSIONS: PI therapy is associated with decreased hospital days and use of outpatient services. Total patient costs decreased, but a concomitant rise in outpatient costs took place. This increase was primarily a result of increased costs of acquiring PI. Increases in the number of nucleoside agents prescribed were not associated with decreased costs.

A retrospective study of the addition of ciprofloxacin to clarithromycin and ethambutol in the treatment of disseminated Mycobacterium avium complex infection.

Disseminated Mycobacterium avium complex (DMAC) infection is associated with increased morbidity and mortality in HIV-infected individuals. The combination antibiotic regimens containing clarithromycin can decrease symptoms and improve survival in patients with DMAC, however, optimal therapy remains to be defined. Quinolones have been widely used in the treatment of DMAC but their utility has not been established. A retrospective cohort study of DMAC infection was established in a metropolitan hospital providing comprehensive care to over 3000 HIV-infected individuals. Medical records of patients with DMAC diagnosed at the Parkland Memorial Hospital from 1991 to 1994 were reviewed for therapeutic regimens for DMAC, concomitant therapy for HIV and Pneumocystis carinii prophylaxis and date of death. Subjects were included if they were treated with clarithromycin and ethambutol. Cases were defined as those patients who received more than 30 days of ciprofloxacin as therapy for DMAC in addition to the other drugs that they received. The primary endpoint was the time to death from the data of DMAC diagnosis. Covariates effecting survival were analysed through the Cox proportional hazards model. Eighty-nine subjects with DMAC who were treated with clarithromycin and ethambutol were identified. Fifty-eight received ciprofloxacin in addition to clarithromycin and ethambutol. The time to death was significantly better in those subjects who were treated with ciprofloxacin than those who were not (489 days vs 281 days, P=0.01). The sole significant predictor of improved survival on Cox proportional hazards model was ciprofloxacin therapy. Subjects treated with combination of clarithromycin, ethambutol and ciprofloxacin had improved survival over those treated with clarithromycin and ethambutol alone.