Roberto C. Arduino

The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.

A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy

Objective To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response. Design A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States. Participants A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor. Interventions Randomization was to antiretroviral therapy guided by PRT or SOC. Main outcome measures The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of ‘active’ (less than fourfold resistance) antiretroviral agents used (secondary). Results At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed;P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml;P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more ‘active’ antiretroviral agents than in the SOC arm (P = 0.003). Conclusion Antiretroviral treatment guided prospectively by PRT led to the increased use of ‘active’ antiretroviral agents and was associated with a significantly better virological response.

Smoking behavior in a low-income multiethnic HIV/AIDS population

The aim of this study was to describe smoking prevalence and smoking behavior in a multiethnic low-income HIV/AIDS population. A cross-sectional survey design was used. The study site was Thomas Street Clinic, an HIV/AIDS care facility serving a medically indigent and ethnically diverse population. Demographic, disease status, behavioral, and psychosocial variables were assessed by participant self-report. Surveys were collected from 348 study participants. Demographic composition of the sample was 78% male, 25% White, 44% Black, and 29% Hispanic. Study participants had a mean age of 40.2 years (SD=7.8). The HIV exposure profile of the sample was diverse: 46% men who have sex with men, 35% heterosexual contact, and 11% injection drug use. Prevalence of current cigarette smoking in the sample was 46.9%. Among participants with a lifetime history of smoking 100 or more cigarettes (62.8%), only 26.6% were currently abstinent, lower than the 48.8% rate seen in the general population. Multiple logistic regression analysis indicated that race/ethnicity, education level, age, and heavy drinking were significantly associated with smoking status. Hispanics were less likely than Whites were to smoke, younger participants were less likely than older participants were to be current smokers, and heavy drinkers were more likely to be current smokers than were those who were not heavy drinkers. As education level increased, the likelihood of smoking decreased and the likelihood of quitting increased. The high smoking prevalence in this HIV/AIDS population demonstrates the need for smoking cessation interventions targeted to the special needs of this patient group.

A randomized trial of a proactive cellular telephone intervention for smokers living with HIV/AIDS

Objective:To assess the efficacy of an innovative smoking cessation intervention targeted to a multiethnic, economically disadvantaged HIV-positive population. Design:A two-group randomized clinical trial compared a smoking cessation intervention delivered by cellular telephone with usual care approach. Methods:Current smokers from a large, inner city HIV/AIDS care center were recruited and randomized to receive either usual care or a cellular telephone intervention. The usual care group received brief physician advice to quit smoking, targeted self-help written materials and nicotine replacement therapy. The cellular telephone intervention received eight counseling sessions delivered via cellular telephone in addition to the usual care components. Smoking-related outcomes were assessed at a 3-month follow-up. Results:The trial had 95 participants and 77 (81.0%) completed the 3-month follow-up assessment. Analyses indicated biochemically verified point prevalence smoking abstinence rates of 10.3% for the usual care group and 36.8% for the cellular telephone group; participants who received the cellular telephone intervention were 3.6 times (95% confidence interval, 1.3-9.9) more likely to quit smoking compared with participants who received usual care (P = 0.0059). Conclusions:These results suggest that individuals living with HIV/AIDS are receptive to, and can be helped by, smoking cessation treatment. In addition, smoking cessation treatment tailored to the special needs of individuals living with HIV/AIDS, such as counseling delivered by cellular telephone, can significantly increase smoking abstinence rates over that achieved by usual care.

A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy.

Objectives: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen. Methods: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history. Results: The mean baseline plasma HIV-RNA level was 4.81 log10 copies/ml and the mean CD4 cell count was 134.8 cells/μl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of −1.33 log10 was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log10 decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/μl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations. Conclusion: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

Short-Term Safety and Antiretroviral Activity of T-1249, a Second-Generation Fusion Inhibitor of HIV

T-1249 is a 39-aa synthetic peptide that inhibits fusion of human immunodeficiency virus (HIV) to the host target cell. A 14-day open-label, phase 1/2 dose-escalation monotherapy study of the safety and antiretroviral activity of T-1249 was performed on 115 HIV-1-infected adults. At baseline, the majority of the patients had advanced HIV disease (baseline median CD4(+) cell count, 57 cells/microL) and had extensive pretreatment (i.e., pre-T-1249) experience with antiretroviral medications (median, 11 antiretroviral drugs). Patients received T-1249 monotherapy by subcutaneous injection, for 14 days, at doses ranging from 6.25 to 192 mg/day. T-1249 was generally well tolerated, and no dose-limiting toxicity was identified. Injection-site reactions were the most commonly reported adverse event (57%). Dose-dependent decreases in plasma HIV-1 RNA load were observed; the median maximum change from baseline across dose groups ranged from -0.29 log(10) copies/mL (95% confidence interval [CI], -0.43 to -0.05 log(10) copies/mL) for the lowest dose to -1.96 log(10) copies/mL (95% CI, -2.02 to -1.37 copies/mL) for the highest dose. These results indicate that T-1249 is a potent new therapeutic agent for HIV-1 infection.

Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an Urban clinic

Ethnic minority, female, and drug-using patients may be less likely to receive highly active antiretroviral therapy (HAART), despite its proven benefits. We reviewed the medical records of a consecutive population of 354 patients entering care in 1998 at the Thomas Street Clinic, an academically affiliated, public, HIV-specialty clinic in Houston, to determine the factors associated with not receiving HAART as recorded in pharmacy records. Ninety-two patients (26.0%) did not receive HAART during at least 6 months of follow-up. Patients who did not receive HAART were more likely to be women and to have missed more than two physician appointments and were less likely to have a CD4 count <200 cells/microL or a viral load > or = 10 copies/mL. In multivariate logistic analysis, missed appointments (OR = 5.85, p<.0001), female sex (OR = 2.53, =.001), and CD4 count > or = 200 cells/microL (OR = 2.50, p=.001) were independent predictors of not receiving HAART. More than half the patients who never received HAART never returned to the clinic after their first appointment. Among patients new to care, women and those with poor appointment adherence were less likely to receive HAART. Efforts to improve clinic retention and further study of the barriers to HAART use in women are needed.

Efficacy of cell phone-delivered smoking cessation counseling for persons living with HIV/AIDS: 3-month outcomes

INTRODUCTION Substantial evidence indicates that cigarette smoking among people living with HIV/AIDS (PLWHA) represents a significant public health concern. However, few efforts to assess smoking cessation interventions targeting this population have been reported. In this brief report, 3-month outcomes from an ongoing treatment trial for PLWHA who smoke are described. METHODS Study participants were recruited from a large HIV care center serving a diverse population of PLWHA. A two-group randomized design was used to compare the efficacy of usual-care (UC) smoking cessation treatment versus a cell phone intervention (CPI). Follow-ups were conducted at the HIV clinic 3 months postenrollment. Using an intent-to-treat approach, a series of multiple regression models were used to compare smoking outcomes in the 2 groups. RESULTS Four hundred and seventy-four participants were enrolled and randomized, UC (n = 238) and CPI (n = 236). Mean age in the sample was 44.8 (SD = 8.1) years, and the majority were male (70.0%), Black (76.6%), and had an education level of high school or less (77.5%). At follow-up, participants in the CPI group were 4.3 (95% CI = 1.9, 9.8) times more likely to be abstinent (7 day) compared with those in the UC group. Similarly, significant point estimates were observed for the other smoking outcomes of interest. CONCLUSIONS Findings from this preliminary report indicate that a smoking cessation intervention for PLWHA consisting of cell phone-delivered proactive counseling results in significantly higher abstinence rates compared with a standard care approach. Evaluation of the long-term (6-month and 12-month) efficacy of the CPI approach is ongoing.

Increasing access to smoking cessation treatment in a low-income, HIV-positive population: the feasibility of using cellular telephones.

This study examined the feasibility of using cellular telephones to improve access to smoking cessation counseling in a low-income, HIV-positive population. Two pilot studies were conducted: (a). A survey of interest and barriers in participating in a smoking cessation intervention (n=49) and (b). a cellular telephone smoking cessation intervention in which participants were provided with free cellular telephones and received six telephone counseling sessions over a 2-week period (n=20). A primary care clinic serving a multiethnic, medically indigent, HIV-positive population served as the setting. Demographics and smoking status were assessed by self-report and expired-air carbon monoxide testing. In study 1, participants reported multiple barriers to participating in a smoking cessation intervention, including transportation, transience, and telephone availability. However, they also reported a high level of interest in participating in a smoking cessation intervention, with the greatest interest in a cellular telephone intervention. In study 2, 19 of the 20 participants successfully completed 2 weeks of smoking cessation counseling with a 93% (106 of 114 calls) contact rate. A total of 19 participants made a quit attempt, and the 2-week end of treatment point-prevalence abstinence rate was 75%. The provision of cellular telephones allowed for the implementation of a proactive telephone smoking cessation intervention providing an underserved population with access to care. Cellular telephones also may provide unique benefits because of the intensity of counseling and support provided as well as the ability to provide counseling in real-world, real-time situations (in vivo counseling).

Impact of a Cell Phone Intervention on Mediating Mechanisms of Smoking Cessation In Individuals Living with HIV/AIDS

Mounting evidence suggests that smokers living with HIV/AIDS have a significantly increased risk of numerous adverse health outcomes (both AIDS- and non-AIDS-related) compared with HIV-positive nonsmokers. Therefore, efforts to design and implement effective cessation programs for this ever-growing special population are warranted. The present study assessed the effects of a cell phone intervention (CPI) on hypothesized mediators (i.e., changes in depression, anxiety, social support, and self-efficacy) demonstrated to influence cessation outcomes in other populations. Ninety-five participants from an inner-city AIDS clinic were randomized to receive either the CPI or recommended standard of care (RSOC) smoking cessation treatment. Participants randomized to the RSOC group (n=47) received brief advice to quit, a 10-week supply of nicotine patches, and self-help materials. Participants randomized to the CPI group (n=48) received RSOC components plus a series of eight proactive counseling sessions delivered via cell phones. A series of regression analyses (linear and logistic) was used to assess the relationships between treatment group, the hypothesized mediators, and biochemically confirmed smoking cessation outcomes. Results indicated that the CPI group experienced greater reductions in anxiety and depression, and increases in self-efficacy compared with the RSOC group. Further, changes in depression, anxiety, and self-efficacy weakened the association between treatment group and cessation outcome. The mediator hypothesis, however, for social support was rejected, as the difference score was not significantly associated with treatment group. These results suggest that the efficacy of the CPI is at least partially mediated by its ability to decrease symptoms of distress while increasing self-efficacy.