Placebo Practice Trials: A Tool to Assess and Improve Adherence Readiness

Abstract

Purpose: Antiretroviral therapy is being increasingly delayed until later stages of illness. Therefore, prior to prescribing HAART, providers are emphasizing the need for patients to be ready to adhere well to the treatment regimen. Unfortunately, providers are no better than chance at predicting a patient's adherence, and there are no established methods for accurately assessing a patient's adherence readiness. This pilot study assessed the utility of a series of up to five 1-week placebo practice trials accompanied by adherence counseling as a clinical tool to both assess and improve adherence readiness. Method: Participants were not prescribed treatment until they demonstrated readiness, which was defined as 90+% adherence during a single practice trial. Once HAART was initiated, adherence to one selected antiretroviral was monitored for 4 weeks. Electronic monitoring caps were used to measure adherence. Results: Twenty men enrolled in the study at two HIV outpatient clinics in Southern California. Mean age was 33, 50% were non-White, 35% were employed, 30% had not completed high school, 15% were Spanish monolingual, and 30% had unstable housing. Nine participants achieved 90+% adherence in the first practice trial, with an additional 8 participants demonstrating readiness after two to four practice trials; two participants withdrew from the study because of intolerance of the restrictions related to the use of the caps; and one participant was removed from the study after no effort was given during two practice trials. Of the 17 participants who completed the program and demonstrated adherence readiness, 15 started on an antiretroviral regimen and 2 decided to defer treatment indefinitely. Of the 15 who started therapy, 13 (87%) achieved 90+% adherence during the first month of antiretroviral therapy. The sample's mean adherence during the first 4 weeks of treatment was 93% (SD = 13). Conclusion: These results suggest that once a patient is able to adhere well to a 1-week practice trial they are likely to adhere equally well to HAART. A larger controlled study is needed to further assess the effectiveness of practice trials as a clinical tool for both assessing and improving adherence readiness.     

Causes and Consequences of Incomplete HIV RNA Suppression in Clinical Trials

Abstract

The current goal of antiretroviral treatment is suppression of HIV RNA below 50 copies/mL. However, there is evidence for residual low-level plasma viraemia below 50 copies/mL for people with HIV RNA suppression on antiretroviral treatment. It is not clear whether more profound suppression of HIV RNA would lead to a lower risk of virological failure on antiretroviral treatment or emergent drug resistance. There is high variability in the currently used HIV RNA PCR assays for samples with HIV RNA levels close to the detection lower limit of 40–50 copies/mL. For patients who have HIV RNA levels just above 50 copies/mL (often called “single blips”), a repeat sample should be taken to investigate the possibility of technical error. In a systematic review of 48-week effi cacy from randomized clinical trials (N = 8,083), patients were signifi cantly more likely to show HIV RNA levels between 50–400 copies/mL while taking fi rst-line boosted PI-based HAART (7.3%) compared with fi rst-line NNRTI-based HAART (4.5%) (p < 0.01). However in a systematic review of emergent drug resistance at failure in the same trials, there was also a signifi cantly lower risk of emerging drug resistance after virological failure of boosted PI-based HAART (p < 0.01). Therefore, HIV RNA blips between 50–400 copies/mL may have different consequences for different classes of antiretrovirals. The most widely used method to analyse HIV RNA in clinical trials — time to loss of virological response (TLOVR) — uses two consecutive HIV RNA measurements to define both virological success and failure. However, other methods may improve precision and increase statistical power.     

Study Protocol for the Evaluation of the Potential for Durable Viral Suppression After Quadruple HAART With or Without HIV Vaccination: The QUEST Study

Abstract

Purpose: By protecting and stimulating HIV-specific CD4 cell responses, treatment of primary HIV infection (PHI) with potent quadruple HAART could lead to prolonged suppression of HIV replication after cessation of antiretroviral therapy. The QUEST trial investigates this hypothesis and aims to determine whether addition of a therapeutic vaccine to HAART increases the likelihood of prolonged viral suppression compared to HAART alone. Method: 148 patients with PHI were recruited. Participants were treated with open-label HAART for at least 76 weeks. Participants with sustained viremia <50 copies/mL were randomized to one of three 5-month, double-blinded study treatment groups: HAART alone, HAART + ALVAC-HIV (vCP1452), or HAART + ALVAC-HIV (vCP1452) + Remune^TM. After a further month of HAART alone, all treatment was stopped where plasma HIV-1 RNA remained at <50 copies/mL. Intensive virologic and immunologic monitoring during a 24-week observation period followed treatment interruption. Patients who met treatment reintroduction criteria were offered HAART rescue.     

Lower CD4 Cell Count and Higher Virus Load,but Not Antiretroviral Drug Resistance,Are Associated with AIDS-Defining Events and Mortality: An ACTG Longitudinal Linked Randomized Trials (ALLRT) Analysis

Abstract

The failure to achieve viral eradication with currently available antiretroviral agents has spawned new approaches to limiting drug exposure. Highly active antiretroviral therapy (HAART) lowers morbidity and mortality of HIV disease but cannot eradicate the virus from the body. Structured treatment interruptions (STIs) have been proposed as a strategy to minimize the toxicities of HAART while providing a mechanism to enhance HIV-specific immunity. STIs have been investigated in three distinct clinical scenarios: during acute infection, during chronic infection, and during virologic failure. However, many questions still need to be answered in controlled trials before STIs can be adopted in clinical practice.     

Magnitude and determinants of nonadherence and nonreadiness to highly active antiretroviral therapy among people living with HIV/AIDS in Northwest Ethiopia: a cross - sectional study

Background  

Adequate antiretroviral drug potency is essential for obtaining therapeutic benefit, however, the behavioral aspects of proper adherence and readiness to medication, often determine therapeutic outcome. Therefore, this study aimed to assess the level and determinants of nonadherence and nonreadiness to highly active antiretroviral therapy (HAART) among people living with HIV/AIDS (PLWHA) at Gondar University Teaching Hospital and Felege Hiwot Hospital in Northwest Ethiopia.     

Determinants of Sustained Virological Suppression in Indigent,HIV-Infected Patients: Is Single Protease Inhibitor-Based Antiretroviral Therapy Truly Highly Active?

Abstract

Background: Effective virological suppression with HAART is dependent on strict adherence to therapy. Compliance with therapy is influenced by clinical and psychosocial factors. Method: We performed a retrospective study investigating determinants of effective virological suppression, defined as <400 RNA at 11-13 months of HAART, in an urban indigent population. The study included 366 new patients presenting for care to the Thomas Street Clinic, Houston, Texas, between April and December 1998. Median age, CD4 count, and viral load (VL) of the study population were 37.5 years, 189 cells/mm³, and 53,000, respectively. Thirty-nine percent had AIDS, 20% had cocaine-positive drug screens, and 64% were antiretroviral naïve. Two hundred and sixty-seven patients were started on HAART. Thirty-four percent showed virological suppression. Results: In multivariate analysis, adherence to HAART, care by experienced primary provider, baseline VL <100,000 copies/mL, age >35 years, and no active substance use were associated with virological suppression. Rates of virological suppression with HAART are unacceptably low in this urban indigent population. Conclusion: Low rates of virological suppression are primarily due to lack of adherence rather than late utilization of care among ethnic minorities. Single protease-inhibitor-based antiretroviral therapy does not appear to be highly active in this patient population.     

Efficacy of an Educational and Counseling Intervention on Adherence to Highly Active Antiretroviral Therapy: French Prospective Controlled Study

Abstract

Purpose: The objective was to evaluate the impact of an intervention for improving adherence to antiretroviral therapies (HAART) in HIV-infected patients. Method: We designed a prospective, controlled, randomized trial to assess the impact of an educational and counseling intervention in addition to standard of care. At M0, the study enrolled 244 HAART-treated patients who attended a medical consultation between September and December 1999 who were not included in another protocol. Patients in the intervention group (IG) were offered three individual sessions by trained nurses. The proportions of adherent patients at 6 months followup (M6) and the change in HIV RNA between M0 and M6 were measured. Results: Between M0 and M6, HIV RNA significantly decreased in the 123 patients of the IG (mean difference = –0.22 log [±0.86], p = .013), while it increased (+0.12 log [±0.90], p = .14) in the 121 patients of the control group. However, the proportion of patients with HIV RNA <40 copies/mL remained similar in both groups. In an intent-to-treat analysis, the only significant predictor of 100% adherence at M6 was the intervention group (p = .05) after adjustment for baseline adherence (p = .001). Among the 202 patients with available data on adherence, the proportion of adherent patients was similar in both groups at M0 (58% vs. 63%, p = .59) but became higher in the IG at M6 (75% vs. 61%, p = .04). Conclusion: The educational and counseling intervention was efficient for increasing adherence to HAART and could be implemented in most clinical settings.     

Readiness: The State of the Science (or the Lack Thereof)

HIV treatment guidelines state that patients’ readiness should be assessed before initiating highly active antiretroviral therapy (HAART) to assure adherence. None of the guidelines provide a way to measure readiness. Therefore, this article sought to review the literature on readiness to determine if there was a viable predictor of adherence. Twenty-seven articles were reviewed. Nine described studies that examined the relationship between a measure of readiness and HAART adherence. No readiness measure demonstrated clinical utility as a predictor of adherence. Study flaws included small sample sizes (only one study >100 patients), short follow-up periods (all ≤1 year and six were ≤5 months, four ≤1 month), measures of readiness that related poorly to adherence, and inconsistent adherence measures (eight different measures were used by the researchers). Neither the guidelines nor the literature will help clinicians judge who should initiate HAART and who should delay treatment.     

Simpler Regimens May Enhance Adherence to Antiretrovirals in HIV-Infected Patients

Abstract

Background: Optimal adherence to highly active antiretroviral therapy (HAART) is necessary to achieve the best and the most durable benefit. Many factors may influence compliance to such demanding regimens, and their identification may help in the design of strategies to enhance adherence. Purpose: To assess the factors associated with lower compliance to therapy, the causes of nonadherence, and the relation of nonadherence with virologic response. Method: We performed an observational, cross-sectional study on HIV-infected patients (pts) receiving unrestricted HAART and attending our clinic from January to May 2002. Pts completed a self-administered (ACTG modified) questionnaire on adherence to their therapy. Virologic response was defined as undetectable viral load at the time of interview. A regression model was used to determine predictors of adherence. Results: 597 out of 623 pts (95.8%) completed the survey. Mean age was 38.2 years (range, 18-79). A total of 448 pts (75.0%) were men, 323 (54.1%) were intravenous drug users, 196 (32.8%) were heterosexuals, 76 (12.7%) were men who have sex with men. Mean time on therapy was 49.3 months (range, 4-145). All pts were on stable therapy (>4 months), 173 pts (29%) were on their first HAART regimen, 309 pts (51.7%) were on NNRTI-based regimen, and 288 pts (48.2%) were on a PI-containing treatment. A total of 304 pts (50.9%) were categorized as adherent (p = .024). Multiple logistic regression showed that older age (p = .002), lower number of pills (p = .024), fewer daily doses (p = .002), and shorter time on therapy (p < .001) were factors associated with adherent behavior. Forgetfulness (59.3%), being away from home (50.2%), and problems with schedule (37.6%) were the most frequent causes of nonadherence. Adherent pts were more likely to have undetectable viral load than nonadherent pts (76.5% vs. 55.3%; p < .0001). Conclusion: Younger age, higher number of pills, higher frequency of doses, and longer time on therapy were predictors of nonadherent behavior. Optimal adherence correlated with the best virologic response. Simpler regimens with a lower number of pills and doses may help patients' compliance to therapy.     

Field adherence to highly active antiretroviral therapy in HIV-infected adults in Abidjan, Côte d'Ivoire

OBJECTIVES: To estimate adherence to highly active antiretroviral therapy (HAART) and its determinants in HIV-infected adults followed in field conditions in Abidjan. METHODS: A standardized questionnaire was administered to all consecutive adults on HAART who attended 3 urban HIV outpatient clinics. Patients were asked to self-report their pill intake during the previous 7 days, and, when necessary, to explain the reason(s) why they missed at least 1 intake. The adherence rate was estimated as the number of pills actually taken divided by the number of pills that should have been taken. The association of incomplete adherence (adherence rate<90%) with patients' characteristics was studied using multivariate logistic regression. RESULTS: Three hundred eight patients (male/female ratio: 1:1, mean time on HAART: 22 months) were interviewed. The median self-reported adherence rate was 78% (interquartile range: 65%-90%), with 76% of patients considered as incompletely adherent (adherence rate<90%). The most frequent self-reported reasons for missing at least 1 intake were an antiretroviral drug being out of stock in the clinic pharmacy (28%), the fear of drug side effects (27%), the impossibility of paying the drug's price (20%), and the intervention of traditional practitioners (18%). The only variables significantly independently associated with incomplete adherence were a school level>or=secondary (odds ratio [OR]=1.88; P=0.03) and the absence of a patient's long-term formal commitment to adhere to HAART (OR=3.08; P=0.01). CONCLUSIONS: These data illustrate the difficulty in obtaining high levels of adherence in field conditions in Abidjan. Sustainable access to treatment should be promoted by combating access barriers such as running out of drugs and costs that are too high.     

Low-Dose Daily Subcutaneous Interleukin-2 in Combination with Highly Active Antiretroviral Therapy in HIV + Patients: A Randomized Controlled Trial

Abstract

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/μL 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/μL in the IL-2 group compared to 19.93 cells/μL 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.     

Antiretroviral Treatment Regimen Outcomes Among HIV-Infected Prisoners

Abstract

Background: Despite the high prevalence of HIV in correctional settings, the duration of therapy and response to various highly active antiretroviral therapy (HAART) regimens in this setting is unknown. Method: Using a retrospective cohort study (1997-2002) of HIV-infected prisoners in Connecticut that linked demographic, pharmacy, and laboratory data, we compared HIV-1 RNA (VL) and CD4 lymphocyte responses to four treatment strategies at baseline and at the end of incarceration. Results: Using an analysis of 1,044 incarceration periods or 1,099 subjects for whom ≥6 months of continuous data were available, HAART regimens that included a triple NRTI, two NRTIs + either a PI or NNRTI, or a three-class (NRTI+NNRTI+PI) strategy demonstrated no difference in virological and immunological outcomes. The proportion of subjects who were initiated with NRTI, NNRTI, PI, or three-class regimens were 14%, 32%, 46%, and 8%, respectively. For all study groups, the mean change from baseline in CD4 and VL was +74 cells/μL and -0.93 log₁₀ copies/mL (p < .0001), respectively. Overall, 59% of subjects had an HIV-1 RNA level below the level of detection (<400 copies/mL) by the end of their incarceration. Using Kaplan-Meier curves to examine the time to change in the initial HAART strategy over the incarceration period, the three-class strategy was significantly more likely to be changed earlier than all others (p < .05). Conclusion: Although the three-class strategy was less durable, initiating HAART with any strategy resulted in similar and impressive virological and immunological outcomes by the end of incarceration, further supporting prison as an important site for the initiation and provision of effective antiretroviral therapy.     

Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection.

OBJECTIVE: To identify the effects of substance abuse status (active, former, and never) on utilization of highly active antiretroviral therapy (HAART), medication adherence, and virologic and immunologic responses to therapy. DESIGN: Prospective cohort study of 764 HIV-1-infected patients who attended an urban HIV clinic and participated in a standardized interview. MAIN OUTCOME MEASURES: Past utilization of HAART, self-reported nonadherence with antiretroviral therapy, and changes in HIV-1 RNA level and CD4+ lymphocyte count relative to prior peak and nadir, respectively. RESULTS: Forty-four percent of active drug users failed to utilize HAART compared with 22% of former drug users and 18% of non-drug users (p <.001 for both comparisons). Among participants who were taking antiretroviral therapy when interviewed, active drug users were more likely to report medication nonadherence (34% vs. 24% of nonusers and 17% of former users), had a smaller median reduction in HIV-1 RNA from baseline (0.8 log10 copies/ml vs. 1.7 in nonusers and 1.6 in former users), and had smaller median increases in CD4+ lymphocyte count from baseline (65 cells/mm3 vs. 116 in nonusers and 122 in former users) (p <.05 for all comparisons with active users). CONCLUSIONS: Active drug use was strongly associated with underutilization of HAART, nonadherence, and inferior virologic and immunologic responses to therapy, whereas former drug users and non-drug users were similar in all outcomes. Effective strategies are needed that integrate HIV-1 and substance abuse treatments.     

The impact of adherence on CD4 cell count responses among HIV-infected patients

BACKGROUND: There have been concerns that irreversible immune damage may result if highly active antiretroviral therapy (HAART) is initiated after the CD4 cell count declines to below 350 cells/microL; however, the role of antiretroviral adherence on CD4 cell count responses has not been well evaluated. METHODS: We evaluated CD4 cell count responses of 1522 antiretroviral-naive patients initiating HAART who were stratified by baseline CD4 cell count (<50, 50-199, and >or=200 cells/microL) and adherence. RESULTS: Among patients starting HAART with <50 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 200 cells/microL (interquartile range [IQR]: 130-290) for adherent patients versus 60 cells/microL (IQR: 10-130) for nonadherent patients. Similarly, among patients starting HAART with 50 to 199 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 300 cells/microL (IQR: 180-390) versus 125 cells/microL (IQR: 40-210) for nonadherent patients. In Cox regression analyses, adherence was the strongest independent predictor of the time to a gain of >or=50 cells/microL from baseline (relative hazard [RH] = 2.88, 95% confidence interval [CI]: 2.46-3.37). Among patients with baseline CD4 cell counts <200 cells/microL, adherence was the strongest independent predictor of the time to a CD4 cell count >200 cells/microL (RH = 4.85, 95% CI: 3.15-7.47). CONCLUSIONS: These data demonstrate that substantial CD4 gains are possible among highly advanced adherent patients and should contribute to the ongoing debate over the optimal time to initiate HAART.     

Antiviral Potency of HAART Regimens and Clinical Success Are Not Strictly Coupled in Real Life Conditions: Evidence from the MASTER-1 Study

Abstract

Purpose: To compare in a real clinical setting the largely unknown midterm clinical effectiveness of two protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens with different potency and tolerability profiles in naïve patients. Method: This study was a multicenter, open-label, randomized trial in naïve patients with less than 400 CD4+ cell count/μL, regardless of viral load. Treatment arms were hard gel capsule saquinavir (HGC-SQV)-based HAART (Arm A), with an expected more favorable tolerability profile, and indinavir (IDV)-based HAART (Arm B), with more potent virologic activity. While viro-immunological surrogate markers and World Health Organization (WHO) grade III toxicity (secondary endpoints) were regularly monitored, primary endpoints of the study were clinical and defined as any AIDS-defining event, AIDS-related death, WHO grade IV toxicity, drop outs, and protocol violations. Results: 262 consecutive patients were enrolled in the study from March 1, 1997 to December 31, 1997, in 24 different Italian clinical centers (132, Arm A; 130, Arm B). After 24 months of follow-up, patients who were enrolled in Arm B showed a significantly higher rate of virological success (75% had viremia below 500 copies/mL, CI = 12.9%, in the on-treatment analysis) and immunological gain (mean CD4+ cell count increase of 274 CD4+ cells/μL, SD = 234) when compared to patients enrolled in arm A (57%, CI = 15.5% and 223 CD4+ cells/μL, SD = 192; p = .0353 and .026, respectively). Despite the significant difference observed in surrogate markers, the number of total primary endpoints did not differ in the two groups (55 out of 132 in Arm A vs. 58 out of 130 person-years in Arm B; p = .86). Conclusion: Our results suggest that, after 24 months of follow-up in a real clinical setting, a PI-based HAART induces significant clinical benefits in naïve patients even in the absence of a complete suppression of viral replication. However, the long-term clinical impact of the possible accumulation of viral mutations in the presence of low-grade viral replication remains to be elucidated.