Abstracts

• A Comparison of Three Highly Active Antiretroviral Treatment Strategies Consisting of Non-Nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors, or Both in the Presence of Nucleoside Reverse Transcriptase Inhibitors as Initial Therapy (CPCRA 058 FIRST Study): A Long-Term Randomized Trial
• CD4 Cell Count Six Years After Commencement of Highly Active Antiretroviral Therapy in Persons With Sustained Virologic Suppression
• Patient, Caregiver, and Regimen Characteristics Associated With Adherence to Highly Active Antiretroviral Therapy Among HIV-Infected Children and Adolescents

A Comparison of Three Highly Active Antiretroviral Treatment Strategies Consisting of Non-Nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors, or Both in the Presence of Nucleoside Reverse Transcriptase Inhibitors as Initial Therapy (CPCRA 058 FIRST Study): A Long-Term Randomized Trial

MacArthur RD, Novak RM, Peng G, et al.

Background: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes.

Methods: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n = 470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n = 463), or a three-class strategy (PI plus NNRTI plus NRTI; n =464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells/mm³ for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922.

Findings: 1,397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80 to 1.41), 0.95 (0.66 to 1.37), and 0.66 (0.56 to 0.78), respectively. One thousand one hundred ninety-six (1,196) patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells/mm³ and +227 cells/mm³ for the three-class and the combined two-class strategies (P = 0.62), respectively. HRs (three-class versus combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class versus combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells/mm³ or less and of more than 200 cells/mm³ (P = 0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100,000 copies/mL and 100,000 copies/mL or more (P = 0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; P < 0.0001).

Interpretation: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV. [Lancet. 2006;368(9553):2107-2109.]

CD4 Cell Count Six Years After Commencement of Highly Active Antiretroviral Therapy in Persons With Sustained Virologic Suppression

Moore RD, Keruly JC.

Background: Sustained suppression of the human immunodeficiency virus (HIV) type-1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4 cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4 cell count in patients in clinical practice who maintained sustained viral suppression for up to six years.

Methods: All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for more than one year while receiving HAART and who had sustained suppression of the HIV RNA load at <400 copies/mL. We analyzed annual change in the CD4 cell count for up to six years after the start of HAART, stratified by baseline CD4 cell counts of <200 cells/µL, 201 cells/µL to 350 cells/µL, >350 cells/µL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis.

Results: A total of 655 patients were observed for a median of 46 months (range, 13 to 72 months). The median change from baseline to most recent CD4 cell count was +274 cells/µL, with 92% of patients having an increase in CD4 cell count. By six years, the median CD4 cell count was 493 cells/µL among patients with baseline CD4 cell counts <200 cells/µL, 508 cells/µL among those with baseline CD4 cell counts of 201 cells/µL to 350 cells/µL, and 829 cells/µL among those with baseline CD4 cell counts >350 cells/µL. In addition to baseline CD4 cell count, injection drug use and older age were associated with a lesser CD4 cell count response, and duration of therapy was associated with a greater CD4 cell count response.

Conclusion: Only patients with baseline CD4 cell counts >350 cells/µL returned to nearly normal CD4 cell counts after six years of follow-up. Significant increases were observed in all CD4 cell count strata during the first year, but there was a lower plateau CD4 cell count at lower baseline CD4 cell strata. These data suggest that waiting to start HAART at lower CD4 cell counts will result in the CD4 cell count not returning to normal levels. [Clin Infect Dis. 2007;44(3):441-446.]

Patient, Caregiver, and Regimen Characteristics Associated With Adherence to Highly Active Antiretroviral Therapy Among HIV-Infected Children and Adolescents

Martin S, Elliott-Desorbo DK, Wolters PL, et al.

Background: This study assesses the relationship between child and caregiver perceptions of medication responsibility, disease knowledge, regimen complexity and adherence to highly active antiretroviral therapy among HIV-positive children. We also examine the association of adherence to child and caregiver demographic characteristics and surrogate markers of HIV disease.

Methods: For this six-month longitudinal study, 24 HIV-positive children (mean age = 14.0 years) being treated with highly active antiretroviral therapy and their caregivers completed measures of medication responsibility and disease knowledge. Medication Event Monitoring System caps calculated adherence across months 1 through 3 (time 1) and 4 through 6 (time 2).

Results: Medication Event Monitoring System data revealed adherence rates of 81% at time 1 and 79% at time 2. Only 8% (n= 2) of child-caregiver pairs reported complete agreement regarding who held responsibility for medication-related tasks. Patients' responsibility for medication was correlated with age based on child (r = 0.51) and caregiver (r = 0.57; Ps < 0.05) perceptions, although their regimen knowledge was not. Greater regimen knowledge among caregivers and fewer child-caregiver discrepancies about medication responsibility predicted better adherence (adjusted r = 0.45). Finally, adherence was correlated with CD4 percentages at time 1 (r = 0.50) and viral load at time 1 (r = -0.56) and time 2 (r = -0.68; Ps < 0.05).

Conclusions: Medication adherence among HIV-infected children is lower than required for optimal viral suppression. Adherence is related to surrogate markers of HIV disease but not to child or caregiver demographic variables. Responsibilities for medication-related tasks should be clarified among family members, regimen knowledge should be emphasized and caregivers should avoid assigning treatment responsibility to a child prematurely. [Pediatr Infect Dis J. 2007;26(1):61-67.]