Disadvantages of Structured Treatment With Multidrug-Resistant HIV
Disadvantages of Structured Treatment With Multidrug-Resistant HIV
Background: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1.
Methods and Results: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n = 140) or an immediate change to an optimized antiretroviral regimen (control arm, n = 134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm). The median baseline HIV RNA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm, and the nadir CD4 count was 32 cells/mm. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P < 0.0001), 50 cells from 4 to 12 months (P < 0.0001), 45 cells from 12 to 24 months (P = 0.006), and 43 cells after 24 months (P = 0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22).
Conclusion: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits.
Many people with HIV-1 disease experience incomplete suppression of their HIV-1 despite highly active antiretroviral therapy (HAART). This can occur for various reasons, including difficulties with treatment adherence, exposure to suboptimal regimens, altered drug metabolism, and acquisition of drug-resistant virus during primary infection. Unfortunately, these conditions frequently lead to multidrug-resistant (MDR) HIV-1 and an absence of effective treatment options.
The optimal therapeutic options for patients with MDR HIV-1 remain unclear. Continuing current therapy in the setting of persistent viremia carries the risk of accumulating additional HIV-1 drug-related mutations that may further compromise the efficacy of future treatments. Maintaining a failing regimen may also expose patients to unnecessary drug-related toxicities. Stopping all antiretroviral therapy can eliminate drug toxicities and permit the re-emergence of drug-sensitive virus but is frequently associated with an abrupt decline in CD4 cell counts. Determining which strategy is best for these patients is important to maximize their health and quality of life while awaiting new drugs that are effective against MDR HIV-1.
To address these issues, we developed a randomized clinical trial within the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA 064) for patients with MDR HIV-1. The primary goal was to determine whether a prescribed 4-month structured treatment interruption (STI) before switching therapy results in an improved response that delays clinical disease progression or death compared with a strategy of immediately initiating a new antiretroviral regimen.
The study was closed to enrollment early (in 2002) based on preliminary findings after a median follow-up of 12 months that showed STI was associated with greater progression of disease or death and did not lead to an improved HIV RNA level or CD4 cell count response. Study visits continued through June 30, 2004 for all randomized patients to assess the long-term impact of STI in this cohort. We report here the final study results, with a median of 37 (minimum of 24) months of patient follow-up.
Abstract and Introduction
Abstract
Background: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1.
Methods and Results: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n = 140) or an immediate change to an optimized antiretroviral regimen (control arm, n = 134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm). The median baseline HIV RNA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm, and the nadir CD4 count was 32 cells/mm. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P < 0.0001), 50 cells from 4 to 12 months (P < 0.0001), 45 cells from 12 to 24 months (P = 0.006), and 43 cells after 24 months (P = 0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22).
Conclusion: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits.
Introduction
Many people with HIV-1 disease experience incomplete suppression of their HIV-1 despite highly active antiretroviral therapy (HAART). This can occur for various reasons, including difficulties with treatment adherence, exposure to suboptimal regimens, altered drug metabolism, and acquisition of drug-resistant virus during primary infection. Unfortunately, these conditions frequently lead to multidrug-resistant (MDR) HIV-1 and an absence of effective treatment options.
The optimal therapeutic options for patients with MDR HIV-1 remain unclear. Continuing current therapy in the setting of persistent viremia carries the risk of accumulating additional HIV-1 drug-related mutations that may further compromise the efficacy of future treatments. Maintaining a failing regimen may also expose patients to unnecessary drug-related toxicities. Stopping all antiretroviral therapy can eliminate drug toxicities and permit the re-emergence of drug-sensitive virus but is frequently associated with an abrupt decline in CD4 cell counts. Determining which strategy is best for these patients is important to maximize their health and quality of life while awaiting new drugs that are effective against MDR HIV-1.
To address these issues, we developed a randomized clinical trial within the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA 064) for patients with MDR HIV-1. The primary goal was to determine whether a prescribed 4-month structured treatment interruption (STI) before switching therapy results in an improved response that delays clinical disease progression or death compared with a strategy of immediately initiating a new antiretroviral regimen.
The study was closed to enrollment early (in 2002) based on preliminary findings after a median follow-up of 12 months that showed STI was associated with greater progression of disease or death and did not lead to an improved HIV RNA level or CD4 cell count response. Study visits continued through June 30, 2004 for all randomized patients to assess the long-term impact of STI in this cohort. We report here the final study results, with a median of 37 (minimum of 24) months of patient follow-up.
