After Virologic Rebound, Should T-20 Be Continued?
After Virologic Rebound, Should T-20 Be Continued?
Patients with viremia on T-20 experienced a slight viral-load increase after selective discontinuation of the drug.
For patients who do not achieve full HIV suppression on potent combination antiretroviral therapy, the key management question is whether to continue or stop the drugs that are incompletely suppressive. The SMART study demonstrated that stopping antiretroviral therapy completely is not a good strategy (ACC Nov 29 2006), but partial treatment interruption may be a viable approach for selected patients. For some agents (such as 3TC), clinical trial data verify that the drug has continued activity and favorable effects despite high-level resistance. For other agents, however, the situation is less clear, and a particularly vexing decision is whether to continue T-20.
T-20 is difficult to administer, is very expensive, and may lead to troublesome adverse events. Moreover, continued use of a failing agent may generate additional resistance over time, compromising future treatment options. If, however, the drug is important for maintaining clinical and immunologic wellness, the improved overall prognosis could more than offset the drawbacks of continuing the drug.
In the present study, investigators assessed the consequences of stopping T-20 in patients with ongoing viral replication. The underlying hypothesis was that if T-20 played an important role in sustaining a favorable effect, then discontinuation of the agent would result in significant increases in viremia and accelerated declines in CD4-cell counts. The study involved 25 patients who had been on T-20based therapy for at least 24 weeks and had persistently detectable viral loads (>400 copies/mL) for at least the preceding 4 weeks, despite >90% self-reported adherence. Steady-state baseline viremia was estimated from two measurements taken just before T-20 interruption. During the interruption, patients remained on stable background regimens and were monitored frequently to assess CD4-cell counts and viral loads.
At the time of interruption, the median viral load was 4.78 log copies/mL, and the median CD4 count was 95 cells/mm. After T-20 was discontinued, patients experienced significant increases in viral load; the greatest increases were seen by week 4, and changes were sustained over the full 24 weeks of follow-up (median increase, 0.19 log copies/mL). CD4 slopes were negative after T-20 was discontinued, but they did not differ significantly from those noted before the drug was stopped. Therefore, researchers could not ascertain whether the observed virologic effect had clinical or immunologic consequences.
These results suggest that T-20 likely continues to exert a meaningful antiviral effect even when resistance is present. The magnitude of the effect likely varies among patients but appears to be relatively modest. Editorialists suggest that these data raise several broad questions. First, what is the virologic and molecular basis for continued drug efficacy in the setting of resistance? Second, what is the contribution of T-20 drug levels to the persistent antiviral effect? Finally, what are the clinical benefits of continuing T-20, and what are the risks (such as selecting for broader resistance of similar future antivirals)? Larger, longer-term trials are needed to answer these questions. However, the difficult decision of whether to stop T-20 may become moot - at least for a while - as new agents in new classes become available (e.g., integrase inhibitors and CCR5 antagonists). Achieving full HIV suppression remains the goal in all patients.
- Charles B. Hicks, MD
Click here for AIDS Clinical Care subscription information.
Summary and Comment
Summary
Patients with viremia on T-20 experienced a slight viral-load increase after selective discontinuation of the drug.
For patients who do not achieve full HIV suppression on potent combination antiretroviral therapy, the key management question is whether to continue or stop the drugs that are incompletely suppressive. The SMART study demonstrated that stopping antiretroviral therapy completely is not a good strategy (ACC Nov 29 2006), but partial treatment interruption may be a viable approach for selected patients. For some agents (such as 3TC), clinical trial data verify that the drug has continued activity and favorable effects despite high-level resistance. For other agents, however, the situation is less clear, and a particularly vexing decision is whether to continue T-20.
T-20 is difficult to administer, is very expensive, and may lead to troublesome adverse events. Moreover, continued use of a failing agent may generate additional resistance over time, compromising future treatment options. If, however, the drug is important for maintaining clinical and immunologic wellness, the improved overall prognosis could more than offset the drawbacks of continuing the drug.
In the present study, investigators assessed the consequences of stopping T-20 in patients with ongoing viral replication. The underlying hypothesis was that if T-20 played an important role in sustaining a favorable effect, then discontinuation of the agent would result in significant increases in viremia and accelerated declines in CD4-cell counts. The study involved 25 patients who had been on T-20based therapy for at least 24 weeks and had persistently detectable viral loads (>400 copies/mL) for at least the preceding 4 weeks, despite >90% self-reported adherence. Steady-state baseline viremia was estimated from two measurements taken just before T-20 interruption. During the interruption, patients remained on stable background regimens and were monitored frequently to assess CD4-cell counts and viral loads.
At the time of interruption, the median viral load was 4.78 log copies/mL, and the median CD4 count was 95 cells/mm. After T-20 was discontinued, patients experienced significant increases in viral load; the greatest increases were seen by week 4, and changes were sustained over the full 24 weeks of follow-up (median increase, 0.19 log copies/mL). CD4 slopes were negative after T-20 was discontinued, but they did not differ significantly from those noted before the drug was stopped. Therefore, researchers could not ascertain whether the observed virologic effect had clinical or immunologic consequences.
Comment
These results suggest that T-20 likely continues to exert a meaningful antiviral effect even when resistance is present. The magnitude of the effect likely varies among patients but appears to be relatively modest. Editorialists suggest that these data raise several broad questions. First, what is the virologic and molecular basis for continued drug efficacy in the setting of resistance? Second, what is the contribution of T-20 drug levels to the persistent antiviral effect? Finally, what are the clinical benefits of continuing T-20, and what are the risks (such as selecting for broader resistance of similar future antivirals)? Larger, longer-term trials are needed to answer these questions. However, the difficult decision of whether to stop T-20 may become moot - at least for a while - as new agents in new classes become available (e.g., integrase inhibitors and CCR5 antagonists). Achieving full HIV suppression remains the goal in all patients.
- Charles B. Hicks, MD
Click here for AIDS Clinical Care subscription information.
Citation(s):
Deeks SG et al. Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen. J Infect Dis 2007 Feb 1; 195:387-91.
Morse C and Maldarelli F. Enfuvirtide antiviral activity despite rebound viremia and resistance mutations: Fitness tampering or a case of persistent braking on entering? J Infect Dis 2007 Feb 1; 195:318-21.
Source...