Reinitiation of Interrupted HIV Therapy: How Fast Does Viral Load Fall?
Reinitiation of Interrupted HIV Therapy: How Fast Does Viral Load Fall?
Abstract & Commentary
Synopsis: Reinitiation of antiretroviral therapy following its complete interruption for one month resulted in a rate of decline in HIV viral load in nine of 10 patients similar to that when HIV therapy was first initiated. Mutational changes in the RT and protease genes were not detected after this brief interruption of therapy early in the treatment course.
Source: Neumann AU, et al. HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. AIDS 1999;13:677-683.
Antiretroviral treatment in hiv-infected patients is unfortunately often interrupted for a number of reasons, including intolerance, toxicity, lack of adherence, or intercurrent illness. The consequences of these "drug holidays" are not known. Neumann and colleagues evaluated 10 treatment-naive patients with an average plasma viral load of 4.8 logs, each of whom received a combination of zidovudine, lamivudine, and indinavir for 28 days, followed by a 28-day washout period off drugs, and then reinitiation of the therapy for an additional 28 days. In order to assess the kinetics of declining viremia, plasma viral load was sampled twice weekly (and sometimes more often). Complete sequencing of the reverse transcriptase and protease genes was performed on all subjects with detectable viral load at baseline and at months 1, 2, and 4.
Compliance was excellent in all but one person. By the end of the first four-week phase of therapy, the mean drop in viral load was 2.0 ± 0.3 logs copies/mL. Six patients had achieved viral loads as low as 200-1000 copies per mL, and three patients had fallen to 20-200 copies per mL. The viral load in the remaining patient took 77 days to fall below 1000 copies per mL, at which time therapy was interrupted.
Following interruption of therapy, viral load remained stable for four to seven days, and then began to rebound at an average rate of 0.4 logs per day. Within 14-21 days of stopping therapy, viral load had reached approximate pre-treatment levels in eight of 10 patients (although there was considerable variability between patients, with viral loads varying from 14-386% of the baseline values). Nevertheless, the response to reinitiation of therapy was just as vigorous the second time around as that observed two months earlier at the time of initiation of treatment, with nearly parallel kinetics. Only the single patient with poor compliance had a significantly slower rate of viral load decay.
Most important, viral sequences showed no evidence of mutational changes in any patient. Viral loads remained below 200 in nine patients who continued therapy for four months, and remained undetectable in five patients who continued for up to 12 months.
Comment by Carol A. Kemper, MD
Although similar results have been previously reported, these data again demonstrate the rapid rate of decay in viral load following resumption of antiretroviral oral administration after a brief period of therapy interruption. These rates of decay can be used to assess the antiviral activity in situ of various drug regimens. Complete interruption of therapy—on one occasion quite early on in the treatment course—did not result in the emergence of mutational changes in the RT or protease gene, or a lack of antiretroviral efficacy. These data are reassuring for those unavoidable circumstances where therapy must be discontinued in a patient with intercurrent illness or significant drug-related toxicity. Experience suggests, however, that more frequent interruptions of therapy may eventually result in the emergence of resistant strains.
Interruption of therapy for several weeks to several months is presently being examined by researchers at UCSF as a possible approach to some patients with HIV infection, especially those who have been heavily treated and who may have high levels of circulating multidrug resistance virus.1 Not only do drug holidays give patients a break from their grueling medication regimens, and may allow some to gain weight, stopping the selective pressure of ongoing therapy may allow wild-type sensitive strains of virus to repopulate the system, possibly providing another opportunity to reintroduce more effective therapies at a later date.
Planned interruption is also being evaluated as an attempt at "auto-immunization" in patients with prolonged suppression of viral replication. v
Reference
1. Carey J. AIDS drugs: Giving it a rest. Business Week. June 14, 1999:94.
Complete interruption of antiretroviral therapy in HIV-infected patients:
a. resulted in emergence of resistant strains.
b. did not result in the emergence of mutational changes in the RT or protease gene.
c. caused a lack of antiretroviral efficacy.
d. caused viral loads to rise above 1500 copies per mL.
e. None of the above
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