March 27, 2012 — Temporary treatment with combination antiretroviral therapy (cART) for people first infected with HIV can defer the start of long-term cART, according to the results of a randomized clinical trial published online March 27 in PLoS Medicine. Under current practices, such treatment is often not started until a person's CD4 cell count falls below a certain level or clinical conditions call for treatment.
"From a clinical perspective, an important question is whether patients who are treated during PHI remain off treatment longer than patients in whom treatment is deferred until indicated based on their CD4 cell count or clinical condition," the researchers write.
To find out, Marlous L. Grijsen, MD, from the Center for Infection and Immunity at the Academic Medical Center of the University of Amsterdam, the Netherlands, and colleagues analyzed the records of 168 patients with primary HIV infection (PHI) who were randomly assigned to 1 of 3 groups in a clinical trial. The patients were recruited between May 1, 2003, and March 31, 2010, and the study included follow-up until September 14, 2011.
They randomly assigned the patients, mostly men, to receive either no treatment during PHI or 24 or 60 weeks of early treatment. The cART consisted of zidovudine/lamivudine, efavirenz, and lopinavir/ritonavir capsules in the beginning of the trial. Changes were allowed in case of drug resistance or lack of toleration. The regimen changed in January 2008, when tenofovir/emtricitabine replaced the first combination, based on Dutch standards of care, and the second combination was changed to tablets.
The primary end points were viral set point (the time at which the virus level is stable in the blood and the immune systems is producing HIV antibodies) and time off therapy. The researchers measured viral set point at 36 weeks after randomization for the no-treatment group, and 36 weeks after therapy interruption for the treatment groups.
The researchers found that mean viral set points were 4.8 log10 copies/mL in the no-treatment group, 4.0 log10 copies/mL in the 24-week treatment group, and 4.3 log10 copies/mL in the 60-week treatment group (between groups: P < .001). Therefore, early cART lowered the viral set point by from 0.5 to 0.8 log10 copies/mL.
The investigators also found that for patients treated for 24 weeks, the median time off therapy until long-term cART was started was 3.0 years compared with 1.8 years for the patients treated for 60 weeks and 0.7 years for patients who were not treated.
"[T]his randomized study demonstrates a clear clinical benefit of temporary cART initiated during PHI. Early cART transiently lowered the viral set point and deferred the need for restart of cART during chronic HIV infection," the researchers conclude. "Although extended follow-up studies are needed to evaluate the long-term benefits of such early treatment, starting cART when the patient is ready to do so seems the most reasonable advice for patients with PHI."
The researchers caution that gains in treatment-free years should be weighed against disadvantages of starting cART during PHI, when "patients are often physically and emotionally distressed and adherence may be suboptimal." Early cART may also lead to overtreatment to reach an effective regimen, and could increase risk for drug toxicity or drug resistance, they write.
"[A] reasonable question is whether early cART should not be interrupted but continued for life, given the concern that uncontrolled HIV replication and chronic immune activation carry an increased risk of morbidity and mortality at all stages of HIV infection," the researchers write. They also note that early cART continuation could have a public health benefit by decreasing infectiousness.
The authors have disclosed no relevant financial relationships.
"From a clinical perspective, an important question is whether patients who are treated during PHI remain off treatment longer than patients in whom treatment is deferred until indicated based on their CD4 cell count or clinical condition," the researchers write.
To find out, Marlous L. Grijsen, MD, from the Center for Infection and Immunity at the Academic Medical Center of the University of Amsterdam, the Netherlands, and colleagues analyzed the records of 168 patients with primary HIV infection (PHI) who were randomly assigned to 1 of 3 groups in a clinical trial. The patients were recruited between May 1, 2003, and March 31, 2010, and the study included follow-up until September 14, 2011.
They randomly assigned the patients, mostly men, to receive either no treatment during PHI or 24 or 60 weeks of early treatment. The cART consisted of zidovudine/lamivudine, efavirenz, and lopinavir/ritonavir capsules in the beginning of the trial. Changes were allowed in case of drug resistance or lack of toleration. The regimen changed in January 2008, when tenofovir/emtricitabine replaced the first combination, based on Dutch standards of care, and the second combination was changed to tablets.
The primary end points were viral set point (the time at which the virus level is stable in the blood and the immune systems is producing HIV antibodies) and time off therapy. The researchers measured viral set point at 36 weeks after randomization for the no-treatment group, and 36 weeks after therapy interruption for the treatment groups.
The researchers found that mean viral set points were 4.8 log10 copies/mL in the no-treatment group, 4.0 log10 copies/mL in the 24-week treatment group, and 4.3 log10 copies/mL in the 60-week treatment group (between groups: P < .001). Therefore, early cART lowered the viral set point by from 0.5 to 0.8 log10 copies/mL.
The investigators also found that for patients treated for 24 weeks, the median time off therapy until long-term cART was started was 3.0 years compared with 1.8 years for the patients treated for 60 weeks and 0.7 years for patients who were not treated.
"[T]his randomized study demonstrates a clear clinical benefit of temporary cART initiated during PHI. Early cART transiently lowered the viral set point and deferred the need for restart of cART during chronic HIV infection," the researchers conclude. "Although extended follow-up studies are needed to evaluate the long-term benefits of such early treatment, starting cART when the patient is ready to do so seems the most reasonable advice for patients with PHI."
The researchers caution that gains in treatment-free years should be weighed against disadvantages of starting cART during PHI, when "patients are often physically and emotionally distressed and adherence may be suboptimal." Early cART may also lead to overtreatment to reach an effective regimen, and could increase risk for drug toxicity or drug resistance, they write.
"[A] reasonable question is whether early cART should not be interrupted but continued for life, given the concern that uncontrolled HIV replication and chronic immune activation carry an increased risk of morbidity and mortality at all stages of HIV infection," the researchers write. They also note that early cART continuation could have a public health benefit by decreasing infectiousness.
The authors have disclosed no relevant financial relationships.
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