Risk of HIV rebound lessens over time in EuroSIDA cohort

The rate of virological failure in people starting a HAART regimen decreased over time, suggesting that the greatest risk of treatment failure may lie in the early months after viral suppression, according to data from the EuroSIDA cohort published in the August 15^th edition of AIDS.

The EuroSIDA study is a prospective cohort involving HIV-positive patients at 70 treatment centres in Europe, Israel and Argentina. Enrollment started in 1994 and data was collected until Spring 2002. In their current analysis investigators wished to establish the rate of virological failure in 2444 patients enrolled in the cohort and the factors related to HIV rebound.

For the purposes of this study, viral suppression was defined as an HIV viral load below 400 copies/mL within twelve months of starting HAART. Rebound was regarded as two consecutive viral load measures above 400 copies/mL after achieving suppression.

Almost three quarters of individuals in the study had taken NRTI monotherapy or dual therapy prior to starting HAART. Patients who had had prior antiretroviral therapy were significantly more likely to be on intensive HAART regimens, with 100% of individuals taking five anti-HIV drugs having pre-treatment with antiretrovirals prior to starting HAART.

Investigators also found that treatment naïve patients tended to start HAART later, have a higher percentage increase in CD4 cell count by the time of viral suppression, and have a higher HIV viral load when HAART was initiated (all p

Viral load rebounded in 1031 patients (42.2%). Only 151 (14.6%) of individuals experiencing virological rebound were treatment naïve.

Investigators found that the rate of virological failure was initially high, but slowed down the longer HAART was used. After twelve months of HAART 27.9% of patients had experienced a rebound in their HIV, but this had slowed to 37.5% by 24 months. Individuals who had previous antiretroviral treatment experienced treatment failure significantly faster than those who were naïve when initiating HAART (p

Multivariate analysis revealed that patients taking four or five drugs were significantly more likely to experience rebound than individuals on a three drug HAART regimen (relative hazard 1.29, 95% CI, 1.08 – 1.54, p=0.0049, and 1.98, 95% CI, 1.48 – 2.64, p

The relationship between treatment experience and rebound was also confirmed in multivariate analysis (RH 0.56, 95% CI, 0.46 – 0.68, p

Further analysis also indicated that treatment experienced patients who were able to add new NRTIs to their regimen had a lower risk of virological rebound, the risk being 19% lower for each new NRTI added to a HAART regimen (RH 0.81, 95% CI 0.74 – 0.88, p

The investigators note that their study “found a substantial number of patients who had a rebound in viral load after initial virological suppression on HAART regimens, but the rate of virological suppression decreased over time, suggesting that if the viral load does not rebound in the initial months after virological suppression there is less risk of …rebound over time”. The investigators also emphasise that treatment naïve patients had the lowest rate of rebound, but that individuals with antiretroviral treatment experience prior to starting HAART were less likely to experience rebound if they were able to add new drugs to their regimen.

Treatment experienced patients are more likely to have drug resistance, the investigators suggest. In addition, individuals taking more complex drug regimens are likely to have more side-effects and find adherence harder, explaining the higher rate of treatment failure in this group.

Regarding the decrease in virological failure over time, the investigators suggest this was due to a “selection effect” with individuals with poorer adherence and more side-effects developing a greater degree of resistance and faster rebound. An alternative explanation could be “that the declining rate of…rebound reflects the decline in newly activated infected cells”.

Individuals taking NNRTI-based therapy experienced a greater rate of treatment failure than those taking a protease inhibitor. The investigators note that nevirapine was the NNRTI used most widely by the study population, and highlight an earlier finding from the EuroSIDA cohort that efavirenz-containing regimens achieve better virological control than those containing nevirapine.