Treatment during primary HIV infection has limited benefit

A short course of HIV treatment soon after a person if infected with HIV protects CD4 cell count in the long-term, but only if such treatment lasts for at least twelve months, according to the results from the CASCADE cohort collaboration published in the November 30^th edition of AIDS. The investigators found few other benefits of treatment at this stage of HIV infection (often called primary infection), although individuals who received treatment at this time were less likely to die of non-HIV-related causes than patients whose HIV treatment was started at a later stage.

There is uncertainty about the benefits of starting HIV treatment during primary HIV infection. There is some evidence to suggest that treatment at this time can have long-term benefits for the immune system. However, such evidence is inconclusive and a large randomised controlled trial, the SPARTAC study, is currently investigating the possible benefits or risks of early HIV therapy.

As the results of this study will not be available until 2009, researchers from the CASCADE collaboration, which involves 23 cohorts of HIV-positive patients in Europe, Australia and Canada, designed an observational study to see if treatment during the six months after infection with HIV had long term benefits.

Their study involved 1023 individuals, all of whom had a documented date of HIV seroconversion. A total of 348 (34%) patients started treatment within six months of their infection with HIV. The investigators divided these patients according to the duration of HIV treatment: under six months; six to twelve months; or over twelve months.

They then compared changes in CD4 cell count and viral load, and rates of death, progression to AIDS and other serious illness amongst the patients who started HIV treatment early and those who deferred HIV treatment until later.

As expected, providing HIV treatment boosted CD4 cell count, and overall patients taking early HIV treatment had an average CD4 cell count of over 700 cells/mm³ compared to an average count of a little under 500 cells/mm³ in the patients who deferred treatment.

The slope of CD4 cell decline was steeper, however, amongst patients who took early HIV treatment in the first six months after they stopped HIV therapy. The investigators estimated that the CD4 cell count five years after infection with HIV for the “average” patient whose CD4 cell count was 550 cells/mm³ at the time of seroconversion would be 234 cells/mm³ for patients who deferred HIV treatment, 241 cells/mm³ for patients who started HIV treatment during primary infection and who took such treatment for less than six months and 304 cells/mm³ for patients who started treatment early and remained on such treatment for six to twelve months. These CD4 cell counts were not significantly different.

However, the researchers did find evidence that early HIV treatment benefited the CD4 cell count in the long-term, but only if such treatment lasted for over twelve months, with such patients having an average CD4 cell count of 430 cells/mm³.

Starting a short course of HIV treatment during primary infection had no long-term effect on viral load. Once patients ceased taking early treatment, their viral load reached levels comparable to that seen in patients who deferred treatment (p = 0.57). The duration of treatment did not affect this outcome.

Next, the researchers examined whether a short period of HIV treatment delayed the need to take HIV treatment later. Of the patients who started treatment during primary infection, 61% stopped their HIV treatment. The investigators’ first analysis suggested that these patients were 35% less likely to have to start taking HIV treatment subsequently than patients who deferred the initiation of HIV therapy. However, after taking into account the amount of time the early treatment group had already spent on treatment the researchers found that this group of patients had significantly higher odds (hazard ratio, 2.63, 95% CI: 2.05-3.37) than individuals who deferred taking HIV treatment. They also found that patients who reinitiated therapy did so at significantly higher CD4 cell counts (351 cells/mm³) than patients who started HIV treatment for the first time (278 cells/mm³, p

Finally, the investigators looked at rates of disease progression. During the whole period of follow-up, similar proportions of patients taking early or deferred HIV treatment developed AIDS (approximately 3%). A lower proportion of patients taking early HIV treatment died (0.6% vs. 1.8%), a difference that just reached statistical significance. Furthermore, the researchers found that three-quarters of the deaths in the delayed treatment group were not due to causes normally associated with HIV, including bacterial infections, respiratory disease and non-HIV-related cancer.

“Our findings suggest that the early immunologic gain from initiating early combination antiretroviral therapy within the six months following HIV seroconversion is unlikely to maintained”.

They speculate that treatment was being started too late to have any long-term benefits, noting recent research that suggests that most of the damage sustained by the immune system occurs in the two weeks following infection with HIV.

A number of limitations with their research are also noted by the investigators. These include the study’s observational design which meant that they were unable to determine the reasons why patients taking early HIV treatment stopped or restarted their therapy.

“Uncertainty in relation to the long-term clinical benefits of early treatment for HIV persists” conclude the investigators, however they add, “evidence from our data suggests that higher CD4 cell gains may result when treatment is maintained for at least twelve months. Continued careful monitoring of such individuals, however, will be crucial while on treatment and once it is stopped.”