Studies suggest possible benefits of treating primary HIV infection

Initiating potent antiretroviral therapy during the acute stage of primary HIV infection may have some long-term benefits, according to the results of a non-randomised observational study published in the September 15^th edition of the Journal of Infectious Diseases. However, another recent study examining the early treatment of HIV infection suggests that initial treatment during primary infection should be untertaken for longer than 24 weeks. An editorial in the same issue argues that more randomised controlled trials are required in order to understand who might benefit from early treatment of primary HIV infection.

The optimal time to begin a potent anti-HIV treatment regimen remains unknown. Current treatment guidelines from North America and the United Kingdom agree that asymptomatic HIV infection should not be treated in most people until it reaches its chronic stage, when CD4 cell counts have fallen below 350 cells/mm³.

Treatment guidelines also recommend that if treatment during primary or early infection is undertaken, this should preferably be done within a clinical trial, such as SPARTAC in the UK (which is also recruiting in Australia, Brazil, Ireland, Italy, South Africa and Uganda); CTN 214 in Canada; and NCT00106171 in North America.

The rationale behind treating primary HIV infection is due to preliminary data which suggest that early treatment may limit the spread of HIV throughout the body and strengthen the body's immune response to HIV. It is hoped that this would result in a significant effect on the course of HIV disease.

Two recent studies have found that this might be the case, in certain individuals. Hecht and colleagues report on analysis of data from the Acute Infection and Early Disease Research Program (AIEDRP), which recruited individuals from ten sites in eight North American cities within a year of HIV antibody seroconversion. This was an observational study and participants self-selected whether to begin potent antiretroviral treatment or not, based on viral load and CD4 cell count measurements.

This analysis compared 58 people who started treatment within six months of seroconversion with 337 individuals who elected not to start treatment within a year of their infection. Primary endpoints of this analysis were viral load and CD4 cell counts at 24, 48 and 72 weeks of untreated observation. For those on treatment, the observation period started four weeks after treatment was stopped: time on treatment, and any time prior to treatment was not included.

For purposes of analysis, the investigators divided the 58 individuals who had taken treatment into two subgroups: those who received anti-HIV therapy within two weeks of seroconversion (the 'acute' group - median estimated time from infection to treatment, five weeks); and those who started anti-HIV therapy after two weeks and within six months of seroconversion (the 'early' group - median estimated time from infection to treatment, ten weeks).

There were no significant demographic differences between the thirteen individuals in the acute group compared with the 45 individuals in the 'early' group.

The majority of treated individuals (11/13 in the acute group and 31/45 in the early group) received PI-based triple anti-HIV therapy. The remainder received NNRTI-based triple therapy, NRTI-based triple therapy or PI- and NNRTI-based quadruple therapy. All members of the early group achieved viral loads below 500 copies/ml during their time on treatment, but only 11 of the 13 in the acute group did so. The median time on antiretrovirals was 81 weeks for the acute group (range 13-173) and 70 weeks for the early group (range 13-260).

After 24 weeks off treatment both the acute and early treatment group had viral loads that measured around half a log lower than those achieved by the untreated group 24 weeks after their enrolment in the cohort. Similarly, after 24 weeks off treatment CD4 counts were around 115 cells/mm³ higher in both the acute and early groups compared to the untreated group after 24 weeks of infection.

After adjusting for baseline viral loads and CD4 counts, a significant virological and immunological advantage was seen in the acute group (-0.68 logs lower, and CD4 counts 125 cells/mm³ higher than the untreated group at 72 weeks; both p3 higher at 72 weeks; both p

A 0.68 log lower viral load advantage would have clinical significance, suggest the researchers, since this corresponds to a 50% reduction in the risk of disease progression over six years, based on the MACS study of HIV disease's natural progression in untreated people.

The investigators recommend that their results should be interpreted with caution because their adjustment for CD4 counts and viral loads “may overstate the benefits of [early] treatment”. This is because the adjusted values may have overcompensated for the possibility that those with higher viral loads and lower CD4 counts would have elected to start treatment, whereas those with lower viral loads and higher CD4 counts would have elected not to start treatment. Consequently, they write, the unadjusted analysis is “more conservative”.

“Our results suggest that treatment given during acute HIV infection may modify the long-term course of disease,” conclude the investigators, who add that “the results must be viewed cautiously because of the lack of statistical significance of the CD4 T cell count and viral load benefits at 72 weeks [in unadjusted analysis], the small sample size, and the need for longer follow-up to asses the durability of benefit.”

Another recent study, from Germany, presented as a poster to the Sixteenth International AIDS Conference in Toronto last month, also concluded that treatment during primary infection may provide longer-term benefits. Here, they found that early treatment in a subset of individuals who had viral loads measuring greater than 50,000 copies/ml during primary HIV-infection significantly delayed (by around six months; p=0.02) a fall in CD4 cell counts to below 350 cells/mm³ and/or an increase in viral load to greater than 100,000 copies/ml, compared to untreated individuals.

However, a German-US collaborative study that is published in the same issue of the Journal of Infectious Diseases as the Hecht study, found that 24 weeks of treatment during primary infection does not appear to make a difference to the course of HIV disease.

Streek and colleagues undertook a pilot study in 20 individuals with acute HIV infection recruited in Berlin, Germany, between 2002 and 2003. The study was designed to test their hypothesis that 24 weeks of potent antiretroviral therapy during acute infection would allow for the maturation and preservation of HIV-specific immune responses, resulting in an enhanced control of viral load.

Twelve individuals elected to start anti-HIV therapy (consisting of Kaletra/Combivir) between 18 and 36 days after the estimated date of infection, and therapy was stopped after 24 weeks.

The investigators examined HIV-specific CD8 cell responses and found that although the twelve individuals who had been on treatment did have stronger HIV-specific CD8 cell responses compared to those who had not been on treatment, this did not affect the viral set point at 48 weeks.

In fact, after 48 weeks neither viral loads nor CD4 cell counts differed significantly between those who had taken treatment and those who had not. The investigators concluded that 24 weeks of antiretroviral therapy initiated during acute infection (with an estimated median time between infection and therapy initiation of 25 days) “may not, in itself, be sufficient to enhance the immune control of HIV-1 replication.”

Writing in an editorial in the same issue of the Journal of Infectious Diseases, Dr Sabine Kinloch-de Loes, of London's Royal Free Hospital, says that together these intriguing data suggest “a strong case for testing interventions early after infection, in an attempt to alter the course of the disease and decrease the overall duration of exposure to drugs.”

She concludes that earlier identification of primary HIV infection remains critical to the future of further randomised trials - which should examine the roll of cell-associated DNA, T cell activation markers, and immune responses, in addition to viral loads and CD4 cell counts - so that sufficient acutely infected individuals can be recruited into these important studies.