Spontaneous sustained undetectable viral load 'not rare' in newly infected

Newly infected individuals achieving a sustained undetectable viral load in the absence of highly active antiretroviral therapy (HAART) are not as rare as previously believed, according to the results of a French study published in the May 1^st online issue of Clinical Infectious Diseases. The study found that 6.7% of HIV-positive individuals who had never been on treatment had a viral load below 400 or 500 copies/ml five years after seroconversion. The authors suggest these data should be taken into consideration when assessing virological outcome in treatment interruption studies of people with primary infection. An accompanying editorial calls for the design of randomised trials in people with primary infection in order to clear up uncertainty over whether or not very early treatment of HIV is beneficial.

Achieving undetectable viral load during studies of HAART interruption in primary infection is often used as a marker of the success of early treatment. However, the majority of these studies have not included a control arm, and a person’s innate ability to control HIV is rarely considered. Consequently, researchers from the Agence Nationale de Recherches sur le SIDA SEROCO cohort study sought to describe the frequency and duration of seroconverters who had spontaneously achieved a sustained (i.e. at least two consecutive undectable tests less than 18 months apart) viral load measurement below 400 or 500 copies/ml (depending on the test used) without the use of HAART.

SEROCO is a multicentre study that includes 1551 HIV-positive individuals recruited since January 1988. For this analysis, the researchers included the 426 cohort members with a known date of seroconversion who were enrolled within 24 months of infection prior to 1996, who had at least two viral load measurements, and who had never taken HAART. The cut-off date for the analysis was 31st December 2002.

Although 112 (26.3%) of this cohort had at least one viral load measurement below the level of detection, only 36 (8.5%) met the researchers’ strict definition of spontaneous sustained undetectable viraemia. CD4 count was higher, and viral load lower at inclusion in the cohort in those who achieved spontaneous sustained undetectable viraemia compared with the others in the cohort (835 vs. 538 cells/mm³; 2.92 vs. 4.10 log₁₀ copies/mL, respectively: both p

The researchers found that women were significantly more likely (Odds Ratio [OR] 4.92, 95% CI 2.45-9.93) than men to have achieved a sustained spontaneous undetectable viral load. Individuals older than 26 years of age at inclusion in the cohort were less likely to have a period of spontaneous sustained undetectable viral load (OR 0.44, 95% CI 0.22-0.88). A baseline viral load greater than 3.96 log₁₀ copies/mL and a baseline HIV DNA level greater than 2.61 log₁₀ copies/mL decreased significantly the probability of spontaneous undetectable viral load. A high CD4 count at cohort entry increased this probability: in fact, each 100 cell/mm³ increase in CD4 counts was associated with an OR of 1.33 (95% CI 1.19-1.48).

Among the 23 spontaneously undetectable participants who had a detectable viral load during part of the study period, the highest viral load measured before becoming undetectable was a median of 3.5 log₁₀ copies/mL (range 2.7-4.5 log₁₀ copies/mL). It took all 36 spontaneously undetectable participants a median of 21.6 months (range 1.7-72.0 months) to achieve a sustained undetectable viral load.

CD4 counts decreased much slower in the individuals with sustained spontaneous undetectable viral loads, even during periods of detectable viraemia. During their undetectable period, the mean CD4 decline was 20 cells/mm³ per year. During periods of detectable HIV RNA, the mean CD4 decline was 45 cells/mm³ per year.

The researchers say that the sustainability of undetectable viraemia was “highly variable”. Thirteen members of the cohort still had undetectable virus five years after infection, and three remained undetectable as long as ten years after seroconversion.

They conclude that the phenomenon of sustained undetectable viral loads in the absence of HAART is “not rare: at five years after seroconversion, 6.7% of the seroconverters who were followed as part of the cohort still had undetectable viremia… These figures should be kept in mind when assessing the virologic outcome for patients who interrupt HAART initiated during [primary HIV infection] in nonrandomized studies.”

An accompanying editorial in the same issue, by Elizabeth Connick and colleagues at the University of Denver, argues that “the lack of randomized controlled clinical trials of interventions among patients with acute and recent HIV infection has been a great disservice to HIV-infected patients and has left clinicians caring for such patients without clear treatment guidelines. It is imperative that clinicians and researchers realise the importance of randomised controlled studies in validating or refuting anecdotal and uncontrolled observations of the treatment received by HIV seroconverters.”

The editorial concludes by acknowledging the challenges in studying people with primary HIV infection, but suggests that “the proper design and performance of these studies are critical to gain better insight into HIV immunopathogenesis and optimal treatment strategies.”