Severity of HIV seroconversion illness associated with subsequent disease progression

Possible implications for use of antiretroviral therapy during primary HIV infection

Michael Carter
Published: 05 December 2013

Severity of symptoms during primary HIV infection (PHI) is associated with subsequent disease progression, results of a study published in PLoS One show. People who had severe clinical symptoms and a lower CD4 count during PHI had a significantly reduced period without AIDS-related illnesses. The researchers hope their findings will help develop guidelines for the use of antiretroviral therapy during primary infection.

The research was undertaken because of ongoing uncertainties about the relationship between the severity of clinical and immunologic symptoms during primary HIV infection – the period when the body first produces antibodies in response to infection with HIV – and the subsequent risk of HIV disease progression. The best way of managing primary infection is unclear, and there is debate concerning the risks and benefits of antiretroviral therapy at this time.

Investigators from the international CASCADE collaboration therefore analysed the relationship between severity of clinical and immunologic symptoms during primary infection and the subsequent rate of disease progression. Their study sample comprised 1108 participants with a known approximate date of seroconversion.

A severe seroconversion illness was defined as the presence in the first six months after seroconversion of clinical symptoms such as thrush in the mouth or throat, bronchitis, pneumonia or a low platelet count. Immunologic markers of a severe seroconversion illness were a single CD4 cell count below 350 cells/mm3 or two counts below 500 cells/mm3.

The investigators compared the subsequent risk of progression to an AIDS diagnosis or death between participants with severe and non-severe symptoms during primary HIV infection.

Almost three-quarters (71%) of participants were men who have sex with men and the median CD4 cell count during PHI was 511 cells/mm3. Clinical progression was observed in 366 participants, comprising 326 who developed an AIDS-defining illness and 40 who died. The overall rate of disease progression was 7.4 per 100 person-years and the median AIDS-free survival time was eight years.

Information on the severity of clinical symptoms during primary HIV infection was available for 865 participants, and this was severe in 127 (15%) individuals.

The median period of AIDS-free survival was significantly shorter for participants with severe symptoms during PHI, compared to participants without (6.3 vs 8.3 years; p = 0.003). After controlling for potential confounders, participants with a severe seroconversion illness had a two-fold increase in their risk of disease progression compared to those without severe illness during PHI (OR = 2.1; 95% CI, 1.4-3.2).

Data on CD4 cell count in the first six months of care were available for 740 participants. During this period, a CD4 count below 500 cells/mm3 was observed in 54% of participants and 28% had a count below 350 cells/mm3.

Compared to individuals with CD4 cells above 500 cells/mm3, individuals with either a count below 350 cells/mm3 or 500 cells/mm3 were twice as likely to progress to an AIDS diagnosis or death.

Analysis was then limited to the 443 individuals with two CD4 counts available from the first six months after seroconversion. Participants with no CD4 cell count below 350 cells/mm3 during this period had a median AIDS-free survival time of 8.1 years. This fell to 5.4 years for participants with one count below 350 cells/mm3 and 3.9 years for individuals with two measurements below this threshold (comparison, p < 0.001).

Similarly, participants who maintained a CD4 count above 500 cells/mm3 during this six-month period had a longer period of AIDS-free survival compared to individuals with two or one test results below this level (7.5 vs 6.7 vs 4.8 years; p < 0.001).

Participants with a combination of severe symptoms and a CD4 cell count  below 350 cells/mm3 or 500 cells/mm3 had a two-fold increase in their risk of an AIDS-related illness or death, compared to participants who had a severe illness alone.

“This study suggests that one or more CD4 < 350 cells/mm3 and/or severe seroconversion illness, may be a useful indicator for identifying patients who are likely to benefit from early treatment and initial close monitoring,” conclude the authors. “More evidence from RCT [randomised controlled trials] is needed to establish the beneficial value of treatment initiation in [primary HIV infection].”

Reference

Lodi S et al. Symptomatic illness and low CD4 cell count at HIV seroconversion as markers of severe primary infection. PLoS ONE 8 (11): e78642. doi: 10.1371/journal.pone.0078642, 2013. See the full article here.