Rapid HIV disease progression in South African infants co-infected with cytomegalovirus (CMV)

Polly Clayden, HIV i-Base

In an oral presentation, Andrew Prendergast from Oxford University showed data from a study looking at the impact of cytomegalovirus (CMV) on HIV disease progression in a small group of South African infants. [1]

This was a sub-study of the Paediatric Early HAART STI Study (PEHSS), conducted in Durban. PEHSS was a feasibility trial of three management approaches in HIV-infected infants who were diagnosed by HIV PCR at either one or 28 days old. They were then randomised 2:1 to immediate or deferred antiretroviral therapy (ART). [2]

In this sub-study, the investigators performed real time CMV PCR on cryopreserved plasma samples taken at 3 to 4 months of age. Pre-ART CD4% decline was compared between CMV-positive and CMV-negative infants.

Samples were available for 54/63 (86%) of infants enrolled in PEHSS taken at a median of 98 (IQR 88-103) days; 32/54 (59%) were CMV-positive at time of evaluation. Baseline characteristics, including maternal disease status, were similar between the CMV-positive and negative infants but CMV-positive infants were more likely to be breastfed, p=0.01.

The investigators found no significant clinical differences in the two groups of infants but they noted a trend towards failure to thrive in CMV-positive infants (43% vs 17%, p=0.07).

CD4 percentage at birth was similar between CMV-positive and CMV-negative infants (median 45%, p=0.56). However the decline in CD4 percentage from birth was twice as fast in CMV-positive compared to CMVnegative infants (median 10.5%/month vs 5.0%/month; p=0.007) and pre-ART CD4 percentage nadir was significantly lower (median 21% vs 37%; p<0.0001). CD4% tends to be used as the preferred marker of immune decline in early childhood because it naturally varies less with age than the absolute CD4 count.

They also found after 12 months post-ART initiation that the difference in CD4 percentage persisted in CMV-positive compared to CMV-negative infants (median 29% vs 36%; p=0.004).

Interestingly, however, absolute CD4 count nadir was no different between CMV-positive and CMV-negative infants. Dr Prendergast demonstrated that the CMV-positive infants had a huge CD8 cell expansion associated with CMV infection and this rise in CD8 proportion causes much of the impact on CD4 percentage. These data question the validity of using CD4 percentage as the preferred marker of immunological status in infancy, since the CD8 count has such an impact on the CD4 levels.

As over half of HIV-infected infants in this study acquired CMV in the first 4 months of life, and these in turn showed more rapid CD4 percentage decline, Dr

Prendergast asked whether CMV prophylaxis or treatment could slow disease progression in infants? Most importantly he emphasised that infants must access early HIV diagnosis and antiretroviral treatment given the speed of CD4 decline, especially in settings of high CMV prevalence.

Comment

Although this study is very small it raises questions and adds to the argument for early HIV diagnosis and initiation of treatment in infants.

It would be interesting to look at responses to treatment by CMV status in CHER to see if the CMV effect is supported in larger patient numbers It would also be interesting to look at whether CMV was acquired during pregnancy or at birth, and the risk of transmission through breastfeeding.

Similar findings were recently reported in a western cohort, which supports both early maternal ART in pregnancy and early ART in infected infants. [3]

A number of studies (including one from Jane Deayton at the Royal Free published in the Lancet) have previously reported that CMV viraemia is a risk factor for disease progression, even in the HAART era.

Whilst CMV prophylaxis is not routinely used in adults, pre-emptive therapy is certainly used in transplant recipients, and some groups do believe that CMV prophylaxis should be considered in high-risk groups. So, this is an issue of debate at the moment. Several trials are underway (including one at the RF) of potential CMV vaccines. This may be particularly helpful for pregnant women as CMV during pregnancy is associated with a large proportion of birth abnormalities.

References:

Oral abstract presentations are also online as web casts.

Prendergast et al. Accelerated HIV disease progression in African infants co-infected with cytomegalovirus. 16th CROI. February 2009. Montreal, Canada Oral abstract 93LB.
http://www.retroconference.org/2009/Abstracts/36757.htm
Prendergast et al. Randomised, controlled trial of 3 approaches to management of HIV-infected infants. 15th CROI, February 2008, Boston, USA. Oral abstract 77LB.
http://www.retroconference.org/2008/Abstracts/33523.htm
Guibert et al. decreased risk of congenital cytomeglavirus infection in children born to HIV-infected mothers in an era of highly active antiretroviral therapy. CID 48:11 p1516-1526. (1 June 2009).