Congenital and postnatal CMV and EBV acquisition in HIV-infected Zimbabwean infants

Hlanai Gumbo, Bernard Chasekwa, James A Church, Robert Ntozini, Kuda Mutasa, Jean H Humphrey, Andrew J Prendergast, Hlanai Gumbo, Bernard Chasekwa, James A Church, Robert Ntozini, Kuda Mutasa, Jean H Humphrey, Andrew J Prendergast

Abstract

Background: HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants.

Methods: 257 antiretroviral therapy-naïve HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan-Meier and Cox proportional hazards methods.

Results: At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV-infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]).

Conclusions: The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CMV viral loads in HIV-infected…
Figure 1. CMV viral loads in HIV-infected infants.
A: CMV viral loads at birth (within 96 hours of delivery) and at 6 weeks of age in 27 infants with congenital CMV. Viral loads were measured following viral nucleic acid extraction from 100 uL plasma by real-time PCR, using the CMV Artus LC kit (Qiagen) on a LightCycler 2.0 (Roche) machine, with limit of detection of 0.65 copies/uL (equivalent to 325 copies/mL; shown as dotted line labeled LOD) and limit of quantification of 10 copies/uL (equivalent to 5000 copies/mL; shown as dotted line labeled LOQ). Infants with low positive results (above LOD but below LOQ) are shown arbitrarily as having a result halfway between the LOD and LOQ. B: Comparison of CMV viral loads at 6 weeks of age in 27 infants with congenital CMV and 108 infants with postnatal CMV. Infants with viral loads between LOD and LOQ are excluded because viral load could not be quantified, but numbers in each group with low-positive viral loads are shown.
Figure 2. Survival in HIV-infected infants by…
Figure 2. Survival in HIV-infected infants by postnatal CMV status.
Survival among infants with postnatal CMV infection (negative CMV PCR at birth, positive CMV PCR at 6 weeks of age) or without CMV co-infection (negative CMV PCR at 6 weeks of age), from time of viral testing (6 weeks of age) through 6 months of age. Adjusted hazard ratio from Cox proportional hazards model is shown, adjusting for maternal education, CD4 count and death, and infant gender, low birth weight and 6-week HIV viral load.
Figure 3. EBV viral loads and impact…
Figure 3. EBV viral loads and impact of EBV co-infection on survival in HIV-infected infants.
A: Infants with congenital EBV had viral loads measured at birth (within 96 hours of delivery) and at 6 weeks of age. Viral loads were measured following viral nucleic acid extraction from 100 uL plasma by real-time PCR, using the EBV Artus LC kit (Qiagen) on a LightCycler 2.0 (Roche) machine, with limit of detection of 5.78 copies/uL (equivalent to 2890 copies/mL; shown as dotted line labeled LOD) and limit of quantification of 10 copies/uL (equivalent to 5000 copies/mL; shown as dotted line labeled LOQ). Infants with low positive results (above LOD but below LOQ) are shown arbitrarily as having a result halfway between the LOD and LOQ. B: Survival among infants with postnatal EBV infection (negative EBV PCR at birth, positive EBV PCR at 6 weeks of age) or without EBV co-infection (negative EBV PCR at 6 weeks of age), from time of viral testing (6 weeks of age) through 6 months of age. Adjusted hazard ratio from Cox proportional hazards model is shown, adjusting for maternal education, CD4 count and death, and infant gender, low birth weight and 6-week HIV viral load.

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