Low-tech assays for plasma C-reactive protein useful for predicting HIV-related outcomes in Tanzanian women

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High maternal C-reactive protein (CRP) levels can independently predict HIV-related outcomes such as disease progression and maternal and child mortality in a resource-poor setting, according to the findings of a study published in the October 1st issue of the journal AIDS.

HIV viral load testing and CD4 cell counts for monitoring HIV-infected patients involve expensive high-tech assays which require highly-trained personnel and sophisticated laboratory facilities and are not generally sustainable under resource-poor settings. There is therefore an imperative need for alternative low-tech assays that are more sustainable in the long term without donor funding.

Measurement of CRP concentration appears to be a suitable low-tech assay. CRP levels increase in acute and chronic inflammatory disorders, and are prognostic for cardiovascular events and mortality in patients with pancreatic and colorectal cancer and pneumocystis pneumonia.

Glossary

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

plasma

The fluid portion of the blood.

WHO stage

A simplified system to describe four clinical stages of HIV-related disease, based on clinical parameters (symptoms, weight loss and different opportunistic infections) rather than decreasing CD4 cell count. Stage I is asymptomatic, stage II mild symptoms, stage III advanced symptoms and stage IV severe symptoms (an AIDS diagnosis).

haemoglobin (HB)

Red-coloured, oxygen-carrying chemical in red blood cells.

An association between higher CRP concentrations, lower CD4 cell counts and higher HIV RNA levels has been reported in HIV-infected patients. However, studies assessing the usefulness of CRP as a predictor for mortality in such patients have yielded conflicting results.

Clinicians in resource-poor settings urgently need reliable low-tech assays for monitoring HIV-infected patients and for clinical decision-making in the care of these patients. In this regard, a team of Tanzanian and US investigators evaluated plasma CRP as a predictor of adverse HIV-related outcomes in Tanzanian mothers and their children.

The substudy took place in Dar es Salaam, Tanzania, in the context of a bigger randomised trial of multivitamin supplementation involving 1,078 HIV-infected pregnant women enrolled from April 1995 to August 2003. Plasma samples were obtained within one year after delivery. None of the women were on antiretroviral therapy (ART). Laboratory measurements included HIV RNA levels, CD4 cell counts, and CRP plasma levels in 611 women.

The CRP data analysed were from 606 HIV-positive women in whom the median CRP concentration was 1.95 mg/l (IQR 0.63-5.17 mg/l). High and normal CRP levels were defined as > 10 mg/l and < 10 mg/l, respectively.

About 16 % of the women had high CRP concentrations; these women were less likely to be breastfeeding on the day of sampling, more likely to have a body mass index < 18.5 kg/m2, a mid-upper arm circumference < 22 cm, haemoglobin < 11 g/dl, and a CD4 count < 200 cells/mm3.

Primary maternal outcomes were defined as progression to WHO stage 4 disease, mortality to AIDS-related causes, and mortality to any cause. Primary child outcomes included mortality by age two years and mother-to-child transmission of HIV (MTCT) by age two years. Statistical models were used to assess the relationship between maternal CRP levels and these outcomes.

During follow-up, 56 women progressed to WHO stage 4 and 188 died. A high maternal CRP concentration was associated with a 2.26-fold [95% confidence interval (CI), 1.64–3.12] greater risk of progression to stage 4 or death. The median time to progression or death was 6.8 and 5.2 years for women in the second and highest CRP quartiles, respectively.

Generally, higher CRP quartiles were associated with adverse maternal HIV-related outcomes in univariate and multivariate analyses. Over 50 % of women in the lowest and third CRP quartiles did not progress to stage 4. CRP was a significant predictor of progression to stage 4 or death only when the CRP sample date was within 2-4 years but not within a year.

One hundred and seventy-four children acquired HIV and 116 died by age two years. A high maternal CRP concentration was associated with a 3.03-fold (95% CI, 1.85–4.96) greater risk of child mortality but not MTCT. The highest but not the lowest CRP quartile was associated with child mortality before age 2 years. This association did not hold up after adjusting for maternal CD4 cell count, HIV viral load, and other prognostic factors.

While previous studies in developed countries confirmed the association between high CRP concentration and AIDS progression and death or survival, the mechanism underlying this association remains elusive. The study of Drain et al. expanded these findings to resource-poor settings.

The usefulness of CRP assays still remains unknown in patients on ART. Studies such as those of Drain et al in patients on ART need to be carried out as more HIV-infected patients gain access to ART in many resource-poor countries.

In conclusion, a high maternal CRP concentration independently predicted HIV-related outcomes in HIV-infected Tanzanian mothers and their infants. In Tanzania, the cost of a CRP test is one-fifth and one-twentieth that of a CD4 cell count and a HIV viral load, respectively. Multivariate analyses revealed that under certain conditions, CRP was even better than the high-tech assays in predicting HIV-related outcomes.

Low-tech assays for CRP, total lymphocyte counts, and haemoglobin levels may be important and inexpensive clinical decision-making tools in the healthcare of HIV-infected women and their children in resource-poor settings.

References

Draina PK et al. C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting. AIDS 21: 2067–2075,2007.