Death rates elevated at all CD4 counts below 500 in sub-Saharan Africa

A comparison of death rates between the HIV-positive and HIV-negative partners in serodiscordant couples in sub-Saharan Africa has found significantly higher death rates in people with HIV with CD4 counts below 500, suggesting that expanding treatment beyond eligibility thresholds of 200-250 would have a substantial impact on mortality.

The findings come from an analysis of survival, in couples recruited into the Partners in Prevention study of aciclovir secondary prophylaxis in HIV/HSV-2 co-infected people in order to prevent HIV transmission to their HIV-negative regular partner.

Current World Health Organization guidelines recommend that antiretroviral treatment should be provided to all people with HIV who have CD4 cell counts below 350, although this recommendation has not been adopted in all low- and middle-income countries.

Since these guidelines were issued in 2010, the HPTN 052 study of early antiretroviral treatment for prevention of HIV transmission in serodiscordant couples has demonstrated a significant reduction in the risk of severe bacterial infections, WHO stage IV clinical events, tuberculosis or death. However data presented at two successive international conferences have shown that this reduction is attributable to a reduction in extrapulmonary TB cases and is not evident across other categories.

Other data to inform guidelines are needed, so the trial investigators carried out an analysis of mortality by CD4 count stratum and viral load in the Partners in Prevention study population. In particular, investigators wished to determine whether people with HIV were at increased risk of death at higher CD4 cell counts when compared to their HIV-negative partners, who lived in the same household or neighbourhood and might be exposed to the same environmental factors for disease, the same diet and the same access to health care.

The analysis looked at death rates in 3295 serodiscordant couples in seven sub-Saharan African countries, followed for a median of 20 months. Participants with HIV had a baseline CD4 cell count of 250 or above and participants already diagnosed with an AIDS-defining illness were excluded from the study. Antiretroviral therapy was provided during the study according to local criteria.

The median CD4 count of partners with HIV at enrolment was 426 in men and 481 in women; by the final visit the median CD4 count had declined to 394 in men and 437 in women, and approximately one-quarter had some HIV-related symptoms during the follow-up period (approximately ten per cent started antietroviral therapy during the study).

One hundred and nine deaths were recorded, 74 in people with HIV and 25 among uninfected persons. Information on causes of death is limited due to incomplete reporting and should be treated with caution, but people with HIV infection were more likely to die of pneumonia, gastrointestinal or other infections (including malaria).

Excess deaths in the partners with HIV were most frequent in those with CD4 cell counts below 250 (29.3 per thousand person-years of follow-up) but were significantly higher in all CD4 cell count strata below 500 when compared to HIV-negative partners.

Univariate Cox regression analysis showed a significantly higher rate of death in partners with HIV with CD4 cell counts in the 350-499 range (HR 2.7, 95% confidence interval 1.2-5.6, p = 0.013) but multivariate analysis which controlled for CD4 cell count, viral load above 100,000 copies/ml, antiretroviral use and WHO HIV disease stage showed an elevated hazard ratio of borderline significance (aHR 2.2, 95% CI 1.0-4.9, p = 0.053).

But after adjustment for antiretroviral therapy use, the rate of excess mortality per thousand person-years was highly significant in this CD4 stratum (8.9 per 1000 person-years, compared to 15.2 in the 250-349 stratum and 29.3 in the <250 stratum) (all p < 0.001).

Viral load above 100,000 copies/ml was also associated with a significantly higher rate of excess deaths (43 per thousand person-years, p < 0.001).

The authors also calculated the number of people who would need to be treated with antiretroviral therapy in order to prevent one death, a measure which can give some indication of the resources that need to be utilised in order to achieve a desired outcome, in this case the prevention of deaths.

One hundred and thirteen people with CD4 counts in the 350-499 range would need to be treated for a follow-up period of 20 months to prevent one death, compared with 66 people in the CD4 range 250-349 and 34 people with CD4 counts below 250.

However, this analysis only looks at the benefit of treatment to the persons treated, and not at the potential effect of treatment on onward transmission.

The authors conclude that their data “support increasing the CD4 threshold for treatment initiation, together with expanding HIV testing for asymptomatic persons in the community.”

De Bruyn G et al. Mortality in members of HIV-1 serodiscordant couples in Africa and implications for antiretroviral therapy initiation: Results of analyses from a multicenter randomized trial. BMC Infectious Diseases 12: 277, 2012. (View the full-text article here).