Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count, found a University College London study.
Initiating, rather than deferring, antiretroviral therapy (ART) reduces the risk of severe bacterial infections in HIV-positive individuals with high CD4 counts, researchers say. Their data are from the START trial, which showed a 57% reduction in the risk of Aids and non-Aids morbidity and mortality in participants with CD4 cell counts >500/uL who received ART immediately upon receiving an HIV diagnosis, rather than deferring treatment.
For the current study, Dr Andrew Phillips of University College London Royal Free Campus, UK and colleagues assessed time from HIV diagnosis to a severe bacterial infection (pneumonia, pulmonary or extra-pulmonary tuberculosis or another serious bacterial infectious disorder) that led to an unscheduled hospital admission or death.
Participants enrolled in the study from 2009 to 2013 and were followed for a median 2.8 years. Data were analysed in 2015.
As reported, 120 individuals (out of the original 4,685 trial participants) had severe bacterial infections: 34 in the “immediate” group and 86 in the “deferred” group.
Compared with delayed ART, immediate ART was associated with a reduced risk of severe bacterial infection (hazard ratio, 0.39). The average neutrophil count during follow-up was 321 cells/uL higher, and the average CD4 cell count was 194/uL higher, with immediate ART (p<0.0001).
Further analyses showed that a higher time-updated CD4 cell count was associated with a reduced risk of severe bacterial infection (HR 0.78, p=0.0001), whereas a time-updated neutrophil count was not associated with severe bacterial infection.
After adjustment for time-updated factors, particularly the CD4 cell count, the HR for the immediate group moved closer to 1 (HR 0.84, p=0.52). Results were similar when subgroups of severe bacterial infection were analysed separately (for example, six individuals in the immediate group had pulmonary tuberculosis versus 17 in the deferred group; one in the immediate group had cellulitis versus four in the deferred group).
Summing up, Phillips is quoted as saying: “These newly published findings from the START trial show that ART has a protective effect in reducing the risk of severe bacterial infections, including infections that are not Aids-defining, and even in people with high CD4 cell counts.”
“This is in agreement with the Temprano trial results and emphasises just how wide are the health benefits of early diagnosis and ART initiation in people with HIV,” he said. “It is important that people follow widely available online advice on HIV testing,” he added.
Dr. Mark Cayabyab of the department of immunology and infectious diseases at Forsyth Institute in Cambridge, Massachusetts is quoted in the report as saying: “The START study clearly shows that immediate treatment of HIV-infected patients with ART reduces the risk of potentially deadly bacterial infections, including tuberculosis, (and) that immediate treatment with ART benefits HIV patients with high CD4 counts.”
Cayabyab concluded, “Results from this study change current thinking and public health policy and argue for the ART treatment of HIV-positive individuals immediately after being diagnosed with HIV in economically developed and underdeveloped countries.”
Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline-ViiV Healthcare, Janssen Scientific Affairs, and Merck.
Phillips and two co-authors receive fees from one or more of these companies and others.
Background: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial.
Methods: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048.
Findings: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26–0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71–0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50–1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately.
Interpretation: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.
Jemma O’Connor, Michael J Vjecha, Andrew N Phillips, Brian Angus, David Cooper,
Beatriz Grinsztejn, Gustavo Lopardo, Satyajit Das, Robin Wood, Aimee Wilkin, Hartwig Klinker, Pacharee Kantipong, Karin L Klingman, David Jilich, Elbushra Herieka, Eileen Denning, Ibrahim Abubakar, Fred Gordin, Jens De Lundgren