Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.
BACKGROUND
According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy (ART) is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of ART is clearly complex and must, therefore, be balanced between individual and broader public health needs.


OBJECTIVE
To assess the evidence for the optimal time to initiate ART in treatment-naive, asymptomatic, HIV-infected adults


METHODS
We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). In August 2009, we searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. We also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. We contacted researchers and relevant organizations and checked reference lists of all included studies.


METHODS
Randomized controlled trials that compared the effect of ART consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating ART at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial.


METHODS
Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, we meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs).


RESULTS
One completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. We combined the mortality data for both trials comparing initiating ART at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of ART to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting ART at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting ART early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI: 0.26, 1.12; P = 0.01). Starting ART at enrollment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One RCT found no statistically significant difference in the number of independent Grade 3 or 4 adverse events occurring in the early and standard ART groups when we conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = 0.06). However, when analyzing only participants who actually commenced ART in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02).


CONCLUSIONS
There is evidence of moderate quality that initiating ART at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. Practitioners and policy-makers may consider initiating ART at levels </= 350 cells/microL for patients who present to health services and are diagnosed with HIV early in the infection.
Siegfried
Nandi
N
South African Cochrane Centre, South African Medical Research Council, PO Box 19070, Tygerberg, South Africa, 7505.
Uthman
Olalekan A
OA
Rutherford
George W
GW
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D006801:Humans; D013997:Time Factors
D019380:Anti-HIV Agents