HIV infection progresses to AIDS disease as the virus replicates in cells of the immune system (CD4 cells), destroying a patient's immune defence and allowing opportunistic infections to take hold. ART works by preventing viral replication.
The decision of when to start ART is generally made according to clinical or immunological criteria. Clinical decisions are based on the presence of one or more severe opportunistic infections, categorised by the World Health Organisation (WHO) as stage III and IV AIDS-defining illnesses. Developed and developing country guidelines all recommend starting ART if a patient presents with a stage III or IV infection, though decisions based on such clinical criteria alone are generally only used in resource-limited settings where laboratory capacity is limited. More commonly, the decision to start ART is based on immunological criteria, as defined by the level of CD4 cells.
Until recently, the level of CD4 indicating ART differed between developed and developing countries. European and US guidelines recommend ART initiation at a CD4 cell threshold of 350 cells/μL (moderate immunodeficiency). A policy of deffered initiation (200 cells/μL) was originally based on concerns related to the accumulative risks of toxicity and drug resistance [7
]. Such concerns have diminished in recent years as newer medicines have become available with fewer toxicities and better potency (reducing the chance of resistance development). The availability of these newer medicines, together with studies that have increased the understanding of the risks of developing life-threatening illnesses over time if ART is initiated at a low CD4 count, have shifted the risk-benefit equation [7
]. Recent evidence from European cohorts showed that starting ART earlier (at least 350 cells/μL) results in significant survival gains [8
Guidelines for developing countries have recently been revised in line with developed world recommendations. Treatment guidelines issued by the International AIDS Society in August 2008 state that "the core principle underlying these guidelines, namely pathogenesis-directed therapy with regimens designed to achieve full virologic suppression with minimal toxicity and maximal simplicity, is applicable to the developing world" [9
], and the latest WHO antiretroviral treatment guidelines for resource-limited settings released at the end of 2009 recommend a move towards earlier initiation at CD4 count <350 cells/μL [10
However, these recommendations have for the most part yet to be translated into country-level policy, and most national guidelines in developing countries continue to recommend "deferred" ART initiation at CD4 <200 cells/μL (severe immunodeficiency). The main concern for developing countries is that providing treatment earlier, for longer, would increase overall drug expenditure costs [11
]. In addition, other significant health systems costs are associated with ART provision to large numbers of people when there are already too few doctors and hospitals are saturated [12
]. Finally, given that most people present at ART services with an even lower CD4 count of around 100 cells/μL [13
], the issue of early initiation has been argued to be a moot point. These issues have led some to voice concern that earlier initiation "may end up doing more harm than good" by weakening already strained ART programmes [14