in resource - rich settings , treatment guidelines are consistent in recommending the immediate initiation of combination antiretroviral therapy ( cart ) in all hiv - positive individuals with a cd4 count of less than 350 cells / mm ; in this group , the benefits of cart clearly outweigh its disadvantages . however , there is inconsistency between the guideline committees as to whether asymptomatic individuals with cd4 counts equal to or greater than 350 cells / mm should begin cart . for example , whilst the 2009 us department of health and human services guidelines   and the international aids society - usa   panel recommend treatment for all patients with a cd4 count of 350 - 500 cells / mm , neither the european aids clinical society   nor the british hiv association   recommends treatment at this level unless specific comorbidities are present . this inconsistency largely results from the limited evidence base ; as only limited data are available from randomized trials on the benefits or risks of earlier cart , guideline committees have based their recommendations on evidence from observational studies and expert clinical opinion . until recently , the main arguments for delaying cart related to the toxicities and inconvenience of the drugs , as well as the concern that patients would be unable to maintain the high levels of adherence necessary to ensure sustained virological suppression . little was felt to be gained from initiating cart in individuals with cd4 counts of greater than 350 cells / mm in whom the risk of aids and consequent mortality was low . however , antiretroviral drugs are now more potent , have fewer toxicities , and are more forgiving to lapses in adherence . furthermore , death rates in hiv - positive individuals remain elevated compared to those in the general population   and it is believed that hiv may play a role in the development of several serious non - aids conditions [ 8 - 10 ] . thus , cart may have a greater positive impact on the health of hiv - positive individuals than anticipated , which may now justify its earlier use . this review briefly summarises the latest evidence on the topic ; recent reviews discuss some of the issues in more detail . however , an individual who is not diagnosed with hiv until his / her cd4 count has fallen to a low level could not have received treatment at a higher cd4 count ( as s / he had not been diagnosed ) but must have survived long enough to be diagnosed at the lower cd4 count . failure to take account of this lead - time may result in biased estimates of the benefits of early treatment . conclusions from early studies that used appropriate methodology to remove the effect of lead - time bias were inconsistent regarding the initiation of cart at a cd4 count of greater than 350 cells / mm . however , these studies were relatively small , and the methods may not have been optimal . investigators from the north american aids cohort collaboration on research and design ( na - accord ) study   identified individuals who had experienced a cd4 count of either 351 - 500 cells / mm or greater than 500 cells / mm ; these groups were then divided again into those who initiated cart immediately and those who deferred its use . the authors used inverse probability weighting methods to control for biases resulting from informative censoring ( which may arise if patients who dropped out of the analysis at any stage had different characteristics to those who did not ) and known confounders . of the 67,527 patients in the study , 8362 had a cd4 count of 351 - 500 cells / mm ( 2084 initiated cart immediately ) and 9155 a cd4 count of greater than 500 cells / mm ( 2220 initiated cart immediately ) . death rates were increased by 69% and 94% , respectively , among those who deferred therapy in each group compared to those who started cart immediately . investigators from the when to start consortium   considered progression to aids and/or death in 24,444 antiretroviral - naive individuals starting cart . using information from 21,247 patients followed in the pre - cart era , the authors estimated the distribution of lead - times , which was then incorporated into the analysis . deferred initiation of cart was generally associated with more rapid progression rates than immediate initiation , although the difference was not statistically significant at cd4 counts of greater than 350 cells / mm . directly estimated the optimal cd4 count at which to initiate cart . using a similar method to the na - accord group , they concluded that the optimal cd4 count depended on whether the ultimate aim of cart was to improve the patient 's health ( defined by an increase in the cd4 count or reduction in the occurrence of new aids events or death ) , in which case the threshold was between 489 and 554 cells / mm , or to improve quality - of - life , in which case the threshold was between 337 and 475 cells / mm . most recently , jonsson funk et al .   presented data from the cascade collaboration   suggesting that whilst the initiation of cart at a cd4 count of 350 - 500 cells / mm may reduce the risk of clinical progression , the low absolute risk of progression meant that 34 patients would need to be treated to prevent one new case of aids or death ( or 71 patients for death only ) over a three - year period . as an alternative approach , estimated that initiation of cart at a cd4 count of greater than 350 cells / mm would result in longer quality - adjusted survival compared to starting cart at lower cd4 counts . .   demonstrated that treatment at a cd4 count of 500 cells / mm resulted in gains in quality - adjusted life - years at all ages , even assuming that patients may not be fully adherent to cart . the validity of results from modelling studies does , however , rely strongly on the assumption that the model accurately describes disease progression . whilst the accruing evidence would suggest that earlier initiation of cart may be beneficial , one limitation of all observational studies is that of unmeasured confounding . under most treatment guidelines , few patients initiate cart at high cd4 counts and those who do may differ from those who do not in terms of their likely long - term outcomes , regardless of cart use . it is unlikely that any observational study will be able to fully control for these differences . even if shown to be beneficial , the full at least one randomised trial of earlier versus deferred cart is underway   and it would be prudent to wait for the results of this before changing guidelines . finally , whilst the decision to initiate cart is predominantly based on an individual 's cd4 count , other biomarkers [ 25 - 27 ] may also provide information about an individual 's risk of clinical events ; incorporation of these biomarkers into the decision - making process may further optimise the timing of cart in individual patients . the author reports that several colleagues are actively involved in the design and management of the strategic timing of antiretroviral treatment ( start ) trial .
recommendations for the initiation of combination antiretroviral therapy in hiv - positive individuals are largely based on data from observational studies . whilst all guidelines recommend immediate treatment in individuals with a cd4 count of less than 350 cells / mm3 , guidelines vary in their recommendations for treatment at higher cd4 counts . 
 several large cohort studies have published findings that contribute to the debate , although conclusions vary and results from these studies may be subject to bias .