Recently released WHO guidelines on the use of antiretroviral therapy (ART) in adults and adolescents with HIV infection recommend that ART is commenced when the CD4+ T-cell count is less than 350/μl . This change from the previous guidelines was based on data obtained from various sources, but very little of it from studies conducted in resource-limited countries. The results of the Comprehensive International Program of Research on AIDS (CIPRA)-South Africa trial reported by Fox et al.  in this issue of the journal and the results of a similar study conducted in Haiti  now provide data that justifies these recommendations.
Fox et al.  compared the outcome of patients who commenced ART with a CD4+ T-cell count of less than 200/μl or a WHO stage IV condition with those who commenced therapy with a CD4+ T-cell count between 200 and 350/μl. Over a median time of observation of 27.5 months, patients in the former group had at least twice the risk of virological failure, death or incident tuberculosis compared with patients in the latter group.
The medical benefits of commencing ART in HIV patients from resource-limited countries who have a CD4+ T-cell count of more than 200/μl are likely to result from preventing the hazards of severe immunodeficiency. As well as increasing the risk of acquiring or reactivating infection by opportunistic pathogens, severe immunodeficiency increases the risk of immune reconstitution disorders after ART is commenced. During the first few months of ART, patients who were very immunodeficient are at greater risk of restoring an immune response against opportunistic pathogens that results in immunopathology [immune restoration disease (IRD)], which usually presents with an inflammatory illness that is commonly referred to as immune reconstitution inflammatory syndrome (IRIS) . In resource-limited settings, tuberculosis-associated IRIS (TB-IRIS) and cryptococcal meningitis IRIS are major causes of morbidity and cryptococcal meningitis IRIS results in death in up to 53% of patients . Prevention and treatment strategies that address the timing of ART after treating opportunistic infections  and therapeutic interventions to modulate the immunopathology caused by the immune response should reduce mortality resulting from IRD. However, data from studies conducted in Africa suggest that the various forms of IRIS are not the main cause of death in patients commencing ART with severe immunodeficiency.
A study conducted by Castelnuovo et al.  in Uganda demonstrated that only 5% of deaths during the first year of ART were attributable to a form of IRIS, whereas 81% were attributable to opportunistic infections or cancers. Mortality was most common in patients with baseline CD4+ T-cell counts of less than 25/μl and a smaller mean increase in CD4+ T-cell count. A study conducted in South Africa by Murdoch et al.  also demonstrated that mortality from a form of IRIS was uncommon. It, therefore, appears that immunodeficiency disease rather than IRD is the major cause of death in the first year of therapy. At present, the best strategy for preventing persistent immunodeficiency during ART is to avoid severe immunodeficiency by the early introduction of ART. This strategy should not only prevent the immune reconstitution disorders that appear to be causing early mortality in patients from resource-limited countries but also those that are causing morbidity and mortality at later times in patients from resource-rich countries. Immune reconstitution disorders in HIV patients receiving antiretroviral therapy are as follows:
1. Immune restoration disease (that usually presents as IRIS);
2. Persistent deficiency and/or dysfunction of lymphocyte subpopulations;
a. Total and naive CD4+ T cells.
b. Memory B cells.
c. Natural killer cells.
3. Clinical manifestations of persistent immunodeficiency;
a. Opportunistic infections and cancers (mainly resource-limited settings).
b. Non-AIDS defining cancers (mainly resource-rich settings).
4. Autoimmune disease, mainly Graves' disease;
5. Immune-mediated inflammatory disease, mainly sarcoidosis.
The CIPRA-South Africa and CIPRA-Haiti studies both found that commencing ART before the CD4+ T-cell count reached 200/μl was associated with a two-fold reduction in the rate of incident tuberculosis after ART. Tuberculosis, presenting shortly after ART is commenced (ART-associated TB), is a substantial problem in resource-limited countries where the incidence is about twenty times higher than in resource-rich countries . In addition, the mortality rate for ART-associated TB was shown in one study to be 3.25 times higher than mortality resulting from TB at other times . Although some cases of ART-associated TB may be immunodeficiency disease, currently available evidence suggests that many cases result from the restoration of a T-cell response against Mycobacterium tuberculosis-specific antigens , probably in a setting of high mycobacterial load and immune dysregulation. Intensive pretreatment screening before ART could identify patients at risk of ART-associated TB [11,12] but a better preventive strategy would be to avoid the severe immunodeficiency that underlies the high mycobacterial load and immune dysregulation.
2. Fox MP, Sanna IM, Conradie F, Zeinecker J, Orrell C, Ive P, et al. Initiating patients on HAART at CD4 counts above 200 decreases virologic failure, death and tuberculosis. AIDS
3. Severe P, Fitzgerald DW, the Haiti CIPRS Team. A randomized clinical trial of early versus standard antiretroviral therapy for HIV-infected patients with a CD4 T cell count of 200-350 cells/mL (CIPRAHT001).
In: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy
; September 2009; San Francisco. Abstract H-1230c.
4. French MA. Immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009; 48:101–107.
5. Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. IeDEA Southern and Central Africa. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis
6. Meintjes G, Wilkinson RJ. Optimum timing of antiretroviral therapy for HIV-infected patients with concurrent serious opportunistic infections. Clin Infect Dis 2010; 50:1539–1541.
7. Castelnuovo B, Manabe YC, Kiragga A, Kamya M, Easterbrook P, Kambugu A. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 2009; 49:965–972.
8. Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008; 22:601–610.
9. Lawn SD, Wilkinson RJ, Lipman MC, Wood R. Immune reconstitution and ‘unmasking’ of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med 2008; 177:680–685.
10. Koenig SP, Riviere C, Leger P, Joseph P, Severe P, Parker K, et al
. High mortality among patients with AIDS who received a diagnosis of tuberculosis in the first 3 months of antiretroviral therapy. Clin Infect Dis 2009; 48:829–831.
11. Elliott JH, Vohith K, Saramony S, Savuth C, Dara C, Sarim C, et al
. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis 2009; 200:1736–1745.
12. Lawn SD, Kranzer K, Edwards DJ, McNally M, Bekker LG, Wood R. Tuberculosis during the first year of antiretroviral therapy in a South African cohort using an intensive pretreatment screening strategy. AIDS