While viral load decreases and CD4 cell increases typically occur together after starting antiretroviral therapy, this does not always happen. Some people who achieve full suppression of HIV do not see much improvement in their CD4 cell counts, whilst others experience good CD4 cell recovery despite continued detectable HIV replication. These so-called ‘discordant’ responses tend to occur more often in highly treatment-experienced patients with drug-resistant HIV.

Studies in industrialised countries have shown that discordant response to therapy occurs in 20% to 40% of treated patients, with isolated immunological response being slightly more common than isolated virological response ^[1]. A recent study of more than 3000 patients receiving HAART in low-income countries in Africa, Latin America and Asia found that the frequency and risk factors for discordant response were similar to those in more developed countries ^[2].

A rising CD4 count indicates improved immune function even in the absence of full HIV suppression. Thus, people on ‘failing’ treatment that does not suppress viral load below 50 copies/ml still may experience reduced risk of opportunistic infections, improved overall health and prolonged survival. In the Frankfurt Cohort, for example, higher viral load was not associated with disease progression or death among patients taking protease inhibitors who achieved good CD4 cell increases^[3].

Conversely, other people on HAART experience good virological suppression without a substantial increase in CD4 cells.^[4] This tends to occur more often among people with advanced immune suppression and highly treatment-experienced people with extensive drug resistance

A retrospective review of more than 1000 patients at Chelsea and Westminster Hospital in London found that after one year on HAART, 16% did not achieve CD4 cell increases of more than 50 cells/mm³ despite viral load suppression, although about half of these did so after a further year of treatment ^[5]. Among more than 1200 individuals in the UK Collaborative HIV Cohort (CHIC) who achieved an undetectable viral load four to eight months after starting HAART, 41% did not experience at least a 100 cells/mm³ rise during this period, but the proportion gradually fell with more time on therapy.^[6]

Minimal CD4 cell increases might not be a problem for patients who start treatment early, when their CD4 cell counts are still close to normal levels and do not have much room for improvement. But persistently low CD4 cell counts are associated with HIV disease progression and death, even in people with viral load suppression.

A recent Canadian study of 300 treatment-naive patients starting therapyl with a median CD4 cell count of 80 cells/mm³, for example, found that about one-third failed to attain CD4 counts of 200 cells/mm³ or higher after one year, despite viral load suppression. These individuals were more likely to experience disease progression, having a 10% risk of AIDS-related clinical events^[7].

In summary, while viral load below 50 copies/ml may be optimal for avoiding disease progression, patients can still derive substantial immune recovery with a lesser degree of viral suppression, at least in the short term. This is an important consideration for highly treatment-experienced patients, who may be unable to achieve an undetectable viral load using current anti-HIV drugs. Discordant immunological and virological responses may not persist over the long term, however, as CD4 cell counts tend to eventually rise in people with viral load suppression and fall in those with ongoing HIV replication.