Immune recovery has often been regarded as a secondary aim of antiretroviral treatment, with a much stronger emphasis being given to controlling viral load. Yet much research indicates that increases in CD4 cell counts and improvements in other parameters of immune function are closely associated with improved health and fewer opportunistic illnesses among people with HIV, regardless of viral load.

A treatment strategy aimed at improving or maintaining immune function and health may be particularly appropriate for individuals who have taken several antiretroviral combinations and are unlikely to achieve undetectable viral load with the current anti-HIV drug options. Several studies have reported that people with detectable viral load on treatment can sustain immune recovery and associated health benefits with antiretroviral therapy despite detectable viral load. For heavily pretreated individuals, partial viral suppression and immune recovery may be the key aim of antiretroviral therapy. A United States study, for example, has shown that individuals with detectable viral load below 20,000 copies/ml have a comparable risk of disease progression to individuals with viral load below 400 copies/ml over a median of 2.4 years (6 vs. 7%; Raffanti 2003).

Several years ago, this strategy would have been considered highly controversial. However, in early 2001, this approach gained legitimacy when leading HIV researcher and physician Dr Steve Deeks published an editorial in the journal AIDS in which he argued that the clinical benefits of undetectable viral load among the highly treatment-experienced were unproven, and that multi-drug combinations required to suppress HIV in these patients have been associated with toxicity and poor adherence.

Immune recovery persists in presence of viral rebound

Subsequently Deeks reported substantial evidence to support the view that for patients who have experienced failure of multiple regimens, treatment continues to provide benefit even when it is not possible to assemble a new regimen that can control viral load below 50 copies/ml (Deeks 2002).

The study, of 483 patients who began receiving protease inhibitor therapy at San Francisco General Hospital before 1998, showed that in those who experienced failure of the regimen, immune system improvements on therapy persisted for a median of three years.

The study also found that the viral load reduction that occurred was a significant predictor of immunologic failure, defined as a CD4 cell count decline to pre-treatment levels. Those who experienced a viral load reduction of less than 1.13log₁₀ after starting the regimen were significantly more likely to experience immunologic failure when compared to those who had experienced a viral load reduction of at least 1.68log₁₀. Those with viral load above 31,000 copies/ml after treatment failure were at significantly higher risk of immunologic failure than those with viral load below 1000 copies/ml.

Another study, of the Swiss HIV Cohort, shows a similar pattern. Ninety-eight patients with extensive prior antiretroviral therapy who commenced protease inhibitor treatment during 1997 were assessed. Sixty-six percent did not maintain suppression below 500 copies/ml. There was no significant difference in the CD4 cell count response after 48 weeks in people who had a durable or a transient virological response to treatment, with increases of 130 and 138 cells/mm³ increases respectively. In those with persistently detectable viral loads, there was an average CD4 cell count increase of 105 cells/mm³ after 48 weeks. For those with lengthy periods off treatment (ranging from 36 to 75 days) there was nevertheless a CD4 cell count improvement of 57 cells/mm³ above baseline. However, it was observed that CD4 cell counts fell when treatment was withdrawn. The investigators suggested that highly active antiretroviral therapy (HAART) may have an effect on CD4 cell counts despite ongoing viral replication because the mutant viruses which emerge are less fit and less destructive than wild-type HIV (Kaufmann 1998).

A larger report on the Swiss HIV Cohort, a study of 2674 people who received HAART for a mean of 16 months, has found no significant difference in the rate of disease progression between those who sustained undetectable viral load (less than 400 copies/ml) and those who experienced viral load rebound after an initial period of undetectable viral load (Ledergerber 1999).

Similar research was presented by the Frankfurt Cohort team. Amongst over 1500 participants in this study who were not taking protease inhibitors, higher viral load was associated with disease progression and death. Amongst people who were taking protease inhibitors, however, higher viral load was not associated with disease progression or death. CD4 cell count was predictive of both disease progression and death in this group. While the reasons for this non-concordant CD4 cell count and viral load response to PIs are not fully understood, this study provides further evidence that antiretroviral therapy can provide clinical benefit despite drug failure and viral rebound (Miller 2000).

Summary

These studies suggest that keeping viral load below the limit of detection is not essential for immune restoration. In fact, some people achieve some degree of response to therapy without ever achieving a viral load below 400 copies/ml. These people may develop resistance to the drugs they are taking, but there still appears to be some benefit to therapy. This approach is of particular use in patients who are heavily drug experienced and who require salvage therapy.

There is increasing interest in treatment strategies which can preserve particular resistance patterns which reduce replicative capacity, since this is thought to limit viral load rebound and thus preserve CD4 cell counts. See Anti-HIV therapy: Resistance, Viral fitness, drug resistance and the immune system and Discordant CD4 cell count and viral load responses in Anti-HIV therapy: Restoring the immune system for more information on this subject. Further information on salvage therapy is found in Choosing a salvage regimen in Anti-HIV therapy: Changing treatment.

References

Deeks SG. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 181: 946-953, 2000.

Deeks SG and Martin JN. Reassessing the goal of antiretroviral therapy in the heavily pre-treated HIV-infected patients - editorial comment. AIDS 15: 117-119, 2001.

Deeks SG et al. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 16: 201-207, 2002.

Kaufmann D et al. CD4-cell count in HIV-1 infected individuals remaining viraemic with highly active anti-retroviral therapy (HAART). Lancet 351: 723-724, 1998.

Ledergerber B et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 353: 862-869, 1999.

Miller V et al. The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load. AIDS 14: 2129-2136, 2000.

Nijhuis M et al. Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy. Proc Natl Acad Sci 95: 14441-14446, 1998.

Raffanti SR et al. Moderate viremia and HIV disease progression. Second International AIDS Society Conference on HIV Treatment and Pathogenesis, Paris, abstract LB35, 2003.