Our data demonstrates that among patients initiating therapy in RLS with (mainly) an NNRTI-based regimen, CD4 cell count recovery is impaired in the presence of on-going HIV-RNA replication over an 18-month period. We were not able to find a minimal HIV-RNA threshold below which viral replication had no impact on immunological restoration. Our analysis showed an impact of HIV-RNA replication at 12 months on the direction of the CD4 cell count slope; thresholds of 10,000 or 5,000 copies were equally predictive of the direction of the CD4 cell count slope in the adjusted analysis.
Current ART guidelines recommend changing therapy when virological failure occurs
[14–16]. The WHO latest recommendations reinforce the role of virological monitoring in informing the switching decision
, a substantial change compared to the earlier versions. We used data from a multicentre cohort collaboration capturing routine data in various RLS on three continents, in which we only included the subset of patients with regular HIV-RNA and CD4 cell count monitoring. In these patients, we confirmed that the percentage of patients with short term virological success on an NNRTI-based first-line therapy was excellent
The optimal response to low or moderate-level viremia in patients on ART in RLS has been controversial. Analyses performed in countries with regular and frequent HIV-RNA monitoring and using PI-based ARV regimens tend to suggest that the use of an HIV-RNA threshold of 5,000-10,000 copies/mL to define failure in a regimen-adherent patient with no other reasons for an elevated HIV-RNA (e.g., drug-drug interactions, poor absorption, and concurrent illness) is not associated with clinical and immunological deterioration in cohort studies
[17, 18, 22]. There are substantial differences between patients in high-income countries and patients in RLS that prevent us from generalising findings from Western cohorts. Firstly, patients starting ART in RLS have much lower CD4 cell counts at treatment initiation when compared with high-income countries
. Secondly, most first-line regimens include a combination of two nucleoside analogues (NRTI) and one NNRTI, unlike high-income countries in which half of new patients are put on a boosted protease inhibitor-based ART. Finally, one might infer that immunity is affected by numerous antigenic stimulations in countries endemic for malaria or tuberculosis
It is thus critical to accumulate data from countries where the majority of patients are now receiving ART, where the treatment switch is going to occur late and where first-line ARV combinations are different from the standard practice in high-income countries from where most clinical guidelines have been issued.
Because the WHO now recommends using targeted or sometimes routine use of HIV-RNA measurements in public-health oriented programs, much effort needs to go into making HIV-RNA determination available in RLS. However, the cut-off describing when to switch patients failing an NNRTI first-line regimen with few remaining therapeutic options has not been firmly established and depends on the objective: if the aim is to impact on HIV transmission or to prevent viral resistance
[25–28], then viral load measurement has to be widely implemented over all ART programs and the lowest threshold must be used to inform the switching decision. However, it is critical to determine whether there is a viral threshold below which the goal of maintaining a reasonable level of CD4 cells and a good clinical outcome is achievable without switching treatment.
In this large multicohort study, we observed that in patients experiencing virological failure, the impact on immune restoration was observed after the first year of ARV treatment; CD4 cell count slope one year after ART initiation was altered by any (even low-level) HIV-RNA replication, regardless of the threshold considered (5,000 or 10000 copies/mL). By contrast, all patients who had a suppressed viral load 12 months after ART commencement experienced a rise in CD4 cell counts (Table
While our study lacked the statistical power necessary to categorise what threshold would best stratify the decision for changing ART regimens, our analysis suggests that any viral replication had a deleterious impact on immune recovery in patients remaining on a failing first-line regimen.
Interestingly, patients who had residual HIV-RNA replication in the first six months on treatment, but were then virologically suppressed at M12, experienced an immune restoration with a positive CD4 cell count slope from M6 up to M18. This could suggest that routine, compared to random, viral load determination may allow for therapeutic intervention leading to successful immune restoration. Hoffmann et al. nicely showed that patients on a first line regimen in South Africa who developed viremia were successfully re-suppressed after implementing intensive adherence support
The individual risk of switching treatment late after recognition of failure in first line treatment has been controversial in resource-limited settings. Seyler et al. showed in Côte d’Ivoire that patients with a detectable viral load had an increased risk of immunological failure, but there was no difference in morbidity at 18 months between the patients who switched during early regimen failure and those who remained on a failing regimen
. In contrast, other studies have shown that delays in switching to second-line regimens resulted in increased mortality when the failing regimen was a non-protease inhibitor-based regimen
. More recently, Keiser et al. demonstrated high mortality prior to and following a switch in treatment in South Africa: the cumulative mortality at 1 year was 4.2% (95% CI 2.2-7.8%) in patients who switched to a second-line regimen, 11.7% (7.3%-18.5%) in patients who remained on a failing first-line regimen, and 2.2% (1.6-3.0%) in patients on a non-failing first-line regimen (P < 0.0001). These results suggest that there are significant consequences to delayed switching
Our analysis also confirmed some interesting determinants of the CD4 cell count slope; subjects with more extreme ages (below 30 years old or above 40 years old) had a better immune recovery when compared with the middle-age group. Additionally, the calendar year of starting ART and the stage at ART initiation were good predictors of early immunological outcome. Considering an HIV-RNA threshold of 10,000 copies/mL, which provided in our multivariate model the best prognostic value for immunological response, elevated HIV-RNA levels were always associated with impaired immune reconstitution.
We recognise several limitations in our analysis. Patients have been included in our study according to the existence of frequent HIV-RNA monitoring, but only a minority of patients fulfilled our criteria of biological monitoring. Selection bias is therefore possible, although we verified that none of the patients in our study had entered specific therapeutic trial protocols but were rather prescribed viral load testing during specific periods when this laboratory exam was available in the clinic. In addition, we were unable to detect differences between treatment regimens, as patients in RLS are generally prescribed with standard NNRTI-based first-line regimens. However, treatment homogeneity is helpful in controlling confounding factors related to different drug regimens. Finally, we could not consider clinical endpoints, as we had a very limited number of deaths in the selected patient population, possibly due to the short follow-up. For this reason, the clinical significance of the differences in CD4 slope reported in our analysis cannot be evaluated – although many cohorts from resource limited settings clearly assessed the relationship between AIDS-related events, non AIDS related events and death and CD4 cells