There is considerable variability in the magnitude and rate of CD4 T cell count recovery in Human immunodeficiency virus type 1 (HIV-1)-infected individuals, receiving antiretroviral therapy (ART). Most patients show a progressive rise in CD4 T cell counts after initiation of ART 12, however, some patients fail to attain CD4 counts that exceed 200 cells/μl, and thus remain profoundly immune suppressed despite suppression of HIV-1 viral replication. The frequency of suboptimal immunological response to ART despite viral suppression varies between 7–20% 34567 depending on the duration of ART and definition of SO-CD4 (see Table 1). There is limited data on the frequency of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in sub-Saharan Africa (SSA) where most patients initiate ART at advanced stages of HIV/AIDS 189 amidst a high background risk acute infections. Moreover, there are conflicting reports about the correlation of SO-CD4 with clinical morbidity and susceptibility to opportunistic infections 4510. We hypothesize that patients with SO-CD4 are at increased risk of clinical events (death and/or recurrent or new AIDS-defining illnesses). In this study, we determined the frequency, predictors and clinical significance of SO-CD4 reconstitution as evidenced by of occurrence of acquired immunodeficiency syndrome (AIDS)-related clinical events (recurrent or new opportunistic infection and/or death).

In this population with good rates of viral suppression as was previously reported 12, the frequency of SO-CD4, using the CD4 increase criteria, was 21%, 45% and 54% at 6,12 and 24 months respectively. Our findings are comparable to results from other developing countries (Africa, Latin America and Asia) where 19% of patients had SO-CD4 using a similar criteria of a CD4 increase of < 50 cells/μl after 6 months of ART 6. Similarly, the frequency of SO-CD4 at 6 and 12 months is comparable to what has been reported in industrialized countries that used similar criteria 41113. Overall, our results show similar profiles of CD4 reconstitution in both the developing and industrialized countries despite the challenges with infrastructure for care delivery in sub-Saharan Africa.

We found that patients with baseline CD4 counts of 50–199 cells/μl were about 3 times more likely to have SO-CD4 than those with baseline CD4 counts of 0–49 cells/μl. Our results are similar to reports from South Africa where patients in the lower CD4 stratum had a higher gradient of CD4 increase 5. This is contrary to previous reports that advanced pre-treatment immunodeficiency is associated with diminished capacity to restore quantitative and functional CD4 T cell responses during antiretroviral therapy 1415. We attribute our results to the peripheral expansion and/or redistribution of CD4 T cells that is described in the initial phase of CD4 reconstitution on ART 16. Our results imply that the CD4 increase criteria of SO-CD4 is not enough in a setting where patients present to hospitals and HIV care units with untreated advanced HIV disease 117. In addition, we used a threshold of 200 cells/μl below which patients were classified as SO-CD4 since this gives an indication of the general susceptibility to opportunistic infections. Using the CD4 threshold criteria, we found that 43%, 42% and 19% had SO-CD4 at 6, 12 and 24 months respectively; thereby remaining at risk of opportunistic infections.

Patients that initiated therapy with a zidovudine-containing regimen were 3.6 times more likely to develop SO-CD4 than patients on a d4T-containing regimen and we attribute this to the myelosuppressive effects of zidovudine 18. We interpret these results cautiously because only 26% of our patients initiated a zidovudine-containing regimen and they were not randomized. However, evidence in the US shows that use of a protease inhibitor (PI)-based regimen is protective against poor immune reconstitution 619 because PIs modulate activation of peripheral blood CD4 T cells and decrease their susceptibility to apoptosis 20. Since the long term prognosis of patients exhibiting discordant responses remains unknown 3, we need to explore the use of the newer and less toxic first line regimens 21 for patients at risk of SO-CD4.

Age was not a significant predictor of SO-CD 4 in our study and this is consistent with what was reported in a US cohort 22. However, some previous studies showed that age above 30 years was associated with SO-CD4 511 because it correlated with thymic involution yet preserved thymic function is necessary for adequate CD4 T cell recovery 1123. Similarly, hepatitis B co-infection did not predict SO-CD4 as was recently reported that hepatitis B co-infection had no impact on the response to ART regarding viral suppression and immune recovery24.

Majority of the patients with SO-CD4 after 6 months, using either of the criteria, still had SO-CD4 at 12 months despite sustained HIV-RNA viral suppression. Since patients with SO-CD4 at 6 months are likely to maintain the phenomenon, they may need evaluation of the recovery of CD4 cell function, more so in Africa where there is an increased background risk of opportunistic infections. It is possible that the CD4 cells do not recover both in absolute numbers and function because of the high levels of T-cell activation in Africans due to frequent infections by the various pathogens endemic in the region 102526.

It is also likely that these patients may require extended periods of prophylaxis against opportunistic infections. Our analysis was however limited to recovery of peripheral CD4 T cell counts and not CD4 T cell function. We recommend studies to examine other markers of recovery of immunological function among patients with SO-CD4.

We found that about a third of the opportunistic infections occurred among patients with SO-CD4 reconstitution as defined by either the CD4 increase or the threshold criteria. Similar to what has been reported in other cohorts, most of the AIDS-related events occurred in the first 6 months 272829 and the spectrum of opportunistic infections was similar to what was found among patients at Mulago hospital where most patients with advanced HIV disease were hospitalized with severe bacterial pneumonias and tuberculosis 17. More AIDS-related events were recorded among patients without SO-CD4 and we postulate that immune reconstitution inflammatory syndrome (IRIS) contributed to this difference 9. However, Kaplan-Meier analysis showed no statistically significant differences in the rates of AIDS-related clinical events among patients with and without SO-CD4 in the setting of HIV-RNA viral suppression. On the contrary, in industrialized countries, patients with SO-CD4 (using similar criteria) have previously been reported to have a higher risk of developing an AIDS-related clinical events 430. In the Swiss cohort, suboptimal responders had a 1.5 fold higher incidence of opportunistic infections than the complete CD4 responders 14. However, we are cautious to compare our results with the latter cohort because the authors used a CD4 threshold below 500 cells/μl after 5 years of ART to define SO-CD4 at a frequency of 35.8%. We need to consider SO-CD4 after longer periods of follow up like has been done in the industrialized countries. Our results add to the emphasis that viral load testing is required for monitoring patients on ART in resource limited settings 31 especially those patients that present with unsatisfactory CD4 reconstitution in order to guide treatment decisions for this subgroup of patients.

The findings in this study are strengthened by the relatively homogenous study population of ART-naive individuals receiving ART at a single facility using standardized clinical protocols. Our patients used NNRTI-based ART regimen that are used in most HIV care facilities in Africa so our results can be generalized to most patients in Africa however they are limited to patients with sustained HIV-RNA viral suppression which, among others, is the ultimate goal of ART. We need to design studies of interventions for patients on ART with poor immune reconstitution and minimize the time spent with CD4 counts below the 200 cells/μl critical threshold. It is important to note that adherence to ART and previous exposure to ART were not considered to contribute to SO-CD4 in our study since all patients were naïve to ART and patients were included in the analysis only if they had HIV-RNA viral load < 400 copies/ml which we used as a proxy for good adherence.

The frequency of SO-CD4 is high in SSA and many of the patients with SO-CD4 at 6 months maintain the phenomenon up to 2 years of therapy. However, the rates of AIDS-related clinical events were no higher in those with SO-CD4. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.

The authors declare that they have no competing interests.

DN conceived of the study, and participated in the design, data analysis, interpretation of data, drafting and revising the paper. AK participated in the study design and statistical analysis. FI participated in the statistical analysis. BC participated in the acquisition of data, coordination of the study and in revising the paper. MRK made substantial contribution to the conception, design and coordination of the study. PJE made substantial contribution study design, statistical analysis and revision of the paper. All authors read and approved the final manuscript.