This study combined data from 27 centers from resource-limited settings in Africa, Latin America, and Asia to assess CD4 trajectories after ART initiation at sites engaged in the scale-up of HIV care and treatment. The data demonstrate robust CD4 responses to ART that are sustained over several years. Our results are thus encouraging regarding the long-term effectiveness of ART in resource-limited settings, but they naturally are only applicable to those who are able to remain on ART for extended periods.
The availability of information on CD4 count in and of itself was likely a critical factor in getting many patients on to ART earlier than they otherwise would have in these programs. Were the programs to rely solely on clinical staging criteria, 77% of patients with less advanced clinical stage had CD4 counts<200 cells/μL, suggesting that they would have started therapy even later or not in time, limiting the full potential to benefit from therapy. Thus, extending access to CD4 testing in programs that don't currently have it would likely improve treatment outcomes substantially.
Apart from the amount of time on ART, the single most important factor determining CD4 trajectories and the maximum CD4 count reached was the baseline CD4 count. Patients with higher CD4 counts at ART initiation achieved a higher CD4 count in the following months and years. While this has been shown by other investigators in both resource-rich12, 20, 45
and resource-limited settings,28, 46
the importance of this observation cannot be overstated. The baseline CD4 count, second only to subsequent medication adherence (which we could not measure), is the most important predictor of clinical progression and survival after ART initiation.7, 22, 23, 30, 47-49
Patients with lower baseline CD4 count remain at risk for opportunistic infections for a substantially longer period than patients starting ART at higher CD4 counts, increasing their risk for serious morbidity and death. In this analysis 35% of patients had a baseline CD4 count below 100 cells/μL, and 29% had a count between 100 and 199 cells/μL. Fortunately, a recent analysis of the ART-LINC database indicated that median CD4 counts at the start of ART, while still low in most of the cohorts, have increased in recent years.50
However, our models predictions suggest that, after several years of therapy, only those few patients initiating ART at 200 cells/μL or higher could be expected to achieve CD4 counts near or above 500 cells/ μL or higher (), the level at which their risk of mortality may diminish to that observed in the general population in some settings.24
While most patients quickly achieved CD4 counts above the important clinical milestone of 200 cells/μL, we also note that there remains increased risk of morbidity and mortality at CD4 counts of 200 cells/μL, especially in developing countries.24
In our study of survival in these cohorts, we showed that the risk of mortality continues to diminish with increasing CD4 count, even among patients with CD4 counts above 200 cells/μL.39
For example, relative to those patients with baseline CD4 counts below 25 cells/μL, we found an RR of 0.67 in patients with baseline CD4 count between 100-200 cells/μL, 0.44 in patients with baseline CD4 between 200 and 349 cells/μL, and 0.26 in patients with baseline CD4 counts above 350 cells/μL. Additionally, in one study of South African patients on ART for 3 or more years, the risk of incident TB was still 5-10 times higher than in the general population.51
Finally, the SMART study recently reported a higher incidence of OIs in those patients who interrupted therapy, almost all of whom had CD4 counts>200 cells/μL.52
Our findings on long-term CD4 response appear to be consistent with those of other long-term investigations in Switzerland12
, the US2
, and the Netherlands17
, which examined immunologic response up to 4, 6, and 7 years after ART initiation, respectively. However, these studies were restricted to continuously treated, virologically suppressed patients, making a comparison with our patients difficult. Other factors may further confound this comparison, such as lower in CD4 counts in the general populations in developing versus developed countries, which could be due to other differences such as the prevalence of TB or helminth co-infections. Nonetheless, an important next step, therefore, is to conduct more direct comparisons of CD4 response between developed and developing countries within strata of baseline CD4 while controlling for other differences between the patient populations.
An intriguing finding in our investigation and others is the differences in trajectories by sex in crude analyses. We have previously reported sex differences in the CD4 count at ART initiation.53
In the present study, females had higher baseline CD4 counts in 25 of the 27 cohorts included in the analysis. Similar to other investigators who have reported sex differences in CD4 response after ART initiation in Spain54
, we found that differences in CD4 trajectories after starting ART were largely explained by different CD4 counts at baseline.
Given that baseline CD4 count is such an important determinant of CD4 trajectories after ART initiation, it is important to gain a better understanding of the determinants of baseline CD4 count among patients initiating ART in resource-limited settings. These determinants operate at multiple levels, starting with knowledge of being at risk for HIV infection, access to and uptake of HIV testing and counseling, intensity of active screening for HIV in the health care setting, entry points in to care, availability of CD4 testing, and, among programs providing pre-ART care, frequency and intensity of clinical monitoring and CD4 testing. Some of these factors are more easily modifiable than others. A recent investigation in the Netherlands suggested that entry into care with low CD4 counts explained a substantial portion of the variation in mortality rates across HIV care and treatment centers.55
Clearly, further studies are needed to help inform efforts aimed at getting patients on to ART at higher CD4 counts.
Most national care and treatment programs have adapted the WHO criteria for ART eligibility. Updated in 2006, they recommend initiating ART in i) patients in WHO stage 4; ii) all patients with CD4 counts below 200 cells/μL (irrespective of WHO stage), and iii) in patients with WHO stage 2/3 and CD4 counts below 350 cells/μL.56
In our analysis, only 6% of patients were eligible based on having less advanced disease with CD4 counts between 200 and 350 cells/μL. In other words, 94% of patients who initiated ART at ART-LINC sites were in the advanced clinical and immunologic stages by the time they initiated treatment. Our analysis clearly suggests that there is substantial room for improvement in earlier initiation of ART across a diversity of geographic settings.
Our study has several strengths. Twenty-seven sites on three continents were represented in the analysis, and the overall finding (substantial improvements in CD4 counts after ART initiation) was consistent across the diversity of geographical settings and contexts. Our results should thus be applicable to a wide range of lower-income settings. In addition, this investigation benefited from a large amount of follow-up time (up to 5 years for some patients). While the numbers of patients remaining in follow-up decreased substantially with time since start of ART, there were still 820 patients from 8 clinics who were actively followed up in the fifth year. These findings are thus encouraging for patients, providers, and program implementers involved in the scale-up of HIV care and treatment service delivery in some of the most affected areas of the world.
Our study also has limitations. We had to exclude a substantial number of patients due to lack of follow-up CD4 counts. These patients differed systematically from those who were included in the analysis: they were more likely to die or be lost before a follow-up CD4 count could be measured. Our analysis will thus probably overestimate the true impact of ART on CD4 counts in all patients initiating ART, particularly in the first 6 months after ART initiation. This is illustrated by the CD4 trajectories of patients known to have died or lost to follow up (). However, since excluded patients had no follow-up CD4 count measurements, we had no way of taking this into account in our analysis. Of note, the median baseline CD4 count among patients excluded from analyses because follow-up CD4 counts were measured was 82 cells/μL for patients who died and 117 cells/μL for patients lost to follow up. This is very comparable to the median counts in patients included in analyses that died or were lost to follow up (79 and 121 cells/μL, respectively). Nevertheless, we emphasize the point that our findings apply only to those patients who survived and remained in care with follow-up CD4 counts.
The range of calendar years during which participating sites contributed data varied. While there was substantial overlap between sites, data were not contributed uniformly over the entire time period. While we controlled for site and calendar year of ART initiation in our statistical model, it is possible that this may have influenced results. Finally, the sites participating in the ART-LINC collaboration of IeDEA represent a convenience sample, which are unlikely to be representative of all treatment programs in the country. While there are no data that we can use to assess this directly, the ART-LINC sites are almost exclusively in urban settings, and more likely to represent secondary and tertiary care facilities or centers of excellence than other sites not participating in the collaboration. Similar studies using data from other scale-up sites in primary health centers and rural settings are therefore needed.
In conclusion, our study demonstrates robust CD4 response to ART among patients in multiple treatment programs in resource-limited settings. The response appears to be sustained among those remaining in programs for up to 5 years. Our results thus support the notion that a programmatic, public health approach to ART in resource-limited settings using a limited repertoire of drugs can result in sustained immunologic and virologic outcomes that are comparable to industrialized countries.57
However, given that the most important determinant of long-term CD4 response was the baseline CD4 count at ART initiation, our data also suggest that many patients in developing countries must be started much earlier in order to achieve an optimal on treatment CD4 count over the long term. In light of evidence suggesting that treated HIV positive persons who achieve a CD4 cell count of 500 cells/μL or higher can expect normal life expectancy24
, we feel that it is very important for programs and clinicians to aim for CD4 counts closer to 500 cells/μL at 3-5 years by enrolling and initiating patients on ART earlier, so that lower risks of morbidity and mortality may be attained. Thus, our study has important implications for development of guidelines and for future trials regarding when to start antiretroviral therapy.