Research Article: CD4 and Viral Load Dynamics in Antiretroviral-Naïve HIV-Infected Adults from Soweto, South Africa: A Prospective Cohort

Date Published: May 15, 2014

Publisher: Public Library of Science

Author(s): Neil A. Martinson, Nikhil Gupte, Reginah Msandiwa, Lawrence H. Moulton, Grace L. Barnes, Malathi Ram, Glenda Gray, Chris Hoffmann, Richard E. Chaisson, Marie-Louise Newell.


CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates.

HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored. 1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm3 (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm3 per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml.

Our data suggests that six and a half years will elapse for an individual’s CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.

Partial Text

Since Mellor’s et al landmark papers on the relative prognostic value of viral load on CD4 count decline [1], [2], there have been few reports describing CD4 cell decline and the influence of HIV RNA on CD4 decline – particularly from developing settings where the HIV subtypes, host factors, and route of HIV acquisition differ to those in North America. Yet infecting HIV type and subtype appear to have a major impact on the rate of CD4 decline [3]–[5]. Estimates of CD4 count decline, however, are important to predict the time to CD4 count based antiretroviral therapy (ART) initiation thresholds. For populations, accurate characterization of CD4 decline is valuable for: epidemiological modeling; forecasting resource needs; and estimating cost-benefits of HIV prevention including initiation of ART at higher CD4 counts. Reports of CD4 decline from South Africa, where HIV-1 subtype C is the predominant infecting strain, have described CD4 decline in ART naïve patients but lack contemporaneous HIV viral load data [6]–[8].

This analysis included 1106 ARV naïve adult participants –184 (17%) were men;– representing 96.3% of the total randomization cohort of the parent trial (Table 1). Participants in this analysis were followed up for a median of 3.7 years (IQR: 2.4–4.5) prior to initiating antiretroviral therapy or being terminated from the study; 166 started antiretroviral therapy at a median CD4 count of 192 cells/mm3 (IQR 149–243) and were censored at the time of antiretroviral initiation. Another 42 participants were also censored, despite not reporting ART initiation, as their HIV RNA values reduced from a prior level of >1000 copies/ml to <400 copies/mL. Sixty-four (6%) died whilst being followed up. The remaining cohort contributed a total of 5,960 CD4 counts and 2,569 viral load measurements. Median CD4 count and viral load at enrollment was 490 cells/mm3 (IQR 351–675) and 16,050 copies/ml (IQR 3,680–57,400), respectively. At termination or censoring, median CD4 count and viral load were 345 cells/mm3 (IQR 220–523) and 7,567 copies/mL (IQR 2,036–24,423), respectively. Our finding of an average decline of 3.2 cells/mm3 per month or 38.4 cells/mm3 per year is lower than that reported for men who have sex with men infected with subtype B HIV; Mellors et al reported annual CD4 declines of 64 cells/mm3 per year overall and 36.3 cells/mm3 per year among participants with HIV RNA of <500 copies/ml, and 76 cells/mm3 per year for those with an HIV RNA >30,000 copies/mL. Recent sero-converters, infected with HIV subtypes A or D from Uganda appeared to have a more rapid CD4 decline than what we report, and subtype D infected individuals declined more rapidly than subtype C. However, our results are similar to those from a clinical cohort from South Africa in which the CD4 decline among those with a CD4 at clinic entry of 201–350 cells/mm3 was 20.5 and for those with >500 cells/mm3 at clinic entry was 47.1 [6]; the equivalent results in our group were declines of 17.2 and 48.5 cells/mm3 per annum, respectively. We posit that differences in CD4 declines reflect subtype differences, differences between recent sero-converters and chronically infected individuals, or innate host susceptibility to HIV infection. Interestingly, an episode TB was associated with the largest decline in CD4. Although we did not confirm infection with subtype C in this study, HIV subtype C is particularly important, as it is the most common subtype in South Africa and globally.