In a national multi-centre project with 68 participating hospitals across France, a large cohort of patients initiating protease inhibitor (PI)-containing HAART was followed up.26 The median baseline CD4 cell count was 0.15 x 109 cells/L and the median baseline plasma HIV RNA level was 35,000 copies/mL. After 6 months of HAART, the median increase in CD4 cell counts in the entire patient sample was 0.086 x 109 cells/L and the median change in plasma HIV RNA level was -0.8 log10 copies/mL. In this study,immunologic response was defined as an increase in CD4 cell count from baseline of more than 0.05 x 109 cells/L and virologic response was defined as a decrease in plasma HIV RNA level from baseline of more than 1 log10 copies/mL or a plasma HIV RNA level less than 1000 copies/mL. After 6 months of HAART, complete immunologic and virologic response was demonstrated in 47.5% of the respondents (complete
44 responders), 16.2% were complete non-responders (those that did not demonstrate immunologic and virologic response at all) while 36.3% had discordant responses (either an immunologic or virologic response, but not the two together). This study demonstrated that patients showing an immunologic response at 6 months were at a lower risk for disease progression, irrespective of their virologic response. Patients showing only a virologic response at 6 months were at intermediate risk for clinical progression, while complete non-responders showed the least favourable prognosis. The study confirmed that increase in CD4 cell counts improved the clinical outcomes of patients on protease inhibitor-containing HAART. The authors concluded that both immunologic and virologic markers should be used in assessing clinical treatment failure. However, the authors had named the study design as being a prospective cohort study although there was no control group.
In the longitudinal observational study of the Johns Hopkins HIV Clinical Cohort in Maryland, USA, data were analyzed for all patients who had sustained viral suppression while receiving HAART.81 Baseline CD4 cell counts were stratified into 3 groups: ≤200 cells/µL, 201–350 cells/µL, and >350 cells/µL. Six years after commencement of HAART, the median CD4 cell count was 493 cells/µL among patients with baseline CD4 cell counts ≤200 cells/µL; 508 cells/µL among those with baseline CD4 cell counts of 201–350 cells/µL; and 829 cells/µL among those with baseline CD4 cell counts >350 cells/µL, respectively. It was concluded that only patients with baseline CD4 cell counts >350 cells/µL returned to nearly normal CD4 cell counts after 6 years of follow-up. Significant increases were observed in all CD4 cell count strata during the first year, but there was a lower plateau CD4 cell count at lower baseline CD4 cell strata. The data suggested that commencement of HAART at a lower CD4 cell count will result
45 in a CD4 cell count that does not return to normal levels; and this may be a reason to consider starting HAART before the CD4 cell count decreases to <350 cells/µL. However, the drawback of this study was that only patients with sustained viral suppression at 6 months of therapy were included. By so doing, this precluded (by exclusion from analysis) the identification of other important predictors of long-term CD4 cell counts that might have been contributed by those who had not achieved viral suppression by 6 months of therapy.
In another study in a Los Angeles outpatient clinic in the USA,37 patients’ median HIV-1 RNA level at baseline was 4.239 log copies/mL while median baseline CD4 cell count was 230 cells/mm3. In this study, virologic response was defined as a decrease in viral load of >1.0 log copies/mL from baseline after 3 months of HAART while immunologic response was defined as CD4 cell count of >200 cells/mm3 after 3 months of HAART. At 3 months, 44% of the subjects had achieved good virologic response with HAART, while 29% had a poor immuno-virologic response and 27% had discordant immunologic or immuno-virologic response. Patients who had a virologic but not an immunologic response were less likely to experience clinical treatment failure (occurrence or recurrence of an AIDS-defining illness, relapse of an opportunistic infection or death) than were patients who had high CD4 cell counts and high viral loads. The authors concluded that while looking at both virologic and immunologic factors when evaluating patients on HAART, physicians should base their decisions to modify treatment more on virologic response than on immunologic response.Nonetheless,the authors had stated that: “the random sample was generated on the basis of the unique patient identification numbers…” But it is rather unclear what they mean, as they failed to specify which sampling technique was used.
46 In an urban tertiary teaching hospital in Madrid, Spain, the clinical data of patients with one complete year’s follow-up before and one year after introduction of protease inhibitors (PIs) was compared. After 1 year of PI-containing HAART, viral load decreased from 5.43 ± 0.10 to 3.43
± 0.10 log copies per ml and CD4 count increased from 129 ± 9.3 to 290 ± 14 cells/µl at the end of the study. As expected, virtually all the viral load response was obtained in the first quarter of therapy; while immunological response was seen to show a steady improvement as the year progressed.42 However, the authors had called it a cohort study, but there was no comparison group (control) reported in the article.
350 cells/µl group was significantly lower than that in CD4 100–200 cells/µl group (P=0.000).
After HAART, no significant differences were observed between these two groups either in the plasma viral load (pVL) or in the viral response rate calculated as the percentage of pVL less than 50 copies/ml or less than 400 copies/ml. The CD4 cell counts were statistically higher in the 201–350 group during the entire follow-ups (p <0.01) though CD4 cell count increases were similar in these two groups. After 100-week treatment, the median of CD4 cell counts were increased to 331 cells/µl for CD4 100–200 cells/µl group and to 462 cells/µl for CD4 201–350 cells/µl group. It was concluded that the pVLs and viral response rates were unlikely to be associated with the baseline CD4 cell counts. Therefore, initiating HAART in Chinese HIV-1
47 infected patients with higher baseline CD4 cell counts had resulted in higher total CD4 cell counts, thereby achieving a better immune recovery. Moreover, the authors believed that the results supported the current guidelines (at that time) which stipulated that HAART should be commenced at a threshold of CD4 cell count of 350 cells/µl. However, this study was flawed for the fact that one of the main exclusion criteria was “anticipated non-adherence”. By so doing, the authors had precluded otherwise very important information that might have been contributed by such patients; because in the HIV literature, non-adherence is one of the major factors influencing HAART efficacy and CD4 response to treatment.
(SAT); while CD4 cell count increases were 218/μL, 267/μL, 205/μL and 224/μL in the DOT, TWOT, WOT and SAT groups, respectively, at 48 weeks of HAART. A major strength of this study was the sound methodology it had demonstrated – with regards to the study design, study population and data analysis.
However, it appears that the authors had several methodological issues. They had named it a retrospective cohort study – when in actual fact it was a review of records; and at the same time they had stated that a convenient sample of patients was chosen by simple random process using a random number table – being that a convenient sample and simple random process are contradictory.
The median increase in CD4 cell count for 98.7% of the patients who had CD4 cell counts at baseline and at 6 months of therapy was 122 cells/µL. The authors concluded that in this cohort
49 of antiretroviral-naive HIV-infected adults, there was a high rate of virological and immunological success after 6 months of HAART, irrespective of the pre-HAART viral load and CD4 cell count. Nonetheless, it appears as though the authors were unclear about the study design because they had named it a prospective observational study and had also referred to the patients as a cohort – but there was no control group. In actual fact it was a cross-sectional longitudinal study.
Several other African countries including South Africa,85 Botswana,86 Cameroon,87 Uganda88 and Congo-Brazzaville,89 have also documented favourable immunologic and virologic outcomes with HAART. In a study that examined determinants of CD4 cell count recovery among patients accessing a community-based ARV programme at the Gugulethu Community Health Centre, Cape Town, South Africa,85 all treatment-naive patients aged over 15 years and with at least a 16-week follow-up time point were included in the analysis. The CD4 cell count increased from a median of 97 cells/µl at baseline to 261 cells/µl at 48 weeks; and the proportion of patients with a CD4 cell count <100 cells/µl decreased from 51% at baseline to just 4% at 48 weeks. A rapid first phase of recovery (0–16 weeks, median rate = 25.5 cells/µl/month) was followed by a slower second phase (16–48 weeks, median rate = 7.7 cells/µl/ month). Among those that achieved a CD4 cell count >500 cells/µl at 48 weeks, 19% had baseline CD4 cell counts <50 cells/µl. Furthermore, the proportion of these patients that attained a CD4 count of 200 cells/µl at 48 weeks was lower than those with higher baseline CD4 cell counts. The authors concluded that patients in this cohort with baseline CD4 cell counts <50 cells/µl have equivalent or greater capacity for immunological recovery during 48 weeks of ART compared to those with higher baseline CD4 cell counts. Thus, a low baseline CD4 cell count did not preclude patients
50 from having an excellent immunological response. However, their CD4 counts remained <200 cells/µl for a longer period, potentially increasing their risk of morbidity and mortality in the first year of ART.Nevertheless, this study had demonstrated sound methodology with regards to the detailed description of the study population, data collection process and data analysis.