Viral load response to a pneumococcal conjugate vaccine, polysaccharide vaccine or placebo among HIV-infected patients

We determined the HIV viral load in 66 adults randomly assigned to receive pneumococcal immunization with one or two doses of protein conjugate vaccine, one dose of polysaccharide vaccine, one dose of each, or placebo. Second doses were given 8 weeks after the first. Mean baseline viral load and CD4 cell count were 3.41 copies/ml (log10) and 457 cells/μl, respectively. We found no change in viral load during 24 weeks of follow-up for any vaccine or combination of vaccines or placebo. Immunization with pneumococcal polysaccharide [1,2] vaccine or influenza vaccine [3–8] may increase the plasma viral load in HIV-infected individuals for 1–4 weeks. Although the clinical significance of transient increases in HIV replication is uncertain, this phenomenon may have untoward virological and immunological outcomes in HIV-infected patients in whom there is ongoing viral replication [5,7]. Furthermore, post-vaccine increases in HIV replication complicate the interpretation of the virological response to antiretroviral therapy. Therefore, as part of a randomized, blinded, controlled trial evaluating antibody responses to pneumococcal protein conjugate and polysaccharide vaccines in HIV-infected adults [9], we evaluated the effect of these vaccines on viral load. HIV-infected individuals over 17 years old with CD4 cell counts of 200 cells/μl or greater within the previous 3 months were eligible. Enrollment occurred from January 1998 to June 1999. Details regarding exclusion criteria as well as vaccine preparation and administration are provided elsewhere [9]. Subjects were randomly assigned to one of four study groups in blocks of 25 assigned to each of two study sites. The study groups received one of the following regimens at weeks 0 and 8: two doses of seven-valent protein conjugate vaccine conjugated to CRM197, a non-toxic mutant diphtheria toxin (Prevnar; Wyeth–Lederle, West Henrietta, NY, USA), one dose of conjugate vaccine followed by one dose of 23-valent polysaccharide vaccine (Pnu-immune 23; Wyeth–Lederle), placebo–polysaccharide, or placebo–placebo. Blood for viral load testing (Amplicor, Roche Diagnostics, Nutley, NJ, USA) was drawn at 0, 8, 9, 16, 17, and 24 weeks. Eight weeks after the second vaccine dose, the study groups were unmasked, and subjects in the conjugate–conjugate and placebo–placebo groups were offered polysaccharide vaccine. With the enrollment of 16 individuals per group, the study had 70% power with 95% confidence to detect a fourfold (0.60 log10) increase in viral load in 50% of immunized patients. Of the 96 enrolled subjects, only data from the 66 subjects for whom there was baseline and at least one follow-up viral load determination were included in this analysis. For the purposes of data analysis, a value of 200 copies/ml was assigned to all viral loads less than 400 copies/ml. Before data manipulation, all viral load concentrations were log-transformed to approximate a normal distribution. The Student's t test (two-tailed) was used for all statistical analyses; when appropriate this was performed for paired values. All viral load determinations were carried out on samples that were coded to mask subject identity and vaccine group assignment. Participants in the four study arms were similar with respect to age, sex, race, baseline CD4 cell count and viral load, and previous receipt of highly active antiretroviral therapy (HAART). Overall, the mean baseline viral load and CD4 cell count were 3.41 ± 1.15 copies/ml (log10) and 457 ± 190 cells/μl, respectively. At study entry, 34 (52%) subjects were receiving HAART, as defined by the receipt of at least one reverse transcriptase inhibitor plus one protease inhibitor; five other individuals started on HAART during the study. Twelve subjects had had a previous AIDS-defining event. No within- or between-group differences were found in paired comparisons of viral loads obtained at the time of vaccination and 1 or 8 weeks later (e.g. between weeks 0 and 8, weeks 8 and 9, or weeks 8 and 16), or between weeks 0 and 24 for any vaccine or combination of vaccines or placebo (Table 1). There was also no difference in the proportion of patients in each group who had a viral load increase greater than 0.5 log10 at any timepoint. Similar results were found when the analysis excluded the 27 (of a total of 186 samples) follow-up samples that were not obtained within 2 weeks of any of the study specified timepoints.Table 1: Change in viral load from baseline. Analyses of the subgroups of patients with baseline viral loads that were 400 copies/ml or less, 401–5000 copies/ml, 5001–20 000 copies/ml or 20 000 copies/ml or greater also showed no differences in the distribution of viral loads at any timepoint. We found no relationship between vaccination and viral load in subanalyses of subjects who were, or were not, receiving HAART (data not shown). Finally, to increase observational power, we pooled results for subjects who received the same vaccine at a specific dosing point (e.g. all subjects who received conjugate vaccine at dose 1, regardless of what they received for the second dose), and analysed the change in viral loads at the next timepoint. Once again, there were no significant within- or between-group differences in paired comparisons of viral loads. We found no short- or longer-term increase in HIV viral load after immunization with pneumococcal vaccines, regardless of whether subjects received one or two doses of conjugate vaccine, one dose of polysaccharide vaccine or one dose of conjugate followed by one dose of polysaccharide vaccine. These results were consistent among subjects who were, or were not receiving HAART, or in whom there was, or was not, evidence of ongoing viral replication. Although two studies in the pre-HAART era demonstrated transient increases in viral load after pneumococcal polysaccharide vaccine [1,2], other observers failed to demonstrate this effect [10–12]. As with all previous studies, we did not demonstrate any long-term effect of pneumococcal vaccination on HIV viral loads [11–14]. Similarly, although several studies demonstrated transient increases in the viral load after immunization with influenza vaccine [5–8], other studies failed to demonstrate significant increases [15–19]. The reasons for these varying results include differences in the potency of antiretroviral therapy, discrepancies in the timing of viral load assays, the lack of control groups, the small sample size, and inconsistent definitions of what constitutes an increase in viral load. Our study benefited from the inclusion of a placebo group, and the capture of viral load results as early as one week and as long as 24 weeks after vaccination. The immunological component of this study showed that the conjugate vaccine may elicit a slightly better immune response than the polysaccharide vaccine in HIV-infected individuals [9]. Data presented here indicate that neither the pneumococcal polysaccharide vaccine nor the protein conjugate vaccine have a significant short- or longer-term effect on HIV replication. Matthew Bidwell Goetza Daniel R. Feikinb Jeffrey L. Lennoxc William A. O'Briend Cheryl M. Elieb Jay C. Butlerb Robert F. Breimanb