HIV-1-specific CD4+ T lymphocyte turnover and activation increase upon viral rebound.

HIV-specific CD4+ T helper lymphocytes are preferred targets for infection. Although complete interruption of combination antiretroviral therapy (ART) can form part of therapeutic manipulations, there is grave concern that the resumption of viral replication might destroy, perhaps irreversibly, these T helper populations. High viremia blocks the proliferation capacity of HIV-specific helper cells. However, cytokine production assays imply that some antigen-specific effector function is retained. Despite this careful work, it remains unclear whether the return of HIV-1 replication physically destroys HIV-1-specific T helper cells in the peripheral blood. Difficulties in producing stable peptide-MHC class II complexes and the very low frequencies of antigen-specific CD4+ T cells have delayed the application of this powerful technique. Here we employ HLA class II tetramers and validate a sensitive, quantitative cell-enrichment technique to detect HIV-1 T helper cells. We studied patients with early-stage HIV infection who were given a short, fixed course of ART as part of a clinical study. We did not find significant deletion of these cells from the peripheral circulation when ART was stopped and unfettered HIV replication returned. The turnover of these virus-specific cells increased and they adopted an effector phenotype when viremia returned.

Comparative potency of three antiretroviral therapy regimes in primary HIV infection.

BACKGROUND: Virally mediated destruction of HIV-specific CD4+ T-cells in primary HIV infection (PHI) may be abrogated by potent antiretroviral therapy (ART) started in acute infection. To best achieve the most rapid reduction in primary viraemia we compared three different ART regimens in PHI. STUDY DESIGN AND METHODS: A sequential, unblinded, non-randomized prospective cohort study. The primary endpoint was time to achieve plasma viral load (pVL) < 50 copies HIV RNA/ml. One hundred and five patients identified with PHI according to the definition: HIV antibody negative with positive HIV DNA (n = 22), HIV antibody positive with a documented negative test within the previous 6 months (n = 53), low-level incident 'detuned' assay (n = 10) or an evolving HIV-antibody test (n = 20) were recruited. Ninety of 105 individuals chose to take a short course of ART at PHI whereas 15 of 105 declined therapy. Seventy-nine of 90 were included for analysis and were allocated sequentially to either three (29 of 79) or four-drug (33 of 79) or protease inhibitor-containing ART (17 of 79). RESULTS: A mathematical model-based analysis of viral decay indicated significantly faster viral load decline in patients receiving the four-drug regimen (P = 0.01). This conclusion was supported by a non-significant on-treatment analysis of the time taken to reach pVL <50 copies HIV RNA/ml (P = 0.07) but not by the corresponding intend-to-treat analysis. This discordance was caused by greater toxicities associated with the four-drug regimen, although the differences were not significant. CONCLUSION: Of the three treatment regimens compared, the four-drug arm enhanced the rate of decline of primary viraemia but at the cost of toxicity.

Treatment of category III A prostatitis with zafirlukast: a randomized controlled feasibility study.

The cause of category III A prostatitis, chronic prostatitis/chronic male pelvic pain syndrome category A (CP/CPPS A), is uncertain. Treatments for it are based on consensus opinion rather than on scientific data. Our aim was to examine the effect of zafirlukast, a leucotriene antagonist, on the symptoms of CP/CPPS A in our genitourinary (GU) medicine unit. CP/CPPS A was diagnosed by comparative white cell counts of split urine (Stamey) analysis or by finding an excess of polymorphs in expressed prostatic fluid. Symptom change was assessed by the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI). Patients were given zafirlukast or placebo for four weeks in a random double-blind fashion. All patients also received doxycycline. In all, 31 patients were asked to participate and 17 entered the study. No difference in outcome could be shown between the active (10) and placebo (seven) patients. Zafirlukast cannot be demonstrated to be useful in the symptomatic treatment of CP/CPPS A. The problems of recruitment into this study (in spite of a large number of patients with prostatic type pain being seen in our unit) suggest that multicentre treatment trials using non-invasive diagnostic techniques such as the CPSI (rather than single GU medicine units diagnosing CP/CPPS A by uncomfortable direct prostatic testing) are likely to be the most effective and objective methods of undertaking treatment trials in the CP/ CPPS A field in the future.