Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study*

Objectives

Patients starting highly active antiretroviral therapy (HAART) may have a suboptimal CD4 increase despite rapid virological suppression. The frequency and the significance for patient care of this discordant response are uncertain. This study was designed to determine the incidence of a discordant response at two time‐points, soon after 6 months and at 12 months, and to determine the relationship with clinical outcomes.

Methods

Data obtained in the UK Collaborative HIV Cohort Study were analysed. A total of 2584 treatment‐naïve patients starting HAART with HIV viral load (VL)>1000 HIV‐1 RNA copies/mL at baseline and <50 copies/mL within 6 months were included in the analysis. Patients were classified at either 6–10 (midpoint 8) months or 10–14 (midpoint 12) months as having a discordant (CD4 count increase <100 cells/μL from baseline) or concordant response (CD4 count increase ≥100 cells/μL).

Results

Discordant responses occurred in 32.1% of patients at 8 months and in 24.2% at 12 months; 35% of those discordant at 8 months were concordant at 12 months. A discordant response was associated with older age, lower baseline VL, and (at 12 months) higher baseline CD4 cell count. In a multivariate analysis it was associated with an increased risk of death, more strongly at 12 months [incidence rate ratio (IRR) 3.35, 95% confidence interval (CI) 1.73–6.47, P<0.001] than at 8 months (IRR 2.08, 95% CI 1.19–3.64, P=0.010), but not with new AIDS events.

Conclusions

Discordant responders have a worse outcome, but assessment at 12 months may be preferred, given the number of ‘slow’ responders. Management strategies to improve outcomes for discordant responders need to be investigated.     

The benefit of long-term interferon alfa therapy for symptomatic mixed cryoglobulinemia (cutaneous vasculitis/membranoproliferative glomerulonephritis) associated with chronic hepatitis C infection

The efficacy of long-term interferon therapy for chronic hepatitis C infection with symptomatic mixed cryoglobulinemia has not clearly been defined. We describe a patient with chronic hepatitis C, symptomatic mixed cryoglobulinemia (cutaneous vasculitis), and membranoproliferative glomerulonephritis (MPGN) who responded clinically, biochemically, and virologically to a 1-year course of interferon therapy. Interferon side effects were minimal. Relapse occurred when interferon was discontinued, and suppressive maintenance interferon therapy was required for clinical, biochemical, and virologic remission. During the 5th year of maintenance therapy, she developed potential side effects that necessitated discontinuation of interferon treatment. After treatment stoppage, a clinical, biochemical, and virologic remission was maintained for more than 1 year. However, the potential side effects, which included eye irritation, arthralgias, myalgias, fatigue, insomnia, memory loss, and depression, persisted. Ophthalmologic, rheumatologic, and neurologic evaluations were nondiagnostic. Psychometric testing revealed dementia and mood disorder. Because the disabling symptoms persisted after 9 months, a health-related quality of life assessment was carried out with the SF-36 survey. Compared with healthy individuals and patients with chronic hepatitis C, our case had a lower health-related quality of life assessment on six out of seven scales and on four out of seven scales of the SF-36 survey, respectively. This case report indicates that long-term maintenance interferon therapy was effective in the treatment of symptomatic mixed cryoglobulinemia and its renal complications and resulted in a clinical, biochemical, and virologic sustained response. It is postulated that the side effects of long-term interferon therapy in this setting may be problematic.     

PPARβ/δ Protects Against Experimental Colitis Through a Ligand-Independent Mechanism

Peroxisome proliferator-activated receptors (PPARs) β/δ and γ have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPARγ protects against experimental colitis in mice. PPARβ/δ can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPARβ/δ may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPARβ/δ-null mice, with and without the PPARβ/δ specific ligand GW0742. PPARβ/δ-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon γ, tumor necrosis factor-α, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPARβ/δ in either genotype. These studies demonstrate that PPARβ/δ expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.     

Phase I trial of combinations of recombinant interferons beta(ser) and gamma in patients with advanced malignancy

Based upon in vitro and in vivo synergistic activity of Type I and Type II interferons (IFNs) in preclinical in vitro and in vivo studies, we initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of combinations of recombinant DNA-produced human IFN-beta ser and IFN-gamma in 27 patients with cancer. Twenty-four patients were treated with a 2-hour infusion of IFN-gamma, followed by a 10-minute iv injection of IFN-beta ser, three times a week. Patients were entered on fixed dose levels of 1 X 10(6), 3 X 10(6), 10 X 10(6), 30 X 10(6), and 100 X 10(6) units of each IFN. In addition, three patients were treated at the highest dose level with a 10-minute iv infusion of IFN-gamma and a 10-minute iv infusion of IFN-beta ser. The maximally tolerated dose when administered by this schedule for greater than or equal to 4 weeks was 30 X 10(6) units of each IFN. Dose-limiting side effects at doses of 100 X 10(6) units of each IFN consisted of fatigue, nausea, vomiting, anorexia, paralytic ileus, and neutropenia. The most common side effects at the three highest dose levels were fever, rigors often requiring parenteral meperidine, and constitutional symptoms. Reversible elevations in SGOT and LDH were also noted. Serum IFN levels were dose related, with peak titers occurring immediately after IFN administration. One patient with a nodular mixed lymphoma had a partial response which has been sustained for over 1 year. We conclude that combinations of IFN-beta ser and IFN-gamma can be safely administered on a chronic basis without enhanced or cumulative toxic effects.     

The possible role of stress in the induction of pneumonic pasteurellosis

Five groups of range bred calves (four calves per group) were used to investigate the effect of stress on susceptibility to aerosol exposures with bovine herpesvirus-1 or Pasteurella haemolytica. Twelve calves were weaned, transported, processed at a commercial feedlot and transported to isolation facilities three days later. An aerosol challenge of either 10 colony forming units of P. haemolytica or 10 plaque forming units of bovine herpesvirus-1 virus was given to two groups of calves and the third group was not challenged. The fourth group was transported directly to the isolation facilities after weaning and aerosol challenged with P. haemolytica. The fifth group remained at the farm after weaning and was not challenged. All transported animals had elevated plasma cortisol levels which remained above normal for at least three days postchallenge. The blastogenic response of all calves was depressed after leaving the farm and remained depressed throughout the experiment. The suppression correlated well with elevated serum cortisol levels. Calves processed through the feedlot encountered bovine herpesvirus-1 because eight out of 12 animals seroconverted to this antigen. Most calves seroconverted to P. haemolytica whether they were experimentally challenged or not. Where the unchallenged calves encountered P. haemolytica is unknown. Calves challenged with bovine herpesvirus-1 but not with P. haemolytica, had significant clinical signs of pneumonia and two animals died due to bovine herpesvirus-1 infection.(ABSTRACT TRUNCATED AT 250 WORDS)