Peter Sklar

Prevalence and clinical correlates of HIV viremia ('blips') in patients with previous suppression below the limits of quantification

Objective: To examine the prevalence and clinical correlates of subsequently measurable viremia in HIV-infected patients who have achieved viral suppression below the limits of quantification (< 50 copies/ml). Design: Non-randomized dynamic cohort study of ambulatory HIV patients in nine HIV clinics in eight cities. Patients: Patients had two consecutive HIV-1 RNA levels < 50 copies/ml (minimum, 2 months apart) that were followed by at least two more viral level determinations while remaining on the same antiretroviral therapy (ART) between January 1997 and June 2000 (median 485 days). Transiently viremic patients were defined having a subsequently measurable viremia but again achieved suppression < 50 copies/ml. Results: Of the 448 patients, 122 (27.2%) had transient viremia, 19 (4.2%) had lasting low-level viremia and 33 (7.4%) had lasting high-level viremia (defined as 50–400 and > 400 copies/ml, respectively). Only 16 (13.1%) of those who had transient viremia later had persistent viremia > 50 copies/ml. The occurrence of transient viremia did not vary with whether the patient was ART-naive or experienced (P = 0.31), or currently taking protease inhibitors or not (P = 0.08). On consistent ART, the median percentage increase in CD4 cell count was statistically different between subgroups of our cohort (Kruskal–Wallis, P = 0.002). Conclusions: Transiently detectable viremia, usually 50–400 copies/ml, was frequent among patients who had two consecutive HIV-1 RNA levels below the limits of quantification. In this analysis, such viremia did not appear to affect the risk of developing lasting viremia. Caution is warranted before considering a regimen as ‘failing’ and changing medications.

Lopinavir-Ritonavir: Effects on Endothelial Cell Function in Healthy Subjects

To differentiate between the effects that antiretroviral drugs have on the endothelium and the secondary effects that they have on immune function, viral load, and dyslipidemia, 6 non-human immunodeficiency virus-infected human subjects were treated with lopinavir-ritonavir for 1 month and, on the basis of forearm blood flow, the treatments effects on endothelial cell function were measured. Surprisingly, after exposure to lopinavir-ritonavir, absolute forearm blood-flow responses to the endothelium-dependent vasodilator, acetylcholine, increased significantly (P=.03), and forearm blood flow decreased to a greater extent during specific inhibition of NO synthase by N(G)-monomethyl-L-arginine. Thus, in this small cohort of subjects, short-term treatment with lopinavir-ritonavir does not appear to directly promote endothelial cell dysfunction.

Clinical efficacy of raltegravir against B and non-B subtype HIV-1 in phase III clinical studies.

Objective:We evaluated the long-term efficacy of raltegravir according to HIV-1 subtype (B and non-B) using data from three phase III studies in treatment-experienced (BENCHMRK-1 and 2) and treatment-naive (STARTMRK) HIV-infected patients. Methods:HIV-1 subtypes were identified from baseline plasma specimens using genotypic data of the PhenoSense GT test (Monogram Biosciences, South San Francisco, California, USA). Non-B subtypes were combined for the current analyses due to small numbers of each specific subtype. An observed failure approach was used (only discontinuations due to lack of efficacy were treated as failures). Resistance evaluation was performed in patients with documented virologic failure. Results:Seven hundred and forty-three patients received raltegravir and 519 received comparator (efavirenz in STARTMRK; optimized background therapy in BENCHMRK). Non-B subtype virus (A, A/C, A/D, A/G, A1, AE, AG, B/G, BF, C, D, D/F, F, F1, G, and complex) was isolated at baseline in 98 (13%) raltegravir recipients and 62 (12%) comparator recipients. Subtypes AE and C were most common, isolated in 41 and 43 patients, respectively. The proportion of raltegravir recipients achieving HIV RNA less than 50 copies/ml was similar between non-B and B subtypes (STARTMRK: 94.5 vs. 88.7%; BENCHMRK-1 and 2: 66.7 vs. 60.7%); change in CD4 cell count also was similar between non-B and B subtypes (STARTMRK: 243 vs. 221 cells/&mgr;l; BENCHMRK-1 and 2: 121 vs. 144 cells/&mgr;l). Phenotypic resistance to raltegravir in non-B virus was associated with integrase mutations observed previously in subtype B virus. Conclusion:In phase III studies in treatment-naive and treatment-experienced patients, raltegravir showed comparable and potent clinical efficacy against B and non-B HIV-1 subtypes.

CD4+ T Cell Responses to Interleukin-2 Administration in HIV-Infected Patients Are Directly Related to the Baseline Level of Immune Activation

BACKGROUND Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4(+) T cell expansions. The factors potentially affecting these expansions were investigated in the present study. METHODS A matched (for baseline CD4(+) T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a <or=10% increase in CD4(+) T cell count 2 months after the third IL-2 cycle (week 24), compared with that at baseline (week 0). Control subjects experienced a >or=50% increase in CD4(+) T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups. RESULTS Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4(+) T cell count, nadir CD4(+) T cell count, or CD8(+) T cell count. At week 0, NRs had lower TREC levels per 1x106 T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4(+) T cells, with TREC levels per 1x106 CD4(+) T cells decreasing significantly only in control subjects. CONCLUSIONS Increased immune activation can adversely affect CD4(+) T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed.

Five-year follow-up of a cohort of profoundly immunosuppressed patients discontinuing therapy for cytomegalovirus retinitis.

Potent antiretroviral therapy stimulates robust and durable immune reconstitution among profoundly immunosuppressed patients that is clinically important. Fifteen patients with cytomegalovirus retinitis (CMVR) were followed after discontinuing anti-cytomegalovirus therapy. No patients had progression or relapse for a median of 51 months. Survival from the diagnosis of CMVR was universal for up to 95 months, with an observation period averaging more than 6 years. The CD4 cell count continued to rise through the fourth year of follow-up.