Residual viraemia is detectable in the majority of human immunodeficiency virus (HIV)-infected subjects with plasma HIV-1 RNA <50 copies ml(-1). In the present study, the impact of repeated treatment ...interruptions on residual HIV-1 viraemia was investigated in 58 subjects enrolled in the ISS-PART, a multicentre, randomized clinical trial comparing 24 months of continuous (arm A) and intermittent (arm B) highly active antiretroviral therapy (HAART). Residual viraemia was measured by a modified Roche Amplicor HIV-1 RNA assay (limit of detection 2.5 copies ml(-1)). At baseline, the median value of residual viraemia was 2.5 copies ml(-1) in both arms; after 24 months, the median value was 2.5 in arm A and 8.3 in arm B. The median change from baseline to month 24 was significantly different between patients under continuous or intermittent HAART: 0 copies ml(-1) (range -125.2 to +82.7) of HIV-1 RNA in arm A versus 2.1 copies ml(-1) (range -80 to +46.8) in arm B (P=0.024). These results suggest that intermittent HAART tends to modify HIV-1 viraemia set point even if a virological response is achieved after HAART reinstitution.
Background
AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/µL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be ...considered equally safe in patients with a previously very low CD4 nadir.
Methods
We evaluated in detail all the AIDS defining events observed during a 48‐week clinical trial in 1251 nucleoside reverse transcriptase inhibitor‐experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/µL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated.
Results
Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per µL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/µL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/µL, with only four deaths occurring in the presence of a CD4 count above 100 cells/µL.
Conclusions
Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/µL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.
ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below ...50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).
Circulating endothelial progenitor cells (EPCs) play an important role in post natal neovascularization. High density lipoproteins (HDL) protect the vascular wall from atherosclerosis. The role ...exerted by HDL on EPCs physiology is unknown. In this study we investigated whether the levels of plasma HDL can modulate the number of EPCs. The number of EPCs was evaluated in 24 subjects as the number of endothelial colony-forming unit (e-CFU) growth in culture. The number of AC133 positive progenitor cells present in the gate of the CD34 bright positive lymphocytes was also evaluated. Plasma levels of HDL, triglycerides and total cholesterol/HDL cholesterol ratio correlated with the number of e-CFU (r=0.62, P=0.006; r=-0.54, P=0.019, and r=-0.61, P=0.007 respectively), but not with the number of CD34/AC133 positive progenitor cells. In vitro, the incubation of the mononuclear cellular fraction with HDL did not increase the number of e-CFU in culture, whereas LDL and VLDL reduced the number of e-CFU. Our results indicate that human HDL plasma levels directly relate to the number of circulating endothelial progenitor cells that can be isolated in vitro, as determined by the number of e-CFU.
Recent data have shown that plasma levels of lipopolysaccharide (LPS) are a quantitative indicator of microbial translocation in HIV infected individuals.
To assess the impact of residual viral ...replication on plasma LPS in HAART-treated HIV+ subjects with <50copies/ml HIV-1 RNA and to evaluate LPS changes during repeated HAART interruptions not exceeding 2-month duration.
LPS was measured in 44 HIV+ subjects at T0 (during HAART) and at day 15 of the first and fourth HAART interruption. Ten uninfected, healthy donors were studied as well. Residual plasma HIV-1 RNA was measured at T0 by an ultra-ultrasensitive method with limit of detection of 2.5copies HIV-1 RNA/ml. Subjects with less than 2.5copies/ml (fully suppressed - FS) were compared to those with 2.5-50copies/ml (partially suppressed - PS).
At T0, plasma LPS levels were comparable in FS and uninfected subjects, whereas in PS they were higher than in uninfected subjects (p=0.049). After 4 HAART interruptions, they did not change significantly. However, LPS values were lower in FS than in PS (p=0.020). An inverse correlation was found between CD4 and LPS levels (p=0.044) in PS group only.
A reduced degree of microbial translocation was seen in subjects with a more complete suppression of viral replication. Repeated HAART interruptions had no significant impact on plasma LPS levels.
Cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens, microbial recall antigens, and CD3 monoclonal antibody were studied in HIV-1-infected asymptomatic patients in a ...phase II, double-blind trial of immunization with recombinant HIV-1 gp160 in or not in association with zidovudine. A vigorous and persistent lymphoproliferative response (LPR) to HIV-1 Env antigens was observed in vaccinated patients. Neither Env-specific lymphocyte cytotoxicity nor LPR to recall antigens was significantly influenced by gp160 administration. The induction of LPRs to HIV-1 envelope proteins did not show positive effects on the course of HIV-1 infection. Patients treated with zidovudine alone or in combination with the immunogen showed improvement of T lymphocyte responses and transient reduction of viremia. These results suggest that antiretroviral therapy is more beneficial than immunization with gp160 and should always be considered in association with future vaccination and immunotherapeutic interventions in HIV-1-infected subjects.
HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in ...patients on protease inhibitor (PI)-based second-line therapy.
HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure.
Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance).
High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.
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