HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection.

OBJECTIVE: To evaluate whether controlled re-exposures to autologous HIV-1 could boost HIV-specific immunity and limit virus replication in patients with chronic HIV-1 infection. PATIENTS AND DESIGN: Subjects with at least 2 years virus suppression during antiretroviral therapy and a CD4 : CD8 ratio > 1 were randomly assigned to interrupt highly active antiretroviral treatment (HAART) three times (n = 12) or to continue their previous HAART (n = 14). RESULTS: In 10/12 interrupter patients a rebound of HIV-1 RNA was detected in all three structured treatment interruptions (STI). Plasma virus doubling time was shorter during the first STI than in the second and third STI, corresponding to an average 13% reduction in viral basic reproductive rate. However, the mean time before plasma viral load rose to > 50 copies/ml was significantly shorter in the second and third STI. The average frequency of HIV-specific CD8 T cells in the interrupter patients at the end of the third STI cycle was significantly higher compared with the baseline and the end of the first STI. A substantial increase in HIV-specific CD8 T cell frequencies was found in four interrupter patients, whereas there were no changes in all 14 non-interrupter individuals. A weak p24-specific T helper response developed in 5/12 interrupter patients compared with no response in non-interruptors, but these responses were transient and disappeared rapidly. CONCLUSION: The increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies.

Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression.

OBJECTIVE: To investigate the virological and immunological impact of a structured treatment interruption (STI) in a cohort of HIV-1 chronically infected patients with a further long-lasting effective virus suppression. METHODS: Twelve HIV-1 chronically infected adults who had maintained viral suppression (< 20 copies/ml) for more than 2 years, as well as a CD4:CD8 ratio > 1 for a median time of 22 months, were included in the study. Participants interrupted their antiretroviral treatment during a maximum period of 30 days or until a viral load rebound > 3000 copies/ml was detected. The same prior antiretroviral regimen was resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days during the treatment interruption period. Flow cytometry and cell proliferation assays were performed before and after STI. Genotypic resistance was assessed at the time of treatment resumption. RESULTS: No adverse events occurred during the interruption period. In two patients no viral rebound was detected after 30 days of treatment interruption. In the remaining 10 patients, viral load became detectable (> 20 copies/ml) at a median time of 14 days after treatment interruption. Afterwards, viral load increased exponentially with a mean t1/2 of 1.6 days. Treatment was successfully resumed in all patients. No resistance-conferring mutations associated with the pre-interruption antiretroviral regimen were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the STI period; however, the level of expression of T-cell activation antigen CD38 on CD8 T cells increased significantly in response to viral rebound. Four patients gained T-helper cell responses to recall antigens (tuberculin and tetanus toxoid), two of who developed an HIV-specific response to p24. CONCLUSIONS: STI in chronically HIV-1-infected patients is not associated with reductions in CD4 T lymphocytes or to clinical complications in this group of patients after 2 years of effective plasma viral suppression. Viral load rebounds in most but not all patients, without evidence of selection of resistance-conferring mutations. Thereafter, viraemia can be effectively controlled by antiretroviral agent reintroduction. HIV-specific T-helper cell responses may be achieved after one cycle of treatment interruption suggesting some degree of immune-stimulation. These data do not discard consecutive cycles of STI as a therapeutic strategy to boost HIV-specific immunity in order to maintain viral replication under effective control.

Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with

The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with 24 weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with their previous antiretroviral regimen (n=13) or to continue with the same treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105+/-65/microL; P<.05) but not in the control group (30+/-78/microL). Memory T cells initially contributed to the CD4 T cell increase at week 4 (P<.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became statistically significant at week 24 compared with the control group (28+/-27/microL; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection.

Short-term risk for AIDS-indicator diseases predicted by plasma HIV-1 RNA and CD4+ lymphocytes.

The objective of this study was to assess the value of quantitative HIV-1 RNA as a predictor for the short-term risk of developing AIDS-defining events in comparison with CD4 cell counts. A total of 1,028 samples from 324 patients were analysed. Median initial CD4 cell counts and HIV-1 RNA were 249 x 10(6)/l (range 0-1400 x 10(6)/l) and 4.5 log copies/ml (range: 2.3-6.4 log copies/ml). CD4 cell counts and viral load (VL) values obtained the year before a single AIDS-indicator disease were selected to define the risk of developing that event. Cox regression models with CD4 cell counts and VL values treated as time-dependent covariates were performed to analyse the risk for developing certain events. Receiver operating characteristic (ROC) curves were used to compare CD4 cell counts and VL values as predictive markers for progression. During a median follow-up of 870 d (range 30-1381 d), 132 patients developed AIDS. Median log VL values during the year before the event were 3.6 for non-progressors and 5.2 for those who developed AIDS (p < 0.0001). Minimum log VL threshold values for developing diseases were 2.3 for tuberculosis, 3.8 for Candida esophagitis, 4.4 for wasting syndrome, 4.5 for CMV disease and 4.7 for PCP. VL values were not, however, a better predictive marker for developing specific events than were CD4 cell counts. Although we have identified VL thresholds for the risk of developing certain AIDS-indicator diseases, the indication for starting prophylactic regimens may still be based on CD4 cell counts.

Efficacy of adding indinavir to previous reverse transcriptase nucleoside analogues in relation to genotypic and phenotypic resistance development in advanced HIV-1-infected patients.

We assessed the efficacy of adding indinavir in patients with advanced HIV-1 infection, who were previously exposed to different reverse transcriptase (RT) nucleoside analogues. Twenty-five patients with an initial median CD4 cell count of 20 cells/mm3 (range, 0-80 cells/mm3) were treated with indinavir (800 mg three times per day) for 24 weeks. The median initial viral load was 5.4 log (range, 3.6-6.7 log). Of these patients, 56% (14 of 25) had an initial decrease in viral load of >1 log and sustained response of >0.5 log of HIV-1 RNA from baseline. Twelve of these 14 responder patients (85%) showed a sustained RNA response undetectable by NASBA assay, and no genotypic changes in protease were detected at week 24. In those with a temporary or absent response to indinavir, either resistant viruses or lack of compliance was observed. In compliant patients (15 of 16), relatively small increases in 50% inhibitory concentration (IC50) to indinavir and only two to three amino acid changes were sufficient to produce treatment failure. Phenotypic drug-resistant assays at 24 weeks revealed cross-resistance to ritonavir in all the patient isolates and to saquinavir in one third of the isolates. We observed an initial and persistent response to the addition of indinavir in patients with advanced disease and prolonged antiretroviral treatment. Therapy failure, as defined by increases in viral RNA, was associated with either lack of compliance or the development of low level indinavir-resistant virus. Clinical studies need to be designed to determine to what extent these viruses may respond to other protease inhibitors.

[Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival]. / Valor de la carga viral del VIH-1 y de los linfocitos CD4+ como determinantes de la progresión a sida y de la supervivencia.

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.

Thrombus in right atrium in two infants successfully treated with tissue plasminogen activator.

The widespread use of central venous catheters in children has increased thrombotic complications that warrant thrombolytic therapy. We report the cases of two infants, aged four and two months, with a mobile thrombus in the right atrium treated with recombinant tissue-plasminogen-activator (rt-PA) infused by a central venous catheter. Clot dissolution was obtained in both patients in eight and 44 hours, respectively. One patient presented mild respiratory distress probably from a pulmonary microembolism that disappeared in a few days. Both had minor bleeding from venipuncture sites, but no major hemorrhage.