Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial.

CONTEXT: While interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART). OBJECTIVE: To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone. DESIGN AND SETTING: Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States. PATIENTS: Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 10(6)/L to 500 x 10(6)/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study. INTERVENTIONS: Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone. MAIN OUTCOME MEASURES: Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels. RESULTS: The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log(10) copies for IL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving IL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received IL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed. CONCLUSIONS: Intermittent therapy with IL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end-point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with IL-2 therapy will translate into improved clinical outcomes. JAMA. 2000;284:183-189

A randomized trial of interferon alpha therapy for HIV type 1 infection.

The immunologic and virologic efficacy and safety of interferon a (IFN-alpha) administered in combination with zidovudine (ZDV) and zalcitabine (ddC) was evaluated in HIV-infected subjects with CD4+ cell counts between 300 and 500 cells/ml and no more than 14 weeks of prior antiretroviral therapy. A total of 256 subjects enrolled in an open-label, randomized controlled trial. Subjects were randomized equally into treatment groups. All subjects received ZDV and ddC, while half also receive IFN-alpha (3 MU subcutaneously every 24 hr). At 48 weeks the median average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA for the two-drug group was -0.68 versus -0.75 log10 copies/ml for the IFN-alpha group (p = 0.046). Mean HIV-1 RNA changes from baseline to 48 weeks for these groups were -0.65 and -1.12 log10 copies/ml, respectively (p = 0.010). The median AAUCMB for CD4+ cell count for the two-drug group was 28 versus -1 cells/mm3 for the IFN-alpha group (p = 0.011). Neutropenia, anemia, and drug intolerance were more common in the IFN-alpha group. This study demonstrates that IFN-alpha inhibits HIV-1 replication but attenuates the CD4+ cell response to dual therapy with ZDV and ddC.

Rapidly progressive herpetic retinal necrosis: a blinding disease characteristic of advanced AIDS.

Eleven patients with rapidly progressive herpetic retinal necrosis (RPHRN) complicating AIDS were investigated retrospectively to study the disease spectrum, systemic involvement, and therapy. The mean CD4 cell count was 24/microL. There was a characteristic disease pattern with rapid progression, 82% bilaterality, relative resistance to intravenous antiviral therapy, and 70% retinal detachment. Varicella-zoster virus was the probable cause in 10 patients (detected by polymerase chain reaction in two eyes investigated), and herpes simplex virus was the probable cause in one. Cutaneous zoster occurred previously in 73% but was not concurrent. Seventy-three percent had central nervous system disease, possibly virus-related. RPHRN may be a local herpetic recrudescence in an immune-privileged site with transneural spread. Only four of 20 affected eyes retained useful vision. Poor ocular bioavailability, retinal ischemia, acquired drug resistance, and strain pathogenicity may underlie treatment failure. Acyclovir therapy appears relatively ineffective. Combined intravenous and intravitreal therapy with foscarnet and ganciclovir may be the best current management. Research advances are needed urgently.

Herpesvirus disease: an update.

The human herpesvirus family is larger than previously appreciated. It is implicated in the causation of illness previously unrecognized or unknown. There are diagnostic developments of useful clinical significance now in herpesvirus disease. The armamentarium of effective tolerable therapeutic agents for herpesvirus infection is expanding greatly. Even more dramatic advances are eagerly anticipated.

Early initiation of antiretroviral therapy for infection with human immunodeficiency virus: considerations in 1996.

In this AIDS Commentary, Dr. Nadler provides a rationale for early initiation of antiretroviral therapy in patients infected with human immunodeficiency virus (HIV). Although no definitive clinical trials have been published that are relevant to the question of whether early treatment will produce long-term benefit, many experienced investigators believe that early reduction in the level of viral replication will effectively prolong clinical latency of the infection and immunologic stability. A second question is that of the best combination of antiretroviral agents to be used for early treatment of HIV infection. A third issue is whether initial therapy should be continued until there is evidence of virological, immunologic, or clinical progression of disease, or alternatively, whether a course of induction therapy with the most potent combination of agents should be followed by a treatment-free period or by less-aggressive maintenance therapy. These issue will continue to be debated over the next several months. Dr. Nadler's review is timely, and it is a useful statement of the questions to be answered regarding treatment of early HIV infection.

Infections in HIV-infected patients with malignancy.

With the increasing prevalence of HIV, better combination treatment regimens, and preventive therapy for opportunistic infections, physicians will be caring for an ever-increasing number of survivors with an ever-dwindling immune function. Increasing this burden is the unfortunate patient who also develops cancer concurrent with HIV infection. The combined risk factors of these diseases make a worst-case scenario in evaluation and treatment of infections. This article reviews AIDS-defining tumors and other malignancies, risk factors for infection, opportunistic infections, and therapy strategies.

Case report: Yersinia enterocolitica necrotizing pneumonia in an immunocompromised patient.

The authors report a rare case of Yersinia enterocolitica necrotizing pneumonia in an immunocompromised patient, who responded with resolution of the infection after 6 weeks of therapy with a third-generation cephalosporin but subsequently expired from the underlying lymphoma. In the few cases of Y. enterocolitica pulmonary infections that have been reported, the prognosis for cure of the infection is excellent with appropriate antibiotic therapy. Y. enterocolitica is likely to be recognized more frequently as a cause of serious infection in the growing immunosuppressed population. Early recognition and appropriate therapy can improve survival significantly.

Abdominal abscess due to Cardiobacterium hominis and Clostridium bifermentans.

A case of abdominal abscess and bacteremia due to Cardiobacterium hominis and Clostridium bifermentans was successfully treated with surgical drainage and ampicillin-penicillin. This case represents the rare occurrence of C. hominis infection without apparent endocarditis.

Amoxicillin-clavulanic acid for treating drug-resistant Mycobacterium tuberculosis.

This report describes two patients with multidrug resistant tuberculosis who were successfully treated with the addition of amoxicillin-clavulanic acid to second-line drugs. Mycobacterium tuberculosis possesses a beta-lactamase contributing to its resistance to beta-lactam antibiotics. The combination of clavulanic acid, a beta-lactamase inhibitor, and amoxicillin has been shown bactericidal for M tuberculosis in vitro. These data suggest that resistant tuberculosis may warrant a trial of treatment including amoxicillin-clavulanic acid.

Hepatitis B virus in a cardiopulmonary resuscitation training course. Risk of transmission from a surface antigen-positive participant.

A group exposure to cardiopulmonary resuscitation training manikins contaminated by saliva from a participant during the immediate presymptomatic infectious stage of "e" antigen-positive hepatitis B recently occurred. None of the 18 susceptible participants developed serologic or clinical evidence of new hepatitis B infection during the six-month postexposure observation period. The risk of transmission in this setting appears to be low. Postexposure prophylaxis does not appear indicated.

The effect of adenosine analogues on the in vitro growth of Trypanosoma cruzi.

Trypanosoma cruzi (Brazil strain) was maintained in liver infusion tryptose and medium supplemented with 5 or 10% foetal calf serum at 27 degrees C on a rotating shaker platform. 85 to 95% of the organisms under these conditions are epimastigotes and the medium supported logarithmic growth for up to 24 hours. The effect of S-isobutyl adenosine and Sinefungin against cultured T. cruzi epimastigotes was studied: growth rate was slowed by both in a dose-dependent fashion; 500 micrometer Sinefungin caused complete inhibition which was irreversible after 24-hour exposure but the effect of S-isobutyl adenosine (100 micrometer) was reversible. Motility and morphology appeared to be unaffected.

Taxol, a microtubule stabilizing agent, blocks the replication of Trypanosoma cruzi.

Taxol, an experimental antitumor agent and stabilizer of microtubules, inhibits in vitro replication of the human pathogenic hemoflagellate Trypanosoma cruzi. Micromolar concentrations of the drug prevent the completion of cell division in these organisms but allow the multiplication of cell organelles such as the nucleus, kinetoplast, and flagellum. The result is the formation of motile organisms that have extra organelles but cannot fully replicate. Division proceeds to a relatively fixed locus on the long axis of the organism, suggesting the presence of a specific affected structure or function at this site. It is postulated that taxol produces these effects by stabilizing a portion of the microtubular cytoskeleton of T. cruzi.