Steven A. Miles

Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine

Bone marrow suppression and anemia are frequent side effects of treatment of the acquired immunodeficiency syndrome (AIDS) with zidovudine (formerly azidothymidine [AZT]). We conducted a randomized, double-blind, placebo-controlled clinical trial of recombinant human erythropoietin (100 U per kilogram of body weight thrice weekly by intravenous bolus) in 63 patients with AIDS treated with zidovudine (29 in the erythropoietin group and 34 in the placebo group). Reductions in the number of units of red cells transfused and the number of patients given transfusions per month became apparent in the second and third months of the trial. The reductions were observed in patients with endogenous erythropoietin levels less than or equal to 500 IU per liter at base line, but not in patients whose levels were greater than 500 IU per liter at the beginning of the study. Although the hematocrit and hemoglobin level were not used as the primary criteria of efficacy because the patients received transfusions when their physicians decided that they needed them, a significantly higher rate of increase in the hematocrit was observed in the patients treated with recombinant human erythropoietin whose levels of endogenous erythropoietin were less than or equal to 500 IU per liter (0.00353 points per week) than in the patients given placebo (0.00116 points per week). This effect was not seen in patients with higher levels of endogenous erythropoietin. Serious side effects did not occur more often in the group treated with erythropoietin than in the placebo group. We conclude that recombinant human erythropoietin may be useful in patients with AIDS treated with zidovudine, although the indicators for its use remain to be clarified.

Recombinant Human Erythropoietin in the Treatment of Anemia Associated with Human Immunodeficiency Virus (HIV) Infection and Zidovudine Therapy: Overview of Four Clinical Trials

OBJECTIVE To assess the effect of recombinant human erythropoietin (r-HuEPO) on anemia in patients with the acquired immunodeficiency syndrome (AIDS) who are receiving zidovudine therapy. DESIGN Combined analysis of four 12-week, randomized, double-blind, controlled clinical trials. SETTING Multiple centers in the United States. PATIENTS Two hundred and ninety-seven anemic (hematocrit < 30%) patients with AIDS who were receiving zidovudine therapy. Of the 297 patients, 255 were evaluable for efficacy, but all patients were included in analysis of safety. INTERVENTION Patients were randomly assigned to receive either r-HuEPO (100 to 200 U/kg body weight) or placebo, intravenously or subcutaneously, three times per week for up to 12 weeks. MEASUREMENTS Changes in mean hematocrit, transfusion requirement, and quality of life. RESULTS Sixty-nine percent of patients had endogenous serum erythropoietin levels less than or equal to 500 IU/L, and 31% had erythropoietin levels greater than 500 IU/L. In patients with low erythropoietin levels (< or equal to 500 IU/l), r-HuEPO therapy decreased the mean number of units of blood transfused per patient when compared with placebo (3.2 units and 5.3 units, respectively; P = 0.003) and increased the mean hematocrit from the baseline level (4.6 percentage points and 0.5 percentage points, respectively; P <0.001). Overall quality of life improved in patients on r-HuEPO therapy (P = 0.13). Patients with erythropoietin levels greater than 500 IU/L showed no benefit from r-HuEPO in any outcome variable. Placebo and r-HuEPO recipients did not differ in the incidence of adverse effects or opportunistic infections. CONCLUSION Therapy with r-HuEPO can increase the mean hematocrit and decrease the mean transfusion requirement in anemic patients with AIDS who are receiving zidovudine and have endogenous low erythropoietin levels (< or equal to 500 IU/L). Such therapy is of no apparent benefit in patients whose endogenous erythropoietin levels are higher than 500 IU/L.

Antitumor activity of oral 9-cis-retinoic acid in HIV-associated Kaposi's sarcoma.

Objective To assess the efficacy, safety and tolerance of oral 9-cis- retinoic acid in HIV-infected patients with Kaposis sarcoma. Methods Sixty-six patients with AIDS-related Kaposis sarcoma were enrolled at 14 centers; 60 received the study medication and were analyzed and, of these, 45 (75%) had received prior therapy for Kaposis sarcoma. Once daily oral 9-cis-retinoic acid (alitretinoin, Panretin) was administered at doses up to 140 mg/m2. Most patients (72%) received a maximum dose of 100 mg/m2. Response was assessed using AIDS Clinical Trials Group (ACTG) criteria. Results The median age was 38 years and the median absolute CD4 cell count was 194 × 106 cells/l (range 6–784 × 106). Despite the use of three- and four-drug antiviral regimens (83%), the median HIV RNA at baseline was 8701 copies/ml [range < 500 (lower limit of detection) to 4.24 × 106]. The tumor response rate was 37% (95% confidence interval 25–49). Tumor response was associated with improved quality-of-life measures. There was a significant increase in interleukin 6 (IL-6) levels from baseline to week 4. Responders had significantly lower baseline soluble IL-6 receptor levels (P = 0.029) than non-responders. The median time to response was 9 weeks (mean, 13 weeks; range, 4–36). HIV RNA levels did not change significantly during therapy nor did they correlate with tumor responses. Study drug was discontinued by 28 patients for adverse events, which included headache (13) and skin toxicity (10). Conclusion Oral 9-cis-retinoic acid is an active antitumor drug for AIDS-related Kaposis sarcoma. Treatment is associated with skin and constitutional toxicity and further studies are needed to improve its long-term tolerance.

Infection of primary dermal microvascular endothelial cells by Kaposi's sarcoma-associated herpesvirus.

Objective:To develop an in vitro model for infection of primary human cells with Kaposis sarcoma (KS) herpesvirus (KSHV). Design:The recent identification of a herpesvirus associated with KS, its successful isolation in vitro, and its complete DNA sequencing facilitates experiments on the pathogenesis of AIDS-related KS. Completed studies demonstrate that the endothelial cells lining the vascular slits in KS lesions are productively infected with KSHV and may be the principal site of virus replication. We have designed a model system to study the infection of primary human cells with KSHV. Methods:A coculture technique was used with KS cells (KS-1) and primary dermal microvascular endothelial cells. Results:We detected increasing viral DNA concentrations as well as viral mRNA suggesting that a productive virus infection occurs in the target cells. Infection of these cells is dose- and time-dependent and is inhibited by lobucavir, foscarnet and 9-(2-phosphomethoxyethyl) adenine. With a modification of the model, KSHV can be serially passaged in primary cells in excess of 16 passages. Conclusions:This novel model assay system makes new studies on the role of KSHV and KSHV-induced cellular products on the pathogenesis of KS possible. It also provides a high volume screening method to detect agents that inhibit KSHV infection of primary endothelial cells.

Beta-Interferon Therapy in Patients with Poor-Prognosis Kaposi Sarcoma Related to the Acquired Immunodeficiency Syndrome (AIDS): A Phase II Trial with Preliminary Evidence of Antiviral Activity and Low Incidence of Opportunistic Infections

STUDY OBJECTIVE To study the efficacy of high doses of beta-ser-interferon (recombinant human 17-serine beta-interferon) in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN A nonrandomized, controlled trial of two high-dose regimens of beta-ser-interferon administered until tumor progression, toxicity, or an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection occurred. SETTING An AIDS treatment clinic at a tertiary care center. PATIENTS A sequential sample of 39 patients with biopsy-proven, AIDS-related Kaposi sarcoma were enrolled during a 2-year period. Thirty-eight patients were evaluable for response. Most patients (35 of 38) had one or more of the following clinical or laboratory predictors for a poor response to interferon therapy: HIV p24 antigenemia, low CD4 cell numbers, elevated beta 2-microglobulin levels, previous opportunistic infections, or previous systemic chemotherapy. INTERVENTIONS Beta-ser-interferon was self-administered subcutaneously at home 5 days per week. The first 21 patients used 90 million IU/d, and the remainder used 180 million IU/d. MEASUREMENTS AND MAIN RESULTS Six patients (16%) had a major clinical response, and 15 (39%) had stable disease for prolonged periods. Toxicities were minimal; the major toxicity was a skin reaction at the injection site. The HIV p24 antigen level declined more than 50% in 8 of the 19 patients with initial values greater than 50 pg/mL. Antiretroviral activity and antitumor activity were seen only in patients with normal initial beta 2-microglobulin levels. Minimal changes were seen in CD4 and CD8 cell numbers. Only 1 patient had an opportunistic infection while on study, but five other patients developed infections after treatment was discontinued for an incidence of six opportunistic infections in 285 patient-observation months. CONCLUSIONS The high doses of interferon did not improve the major response rate in patients with poor-prognosis, AIDS-related Kaposi sarcoma. There was, however, a suggestion of antiviral activity in patients with normal beta 2-microglobulin levels and a decrease in the expected incidence of opportunistic infections.

Pathogenesis of AIDS-related Kaposi's sarcoma : Evidence of a viral etiology

The occurrence of Kaposis sarcoma (KS) in patients with HIV infection is more than 7,000 times higher than in the non-HIV infected population. The reason for this association is unclear but may involve decreased immune surveillance as a result of the profound cellular immune deficiency caused by HIV, a sexually transmitted KS-inducing virus, whose KS-transforming capabilities may be enhanced by HIV, or a direct or indirect effect of HIV itself in susceptible individuals. Over the last few years, advances have been made in our understanding of the pathogenesis of this tumor, and several models have been proposed for its development in the setting of AIDS. Better characterization of the processes involved in the development of KS will ultimately lead to more effective methods of treating and preventing this unusual tumor.

Phase I AIDS Clinical Trials Group (075) study of adriamycin, bleomycin and vincristine chemotherapy with zidovudine in the treatment of AIDS-related Kaposi's sarcoma.

ObjectiveTo determine the toxicity and maximum tolerated dose of doxorubicin (adriamycin) in combination with fixed doses of bleomycin, vincristine (ABV) and zidovudine in patients with advanced AIDS-related Kaposis sarcoma. Patients and methodsTwenty-six HIV-seropositive men with Kaposis sarcoma were treated daily with 100 mg zidovudine orally every 4 h, along with combination chemotherapy using bleomycin 10 U/m2 and vincristine 1.4 mg/m2 (maximum, 2 mg) given intravenously in 2-week cycles. In addition, three successive cohorts of eight patients received escalating doses of doxorubicin each beginning with no doxorubicin (level I), doses of 10 mg/m2 (level II), and 15 mg/m2 (level III). ResultsThe major dose-limiting toxicity experienced with the combination therapy was severe neutropenia in eight patients, four of whom received level III doxorubicin (15 mg/m2). Therefore, 10 mg/m2 of doxorubicin in combination with zidovudine and BV chemotherapy was defined as the maximum tolerated dose. Other dose-limiting toxicities included neuropathy (n = 2), cutaneous toxicity associated with bleomycin (n = 1), and diarrhea (n = 1). Seventeen patients (71 %; 95% confidence interval, 46–85) experienced either partial (n = 13) or clinical complete remission (n = 4) to therapy after a median of five cycles (range, 2–9). ConclusionThe maximum tolerated dose of doxorubicin is 10 mg/m2 when given in combination with zidovudine and BV chemotherapy. Response rates observed with the combined antiretroviral and chemotherapy regimen are similar to those previously reported with ABV chemotherapy alone.

Improved survival for patients with AIDS-related Kaposi's sarcoma.

PURPOSE We retrospectively analyzed all patients with AIDS-related Kaposis sarcoma (AIDS-KS) seen at one large California medical center to delineate factors that may have contributed to a relative decline in survival. METHODS Potential prognostic factors were analyzed individually, using the Cox proportional hazards regression model, for their association with survival. After a stepwise Cox regression procedure was applied to those factors that showed a significant effect on survival, a subset of factors that best predicted survival was identified. We then quantified the effect of the year of diagnosis on survival using a univariate Cox model. Next, we combined the year of diagnosis with the subset of prognostic factors previously identified into the Cox model to examine survival after adjustment for the prognostic factors. Survival distribution was estimated by the Kaplan-Meier method, and the 95% confidence interval for the median survival was computed using the modified reflected method. RESULTS In 688 patients, we identified four baseline variables that best predicted survival: CD4 cell number, hematocrit, number of KS lesions, and body mass index (BMI). Adjusted for these predictive factors, there was a significant improvement in survival for patients with AIDS-KS over the last 6 years. CONCLUSION Contrary to prior reports, survival has increased for patients with AIDS-KS. The apparent increase in observed mortality is most likely due to a decline in the CD4 cell number at presentation.

Reduced Mobilization of CD34+ Stem Cells in Advanced Human Immunodeficiency Virus Type 1 Disease

Granulocyte colony-stimulating factor (r-met Hu G-CSF; filgrastim; 10 microgram/kg/day for 7 days) was used to mobilize CD34+stem cells into the peripheral blood of human immunodeficiency virus type 1 (HIV-1)-infected individuals and a group of HIV-1-uninfected donors as a measure of immunologic reserve in HIV-1-infected people. G-CSF mobilized CD34+ cells of HIV-1-infected individuals with cell counts >500 CD4+ cells/mm3, as well as in HIV-1-uninfected donors. In contrast, CD34 cell mobilization was significantly blunted in HIV-1-infected individuals with cell counts <500 CD4+ cells/mm3 (<200 cell days vs. >650 cell days, P<.0005, compared with the >500 CD4+ cell cohort). At least 1.75x10(7) CD34 cells were harvested by leukapheresis from patients in each study cohort. CD34+ cell viability and the ability to differentiate precursor cells into myeloid and erythroid progenitor cells were not affected by HIV-1 infection.

Immune dysfunction and the pathogenesis of AIDS-associated non-Hodgkin's lymphoma.

Much has been learned about how HIV-induced immune dysfunction contributes to B cell hyperactivation, and potentially, to the pathogenesis of AIDS-lymphoma. However, further studies are needed to fully understand how HIV infection and immune dysfunction promote B cell hyperactivation and the development/growth of AIDS-lymphoma. In particular, studies are needed to define the role of HHV8 vIL6, IL6 receptor-expression, and lymphocyte surface stimulatory molecules, in promoting B cell hyperactivation or lymphoma cell growth.