Browsing by Author "Lederman, Michael M."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Changes in Immune Activation During Pregnancy and the Postpartum Period in Treated HIV Infection
    (Oxford University Press, 2021) Schnittman, Samuel R.; Byakwaga, Helen; Boum, Yap; Kabakyenga, Jerome; Matthews, Lynn T.; Burdo, Tricia H.; Huang, Yong; Tracy, Russell P.; Haberer, Jessica E.; Kembabazi, Annet; Kaida, Angela; Moisi, Daniela; Lederman, Michael M.; Bangsberg, David R.; Martin, Jeffrey N.; Hunt, Peter W.
    Pregnant women with HIV (PWWH) have high postpartum morbidity and mortality from infections like tuberculosis. Immunologic changes during pregnancy and postpartum periods may contribute to these risks, particularly the immunoregulatory kynurenine pathway of tryptophan catabolism, which contributes to both HIV and tuberculosis pathogenesis and increases in the early postpartum period. Women with HIV initiating antiretroviral therapy (ART) in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort who were pregnant at enrollment or became pregnant during observation were studied (n = 54). Plasma kynurenine/tryptophan (KT) ratio, soluble CD14 (sCD14), sCD163, sCD27, interferon-inducible protein 10 (IP-10), D-dimer, interleukin-6, and intestinal fatty-acid binding protein levels were assessed through the first year of ART and at 3-month intervals throughout pregnancy and 1 year postpartum. Biomarker changes were assessed with linear mixed models adjusted for ART duration. Hemoglobin concentration changes were used to estimate pregnancy-related changes in plasma volume. Results. The median pre-ART CD4 count was 134. D-dimer increased through the third trimester before returning to baseline postpartum, while most other biomarkers declined significantly during pregnancy, beyond what would be expected from pregnancy associated plasma volume expansion. IP-10 and sCD14 remained suppressed for at least 12 months postpartum. KT ratio was the only biomarker that increased above prepregnancy baseline postpartum (mean + 30%; P < .001) and remained higher than baseline for ≥9 months (P ≤ .045 for all time points). Several immune activation markers decline during pregnancy and remain suppressed postpartum, but the kynurenine pathway of tryptophan catabolism increases above baseline for ≥9 months postpartum. The mechanisms underlying postpartum kynurenine pathway activity are incompletely understood but may contribute to increased tuberculosis risk in this setting.
  • Thumbnail Image
    Item
    Dose-Modified Oral Chemotherapy in the Treatment of AIDS-Related Non-Hodgkin’s Lymphoma in East Africa
    (2009-05-26) Mwanda, Walter O; Orem, Jackson; Fu, Pingfu; Banura, Cecilia; Kakembo, Joweria; Onyango, Caren Auma; Ness, Anne; Reynolds, Sherrie; Johnson, John L.; Subbiah, Vivek; Bako, Jacob; Wabinga, Henry; Abdallah, Fatuma K.; Meyerson, Howard J.; Whalen, Christopher C.; Lederman, Michael M.; Black, Jodi; Ayers, Leona W.; Ayers, Leona W.; Katongole-Mbidde, Edward; C., Scot; Remick, Scot C.
    Purpose Africa is burdened by the AIDS epidemic and attendant increase in HIV/AIDS-related malignancies. Pragmatic approaches to therapeutic intervention could be of great value. Dose-modified oral chemotherapy for AIDS-related non-Hodgkin's lymphoma is one such approach. Patients and Methods The oral regimen consisted of lomustine 50 mg/m2 on day 1 (cycle 1 only), etoposide 100 mg/m2 on days 1 to 3, and cyclophosphamide/procarbazine 50 mg/m2 each on days 22 to 26 at 6-week intervals (one cycle) for two total cycles in HIV-infected patients with biopsy-proven non-Hodgkin's lymphoma. Results Forty-nine patients (21 in Uganda and 28 in Kenya) were treated. The majority of patients were female (59%) and had a poor performance status (63%); 69% of patients had advanced-stage disease; and 18 patients (37%) had access to antiretroviral therapy. In total, 79.5 cycles of therapy were administered. The regimen was well tolerated, had modest effects (decline) on CD4+ lymphocyte counts (P = .077), and had negligible effects on HIV-1 viral replication. Four febrile neutropenia episodes and three treatment-related deaths (6% mortality rate) occurred. The overall objective response rate was 78% (95% CI, 62% to 88%); median follow-up time was 8.2 months (range, 0.1 to 71 months); median event-free and overall survival times were 7.9 months (95% CI, 3.3 to 13.0 months) and 12.3 months (95% CI, 4.9 to 32.4 months), respectively; and 33% of patients survived 5 years. Conclusion Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the United States in the pre–highly active antiretroviral therapy setting, has an acceptable safety profile, and is pragmatic in sub-Saharan Africa. The international collaboration has been highly successful, and subsequent projects should focus on strategies to optimize combination antiretroviral therapy and chemotherapy and follow-up tissue correlative studies.
  • Thumbnail Image
    Item
    Immunologic Pathways That Predict Mortality in HIV-Infected Ugandans Initiating Antiretroviral Therapy
    (The Journal of infectious diseases, 2017) Lee, Sulggi; Byakwaga, Helen; Boum, Yap; Burdo, Tricia H.; Williams, Kenneth C.; Lederman, Michael M.; Huang, Yong; Tracy, Russell P.; Cao, Huyen; Haberer, Jessica E.; Kembabazi, Annet; Bangsberg, David R.; Martin, Jeffrey N.; Hunt, Peter W.
    The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings.
  • Thumbnail Image
    Item
    Therapeutic Challenges of AIDS-Related Non-Hodgkin’s Lymphoma in the United States and East Africa
    (2002-05) Otieno, Mwanda W.; Banura, Cecily; Katongole-Mbidde, Edward; Johnson, John L.; Dowlati, Afshin; Renne, Rolf; Arts, Eric; Whalen, Christopher; Lederman, Michael M.; Remick, Scot C.
    Abstract Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. As we enter the third decade of the acquired immunodeficiency syndrome (AIDS) epidemic, it is apparent that the evolution of antiretroviral therapy and the emergence of combination antiviral strategies have greatly affected the natural history of HIV infection and its neoplastic complications. For example, there may be a trend for declining incidence of AIDS-related lymphoma in the United States for the first time. However, in regions of the world where the burden of HIV infection is greatest, such as in East Africa, AIDS-related lymphoma is an increasing cause of morbidity and mortality. Treatment of lymphoma has evolved coincident with improvements in antiretroviral therapy. Infusional chemotherapy regimens may offer advantages over other regimens and schedules, but comparative trials have not been done. Clinical trial data are available on which to develop therapeutic strategies to treat this disease in East Africa where pragmatic approaches are needed. Both the differences in manifestations of HIV infection and the inherent difficulties in administering cytotoxic chemotherapy in this part of the world must be taken into consideration in planning therapeutic strategies. Improved understanding of the pathogenesis of HIV infection and lymphoma will likely yield improved therapeutic interventions as well.