Carinii Prophylaxis Research Articles

Bacterial Infection Among Patients With Multiple Myeloma Treated With Bortezomib-based Induction Therapy: Real-World Experience in an Asian Cancer Center

BackgroundThe treatment landscape for multiple myeloma (MM) has progressed significantly, and over the past decade, bortezomib-based induction therapy has been a standard of care. However, the practice of antibacterial prophylaxis during induction therapy has been diverse. The aim of our study is to evaluate the proportion of patients with febrile episodes and bacteremia among patients with MM, during the first 12 weeks of bortezomib-based induction therapy, without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), in a region with high fluoroquinolone resistance rate. Of note, these patients have direct access to health care facilities and timely supportive care. Patients and MethodsWe evaluated newly diagnosed MM patients from 2014 to 2018 receiving bortezomib-based induction therapy for the proportion of patients who had febrile episodes and bacteremia in the first 12 weeks of bortezomib-based induction therapy. We also evaluated if there were factors associated with increased febrile episodes including age, absolute neutrophil count, creatinine clearance, M-band level at diagnosis, nadir platelet count, International Staging System, and Revised International Staging System. ResultsOf the 108 evaluable patients, there were a total of 25 (23.1%) patients who had febrile episodes, and 1 (0.9%) patient who had bacteremia during the first 12 weeks of bortezomib-based induction therapy. All patients recovered well. No deaths were seen. Febrile episodes were associated with lower absolute neutrophil count (P = .036), renal impairment (P = .013), and ISS stage (P = .026). ConclusionThe proportion of patients with significant bacterial infection during the first 12 weeks of bortezomib-based induction therapy without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), is low in a population with adequate access to health care facilities and timely supportive care.

76-Year-Old Woman With Generalized Weakness

76-Year-Old Woman With Generalized Weakness

Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens

Anti-human leukocyte antigen (HLA) antibodies are associated with several complications in solid organ transplantations, but their impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not yet well defined. To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allo-HSCTs after reduced-intensity conditioning regimen between 2005 and 2010. Acute myeloid leukemia and multiple myeloma were the most frequent malignancies in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Anti-HLA antibodies were present in 24 patients (22%). There was no significant impact of anti-HLA antibodies on engraftment, incidence of relapse, and incidence of acute graft-vs-host disease. The presence of anti-HLA antibodies was associated with significantly worse overall survival (p = 0.006) and event-free survival (p = 0.024) after stratification on sex. The 3-year probability of overall survival was 34% without anti-HLA antibodies and 16% in their presence. Patients with anti-HLA antibodies had a higher transplant-related mortality associated with life-threatening vascular complications. Our study supports that anti-HLA antibodies should be tested and considered as an important impacting factor for transplantation outcomes after reduced-intensity conditioning allo-HSCT. We recommend its consideration before allo-HSCT in the donor-recipient selection parameters.

Fever and Rash in an 8-month-old Girl

Fever and Rash in an 8-month-old Girl

The Vermont Model for Rural HIV Care Delivery: Eleven Years of Outcome Data Comparing Urban and Rural Clinics

Provision of human immunodeficiency virus (HIV) care in rural areas has encountered unique barriers. To compare medical outcomes of care provided at 3 HIV specialty clinics in rural Vermont with that provided at an urban HIV specialty clinic. This was a retrospective cohort study. Over an 11-year period 363 new patients received care, including 223 in the urban clinic and 140 in the rural clinics. Patients in the 2 cohorts were demographically similar and had similar initial CD4 counts and viral loads. There was no difference between the urban and rural clinic patients receiving Pneumocystis carinii prophylaxis (83.5% vs 86%, P= .38) or antiretroviral therapy (96.8% vs 97.5%, P= .79). Both rural and urban cohorts had similar decreases in median viral load from 1996 to 2006 (3,876 copies/mL to <50 copies/mL vs 8,331 copies/mL to <50 copies/mL) and change in percent of patients suppressed to <400 copies/mL (21.4%-69.3% vs 16%-71.4%, P= .11). Rural and urban cohorts had similar increases in median CD4 counts (275/mm(3)-350/mm(3) vs 182 cells/mm(3)-379/mm(3)). A repeated measures regression analysis showed that neither fall in viral load (P= .91) nor rise in CD4 count (P= .64) were associated with urban versus rural site of care. Survival times, using a Cox proportional hazards model, were similar for urban and rural patients (hazard ratio for urban = 0.80 [95% CI, 0.39-1.61; P= .53]). This urban outreach model provides similar quality of care to persons receiving care in rural areas of Vermont as compared to those receiving care in the urban center.

Phase I/II trial of clofarabine in refractory and/or relapsed non-hodgkin’s lymphoma (NHL)

8564 Background: Clofarabine (CLO) is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. Given the lack of standard therapy in refractory and transplant-ineligible relapsed NHL, we investigated the activity of CLO in this patient (pt) population regardless of histology. Methods: Eligible pts had relapsed and/or refractory NHL with measurable disease, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease- related). CLO was given intravenously over 1-hour days 1–5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti- pneumocystis carinii prophylaxis. A standard 3x3 phase I study design was used with CLO 4 mg/m2 in cohort 1 and subsequent cohorts escalated by 2 mg/m2. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression. Results: To date, 14 pts have been enrolled with 7 patients each in the phase I and II portions. Including all pts, median age was 78 years (27–84), median number of prior therapies was 2.5 (1–8), and 3 pts (21%) relapsed after autologous stem cell transplantation. Histologies included 4 diffuse large cell, 3 small lymphocytic, 2 anaplastic large cell, 2 mixed large cell/follicular, 1 follicular, 1 refractory marginal zone, and 1 Richter’s transformation. Median CLO cycles were 2.5 (1–6). Grade 3/4 non-hematologic toxicities were: 1 (7%) grade 3 pleural effusion and 2 (14%) grade 3 fatigue. All pts required growth factor support and 2 pts on the phase II portion required a dose reduction. Thrombocytopenia was the dose-limiting toxicity at 6 mg/m2 in 2/6 patients. The MTD and recommended phase II dose was 4 mg/m2. Responses: 2 (14%) complete responses lasting 4 and 12+ months, 3 (21%) partial responses, 1 minor response, and 1 stable disease. The overall response rate was 35% for this heavily pretreated pt population. With a median follow up of 5 months (1–13), the median duration of response has not been reached and 6 patients remain alive (42%). Conclusions: To our knowledge, this is the first report to establish clinical activity with CLO in refractory and/or relapsed NHL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genzyme Genzyme

Clofarabine (CLO) Is Active in Patients (pts) with Refractory and/or Relapsed Non-Hodgkin's Lymphoma (NHL): A Phase I/II Study.

There is no known standard of care for pts with relapsed and/or refractory NHL who cannot undergo stem cell transplantation (SCT) or have relapsed after SCT. Such pts are candidates for new therapies. CLO is a novel nucleoside analogue with known activity in acute leukemia and myelodysplasia. Previous clinical trials with CLO have established safety and potential activity in a variety of tumors. We performed a phase I/II study of CLO in a heavily pretreated pt population with refractory and/or relapsed NHL regardless of cell type, histology, or grade. Eligible pts were adults over 18 years of age who have relapsed and/or refractory NHL with measurable disease. Pts were required to have adequate performance status, bone marrow function (unless cytopenias were related to disease involvement), renal, cardiac, and liver functions. Pts with bulky disease (>10 cm at any site), known HIV, or immune-related cytopenias were excluded. CLO was given as a 1-hour intravenous infusion for 5 consecutive days every 28 days for a maximum of 6-cycles. All enrolled pts received anti-viral and anti-pneumocystis carinii prophylaxis. Growth factors were administered at the investigator's discretion. Pts were divided into cohorts of 3 each. CLO was given at 4 mg/m2 to the first cohort with escalated doses by 2 mg/m2 increments for each cohort. Once the dose-limiting toxicity (DLT) was reached, the phase II portion of this study was initiated at the dose below the DLT level. All pts were followed until disease progression. To date, 13 pts have been enrolled with 7 on the phase I portion and 6 on the phase II portion. For the phase I portion, the median age was 79 (range: 27–81); the median number of prior therapies was 5 (range: 2–6) with 3 pts having relapsed after prior SCT. The median number of given CLO cycles in the phase I portion was 2 (range: 1–5). The DLT at 6 mg/m2 was thrombocytpenia establishing 4 mg/m2 as the appropriate dose for phase II. For the phase II portion, the median age was 78 (range: 50–83), median number of prior therapies was 2 (range: 1–8). Taken all together (phase I and II pts), 9 out of 13 pts are evaluable for response. (All received at least 1 cycle). There was 1 complete response (CR) and 4 partial responses (PR) for an overall response rate (OR) of 55%. Four patients demonstrated stable disease (SD) with one of them progressing shortly after 2 months. Eight patients remain alive (overall survival: 61%) at a median follow up of 4 months (range: 1–13). Median times to progression and duration of response have not been reached in responding pts. [Display omitted] CLO is active in heavily pretreated refractory and/or relapsed NHL. The drug has an acceptable toxicity profile. Myelosuppresion is the major adverse event in this heavily pretreated population. The study continues to accrue patients and will be updated at the meeting.

Subcutaneous Alemtuzumab Is Safe and Effective for Treatment of Global or Single-Lineage Immune-Mediated Marrow Failure: A Pilot Study.

Acquired marrow failure syndromes may globally affect all hematopoietic lineages, as in severe aplastic anemia (SAA), or may selectively involve single lineages, as in pure red cell aplasia (PRCA) or in agranulocytosis (AGR). All these conditions share a cellular immune-mediated pathophysiology, which is supported by many experimental data; thus, various immunosuppressive (IS) strategies have been exploited. Alemtuzumab (MabCampath®) (ALE) is a lympholytic MoAb with strong and prolonged IS activity, more reliable than ATG or ALG as for activity, dosing and commercial availability. Here we report a phase II/III pilot study with ALE followed by low-dose cyclosporine A (CsA) on 11 patients suffering from SAA (n=4), PRCA (n=5) or AGR (n=2). All patients received ALE as s.c. injection premedicated by betamethasone, clorpheniramine and paracetamol, with a dose escalating schedule of 3-10-30-30-(30) mg in consecutive days; the total dose was 103 mg for SAA, and 73 for PRCA and AGR. Six patients received one or more additional courses as a result of relapse, so a total of 18 courses were administered. All patients on day 7 started oral low dose CsA (1 mg/kg). Valgancyclovir 450 mg bi-daily and trimethoprim-sulphamethoxazole bi-daily thrice a week were administered as anti-CMV and anti-Pneumocystis Carinii prophylaxis, respectively. All patients completed the treatment, with severe or moderate infusion-related side effect (fever, chills and/or injection site reaction) occurring in 1 (not premedicated) and 3 cases, respectively. No significant abnormality of routine biochemical testing, nor other medically significant adverse events were reported. A complete lympho-ablation was observed in all patients within 2–3 days, which persisted for several weeks; in addition, transient worsening of neutropenia (managed by occasional G-CSF support) and of thrombocytopenia were observed in some patients. At a median follow-up of 6 months, infectious events were irrelevant: in cumulative 75 patient-months, 1 HSV and 1 flu have been recorded (globally 1 day of fever), all resolving quickly. No CMV reactivation was demonstrated. Immune reconstitution was delayed up to several months, with absolute lymphocyte count ranging between 30–200/uL, 100–400/uL, 250–800/uL and 500–2000/uL at months +1, +3, +6 and +12 from the treatment. The CD4+ compartment was significantly more affected than the CD8+, with a persistent inversion of the CD4/CD8 ratio. As for efficacy, the 4 SAA patients showed 1 CR, 1 PR (both relapsing at 6 months and re-treated with additional ALE courses), 1 NR at 3 months (addressed to early stem cell transplantation due to life-threatening hemorrhages); 1 is not evaluable yet. In the 5 PRCAs, there were 4 CR and 1 NR (at 3 months); 3 responding patients relapsed and were successfully managed by further courses of ALE. The 2 AGRs showed both CR, followed by late relapse (at 18 months) in one case (now receiving a second course). In conclusion, ALE administered as subcutaneous injection is a feasible and safe IS regimen for patients suffering from immune-mediated marrow failure syndromes. Infectious complications were unremarkable, and preliminary results suggest good efficacy, especially in lineage-restricted forms; as with other IS regimens, the hematological response is late (3–4 months) and relapses may occur, which are sensitive to further ALE courses. Such favorable risk-to-benefit ratio predicts for this regimen a leading position in the future IS strategies.

Dose-Dense Rituximab in Combination with Biweekly CHOP-14 for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of a Phase-I/II and Pharmacokinetic Study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Biweekly application of rituximab in combination with biweekly CHOP (R-CHOP-14) results in a slow increase of rituximab serum levels up to cycle 5 and the achievement of a plateau between the 5th and the last rituximab application suggesting a saturation kinetics of rituximab(Reiser et al., JCO 2006., 24:431s). With the aim of achieving high rituximab levels early during the treatment phase, a phase I/II and pharmacokinetic study was started in elderly patients with DLBCL. Elderly patients (61–80 years, stages I–IV) received 6 cycles of CHOP-14 together with 12 applications of rituximab (375 mg/m2) given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Blood samples were taken before and after rituximab, as well as 1 week, and 1, 2, 3, 6 and 9 months after the last rituximab infusion. Fresh frozen serum samples were analyzed by Xendo Lab., Groningen, The Netherlands. By June 30, 2006, 76 patients with DLBCL (median age 70 years; IPI=1: 21%, IPI=2: 24%; IPI=3: 37%; IPI=4,5: 18%) have been enrolled. Pharmacokinetic data were obtained from the first twenty patients. The median trough serum levels (mg/ml) of rituximab before each rituximab infusion were: day 0: 0; day 1: 132; day 4: 171; day 8: 172, day 15: 153, day 22: 187, day 29: 175, day 43: 153, day 57: 140, day 71: 129, day 85: 128, day 99: 154. After therapy rituximab levels were 122 at 1 month, 50 at 2 months, 25 at 3 months, with levels at 6 months and at 9 months remaining to be determined. Of the first twenty patients three died of therapy-associated complications (1 sepsis, 2 interstitial pneumonia). 4 additional patients had interstitial pneumonia. After the first 20 patients, pneumocysits carinii (co-trimoxazole) and CMV prophylaxis (acyclovir) became mandatory and no interstitial pneumonia has been observed since in patients under prophylaxis. 46 patients have completed immunochemotherapy and no progression was observed under immunochemotherapy. In summary, this schedule of early rituximab dose-densification achieves a rituximab serum level plateau already with the second application of rituximab, i.e. on day 1 of the first CHOP-14 cycle. This is in contrast to a bi-weekly application, whereby the plateau is not achieved until day 57, i. e. nearly 2 months later or compared to the conventional three-weekly application, where a plateau can be expected to be achieved even later. Infectious complications, in particular interstitial pneumonias are of concern, but appear to be controlled by pneumocystis and CMV prophylaxis. The fast and high response rate together with the apparently reduced rate of progressions under therapy are encouraging. An update of the phase-II trial will be presented.

Fludarabine, Mitoxantrone and Dexamethasone for the First Line Treatment of Patients with Indolent Non-Hodgkin Lymphoma (NHL): GATLA First Interim Report (Grupo Argentino de Tratamiento de la Leucemia Aguda).

Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL.Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006).Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age > 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging:5,8%,14,5%,24,6% and55%.FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year.Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR.Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.

Subcutaneous Alemtuzumab as Treatment Option for Patients with Severe Aplastic Anemia or Lineage-Restricted Aplasia.

Severe aplastic anemia (SAA) is a typical acquired marrow failure syndrome, presenting with pancytopenia associated to an empty marrow. Less frequent forms of mono-lineage cytopenia may be due to selective aplasia, as in pure red cell aplasia (PRCA) or in agranulocytosis. The link among these conditions is their cellular immune-mediated pathophysiology, which is supported by many experimental data; for these conditions different immunosuppressive strategies have been employed. Here we report our preliminary experience with alemtuzumab as alternative immunosuppressive therapy in patients failing or not eligible for standard immunosuppression. Three patients have been treated: (i). a 39 year-old male affected by SAA, who had failed to respond to two lines of therapy; (ii). a 55 year-old female, suffering from recurrent agranulocytosis, responding to methylprednisone (MP) for 4 years but then refractory to MP, cyclosporine A (CsA) and G-CSF; (iii). a 60 year-old male affected by PRCA, who developed significant early toxicity by steroid treatment. All patients received alemtuzumab as subcutaneous injection, with a dose escalating schedule of 3–10–30–30–(30) mg in consecutive days; the total dose was 103 mg for SAA, and 73 for PRCA and agranulocytosis. The patients received MP 1 mg/kg in concomitance with alemtuzumab, with the exception of the PRCA patient, due to his previous steroid toxicity; all patients on day 7 started low dose CsA (1 mg/kg). Valgancyclovir 450 mg bi-daily and trimethoprim-sulphamethoxazole bidaily twice a week were administered as anti-CMV and anti-Pneumocystis Carinii prophylaxis, respectively. Two of the patients completed the treatment without any side effect, while the PRCA patient experienced injection-related febrile reactions, managed by doubling the dose interval. No significant abnormality of routine biochemical tests was reported. A complete lympho-ablation was observed in all patients within 3–4 days, which persisted for 3 months. No infectious event was observed at a median follow-up of 6 months, nor other medical complications. After 6 months, flow cytometry documented a partial T cell recovery, with persistence of CD4+ cells reduction. No GPI-anchored protein deficient clone was documented within each blood cell lineage. As efficacy of the treatment is concerned, the patients will be described individually. The SAA patient did not show any clinical improvement at +8 months from treatment, with persistent platelet and red cell transfusion requirement. In contrast, the women affected by agranulocytosis showed early and stable response, with absolute neutrophil counts raising from 0 to 3,000/uL (15,000/uL during G-CSF administration); at +6 months from treatment, she is well, free from any treatment, with the exception of a weekly dose of G-CSF. Finally, the PRCA patient did not show any improvement for 3 months, still requiring transfusions. In the fourth month, he suddenly showed a marked rise of reticulocyte count (130,000/uL), which leaded in few weeks to transfusion independence and hemoglobin stabilization; at +6 months, he is on low dose CsA with hemoglobin >12 g/dL. In conclusion, alemtuzumab administered as subcutaneous injection is a feasible and safe treatment which may be indicated for patients suffering from immune-mediated acquired marrow failure syndromes. Its positioning in the setting of immunosuppression is still to be established, and promises to be pivotal if the favourable risk-to-benefit profile shown in this preliminary experience will be confirmed.

A 5-Year-Old Girl With Impaired Renal Function After Autologous Bone Marrow Transplantation

ONE MARROW TRANSPLANTATION(BMT) increasingly is used for the treatmentof patients with hematologic malignancies, somemetabolic and immunologic diseases, and de-pressed bone marrow after cancer treatment. Renalinsufficiency after BMT is common and related tomanycauses.Wepresentthecaseofagirlwhohadrenalinsufficiency4monthsafterautologousBMT.

Children's care.

Deputy health minister Lewis Macdonald this month launched an emergency care framework for children and young people in Scotland.

Complications du traitement de la leucémie lymphoïde chronique par Campath-1H (alemtuzumab ou MabCampath ®) et par flavopiridol

Treatment of chronic lymphocytic leukaemia (CLL) is rapidly evolving, with emerging new drugs and new therapeutic associations. Campath-1H (alemtuzumab) is a monoclonal antibody recongnizing CD52 antigen, whose action is mainly mediated by ADCC (Antibody Dependant Cell Mediated Cytotoxicity) but also by complement activation and induction of apoptosis. Campath is approved in the treatment of relapsing–refractory CLL after fludarabine. The most frequent complications are infectious with frequent CMV, cocci Gram+ and herpes virus. These complications are especially observed in heavily pre-treated hypogammaglobulinemic patients. Pneumocystis carinii and herpes prophylaxis are recommended, and monitoring of CMV viral load is essential. General symptoms (fever, hypotension, nausea, cutaneous eruption…) during the perfusion may be severe and can be controlled by premedication including steroids. Subcutaneous route of administration seems better tolerated. Flavopiridol, a CDK inhibitor, have recently been tested in CLL. Early developments were disappointing; however, spectacular responses have been recently observed with new modalities of administration but with severe tumor lysis syndromes, which are exceptional in this disease.

Sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab

A 73-year-old woman presented with acute lower back pain, fever, chills and arthralgias. She had previously had a positive protein derivative test with a negative chest X-ray; her medical history was also remarkable for a mitral valve prolapse. Initial symptoms resolved spontaneously without therapy, but fever recurred with associated arthralgias, myalgias, diffuse and worsening lymphadenopathy, splenomegaly, and bilateral pulmonary infiltrates. Physical examination, blood and urine cultures, MRI of the spine, echocardiogram, extensive serologies, serum and urine protein electrophoresis, immunofixation electrophoresis, bone-marrow aspiration and biopsy with flow cytometry, cytogenetics, and gene rearrangement studies, CT scan of the chest, abdomen and pelvis, whole-body PET, and lymph-node biopsy for histological examination, immunohistochemistry, and gene rearrangement studies. Angioimmunoblastic T-cell lymphoma. Steroids (prednisone, methylprednisolone), levofloxacin, isoniazid with pyridoxine, ciclosporin A, methotrexate, alemtuzumab, broad-spectrum antibiotics, Pneumocystis carinii prophylaxis, vancomycin, and clindamycin.

Zidovudine-induced pure red cell aplasia presenting after 4 years of therapy

Reversible pure red cell aplasia is a recognized complication of both zidovudine and lamivudine, typically occurring within the first 3 months of therapy [1,2]. We report the case of a 29-year-old man with HIV, severe haemophilia A and hepatitis C, who developed reversible pure red cell aplasia 4 years after commencing zidovudine. The patient presented to our centre in September 2004 with a 2-week history of exertional dyspnoea and palpitations. He had severe haemophilia A and chronic hepatitis C (genotype 3B), which had never been treated. HIV was diagnosed in 1984; highly active antiretroviral therapy (HAART) was commenced in February 1999 with zidovudine, lamivudine and indinavir. In 2002, his HAART regimen was changed to Trizivir (zidovudine, abacavir and lamivudine). As he had previously developed Stevens–Johnson syndrome on co-trimoxazole, monthly nebulized pentamidine was used as Pneumocystis carinii prophylaxis. His haemophilia A was managed with plasma-derived factor VIII on demand (Fandhi 3000 units), which he used two to three times a month. He was taking no other medications. On examination, he appeared pale but otherwise well. There was conjunctival pallor, but no jaundice. Respiratory and abdominal examination was normal. He had a hyperdynamic circulation with a grade 3/6 ejection systolic flow murmur confined to the left sternal edge. There were no symptoms or signs of bleeding. Initial laboratory investigations showed a severe macrocytic anaemia with a haemoglobin level of 3.5 g/dl and mean corpuscular volume of 115 fl. The reticulocyte count was low at 3 × 109/l. Platelet and white cell counts were normal. The blood film showed an oval macrocytosis. On review of previous blood counts, the patient had had a macrocytosis (range 117–122 fl) without anaemia since commencing HAART in 1999. At the time of presentation, his HIV-RNA level was less than 50 copies/ml and the CD4 cell count was 391 cells/μl. Serum ferritin, B12 and folate were normal, as were plasma methylmalonic acid and homocysteine (functional markers of B12 and folate deficiency, respectively). Renal and liver function tests were normal. The serum erythropoietin level was appropriately raised at 584 U/l. Bone marrow aspirate and trephine biopsy were performed with factor VIII cover. The aspirate showed a megaloblastic picture with maturation arrest of the erythroid series at the early erythroblast stage. The trephine biopsy was hypercellular and megaloblastic with disorganized haematopoeisis. Parvovirus IgG was positive but IgM was negative. Mycoplasma serology was negative. Bone marrow trephine stains for acid-fast bacilli, fungi, parvovirus, human herpes virus 8 and Epstein–Barr virus were negative. Polymerase chain reaction testing of bone marrow aspirate for parvovirus B19 and HHV-6 DNA was negative. Peripheral blood flow cytometry for paroxysmal nocturnal haemoglobinuria was negative. Four units of packed red cells were transfused, and the patient was monitored for 10 days. As he failed to mount a reticulocyte response and the virology findings proved negative, his HAART regimen was changed to lamivudine, tenofovir and efavirenz. Eight days after stopping zidovudine, he mounted a reticulocyte response of 120 × 109/l. The full blood count normalized 20 days after the cessation of zidovudine. Six months later, he remains well with a normal full blood count and normal mean corpuscular volume. Pure red cell aplasia is a well-documented adverse reaction of HAART regimens containing both zidovudine and lamivudine. In this instance, the discontinuation of zidovudine, but not of lamivudine, led to the prompt resolution of the anaemia. This is the first published case of zidovudine-induced pure red cell aplasia occurring so late in zidovudine therapy, and illustrates that this complication is not restricted to the first 3 months of treatment.

Trimethoprim-Sulfamethoxazole–Induced Methemoglobinemia in an HIV-Infected Patient

Trimethoprim-Sulfamethoxazole–Induced Methemoglobinemia in an HIV-Infected Patient

Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome.

We prospectively followed up 589 patients to evaluate the relationship of anti-cytomegalovirus (CMV) treatment and immune reconstitution in response to highly active antiretroviral therapy (HAART) on the mortality risk of patients with CMV retinitis and acquired immune deficiency syndrome. The use of HAART was associated with an 81% lower mortality rate (95% confidence interval [CI], 74%-86%); it was 96% lower (95% CI, 92%-98%) for those who developed immune recovery and 49% lower (95% CI, 30-63%) for those who did not. Using time-updated multivariate analysis, current systemic anti-CMV treatment was independently associated with a 28% lower mortality rate (95% CI, 8%-43%). On the basis of these results, for patients who continue to have profound immunodeficiency despite HAART, the continued use of HAART and systemic anti-CMV therapy is predicted to reduce the risk of mortality by 65%, over and above the benefits of Pneumocystis carinii and Mycobacterium avium prophylaxis.

Mycobacterium gordonae bacteremia in an asymptomatic adolescent with acquired immunodeficiency syndrome.

Mycobacterium gordonae is historically viewed as an organism with low pathogenic potential, but it has increasingly become implicated in clinical disease in immunocompromised hosts. Illness related to M. gordonae infection ranges from localized infections to rare cases of disseminated disease. This report describes treatment of the first case of occult M. gordonae bacteremia in an adolescent with AIDS.

Pneumocystis carinii pneumonia in patients in the developing world who have acquired immunodeficiency syndrome.

We review Pneumocystis carinii pneumonia (PCP) in patients in the developing world (i.e., Africa, Asia, the Philippines, and Central and South America) who have acquired immunodeficiency disease (AIDS). During the first decade of the AIDS pandemic, PCP rarely occurred in African adults. More recent reports have noted that PCP comprises a significantly greater percentage of cases of pneumonia than it did in the past. This trend dramatically contrasts with that observed in industrialized nations, where a reduction in the number of cases of PCP has occurred as a result of the widespread use of primary P. carinii prophylaxis and highly active antiretroviral therapy. Throughout the developing world, the rate of coinfection with Mycobacterium tuberculosis and PCP is high, ranging from 25% to 80%. Initiation of treatment when PCP is in an advanced stage may account for the high mortality rates (20%-80%) associated with pediatric PCP in the developing world.