Correspondence AIDS 2014, 28:797–802
Oral treatment for patients with Buruli ulcer co-infected with HIV: think twice In their opinion article, O’Brien et al. [1] argue that moxifloxacin (MFX) is preferable to clarithromycin (CLA) as a companion drug to rifampicin (RIF) when treating Buruli ulcer with an oral regimen in HIV-coinfected patients. Fortunately, HIV is not the driving force in the emergence of Buruli ulcer. Buruli ulcer mainly affects children, and the highest Buruli ulcer case rates are observed in rural areas of West Africa where HIV prevalence is low [2]. We concur that oral therapy is highly desirable. However, we believe that the combination of RIF and CLA is currently the better alternative. In the mouse model, there were clear indications that MFX was inferior to CLA either given alone or in combination with RIF [3]. The authors argue that anefavirenz (EFV) containing combination antiretroviral therapy, in combination with RIF, would induce CYP3A4-mediated metabolism of CLA, potentially leading to sub-therapeutic concentrations of CLA. The interaction of CYP3A4 inducers with CLA is indeed a concern. Pharmacokinetic data in Buruli ulcer patients treated with RIF-CLA combination show that a dosage of 7.5 mg/kg already gives median concentrations above the minimum inhibitory concentration of Mycobacterium ulcerans [4] resulting in cure of Buruli ulcer in nearly all patients [5,6]. However, the CLA dosage can safely be doubled to 15 mg/kg, and administered once-daily with an extended release formulation, which is likely to give therapeutic plasma concentrations, even in the presence of CYP3A4 induction; this approach is currently utilized in an ongoing WHO-sponsored clinical trial in West Africa (http:// www.clinicaltrials.gov/ct2/show/NCT01659437 NLM Identifier: NCT01659437). Next, the authors argue that the combination of MFX and RIF would be better suited to treat a possible concurrent tuberculosis (TB)-infection. Though theoretically possible, Buruli ulcer-TB co-infection is uncommon as O’Brien et al. [1] admit; indeed, no single case of Buruli ulcer-TB-HIV co-infection has ever been reported in the literature. Buruli ulcer is a predominantly rural disease, whereas TB is more prevalent in urban areas. Should an HIV-positive patient present with both manifest TB and Buruli ulcer, we propose that initial therapy be directed at TB and HIV only. In such extremely rare cases, a MFX and RIF containing anti-TB regimen will indeed likely suffice to treat Buruli ulcer as well; the larger risk for patients with this triple infection would clearly be HIV and TB, not Buruli ulcer.
Treatment with MFX and RIF for 8 weeks is not an established therapy for the treatment of latent TB and certainly not for the treatment of active TB. We rather propose that latent TB in HIV-infected patients is viewed as a separate entity, which needs proper diagnosis and treatment according to local and WHO guidelines. The authors mention the risk of the development of resistance of Mycobacterium tuberculosis during treatment with MFX. Other concerns with the use of MFX instead of CLA are the high costs, low availability and development of resistance amongst Gram-negative bacteria. In addition, it is contra-indicated in those under 18 years, the age group most affected by Buruli ulcer. In conclusion, we believe that there is currently no compelling reason to introduce MFX as a first-line drug for the treatment of HIV-positive Buruli ulcer patients. Priorities in research and treatment in Buruli ulcer cannot be copied from TB. Antimicrobial treatment is only part of the treatment in Buruli ulcer. Considering the median time to healing of 12–20 months [5,6], most of the healing takes place in the period after drug treatment, when local wound care and possibly, surgical interventions are important – not drug treatment. The need to start with combination antiretroviral therapy (cART) during the first 8 weeks of drug treatment for Buruli ulcer should be balanced with the risk of compliance problems and increased risks of side-effects. Vertical control programs may further limit the early start of cART in many Buruli ulcer centers. We propose that the pharmacokinetics of extended release CLA at 15 mg/kg in combination with RIF and EFV be studied in a small series of Buruli ulcer-HIV co-infected patients, and that the available research funding is directed at firmly establishing the efficacy and safety of the combination of RIF and CLA as oral therapy for Buruli ulcer.
Acknowledgements Conflicts of interest There are no conflicts of interest. Sandor Klisa, Tjip S. van der Werf a,b, Richard O. Phillipsc,d, Fred S. Sarfoc, Mark Wansbrough-Jonese and Ymkje Stienstraa, aDepartment of Internal Medicine – Infectious Diseases, bDepartment of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, cKomfo Anokye Teaching Hospital,
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Kwame Nkrumah University of Science and Technology, Kumasi, Ghana, and eSt George’s University of London, London, UK. Correspondence to Sandor Klis, University Medical Center Groningen, PO Box 30 001,9700 RB Groningen, the Netherlands. E-mail: [email protected] Received: 6 November 2013; revised: 8 November 2013; accepted: 8 November 2013.
References 1. O’Brien DP, Comte E, Ford N, Christinet V, Cros du P. Moxifloxacin for Buruli ulcer/HIV coinfected patients: kill two birds with one stone? AIDS 2013; 27:2177–2179.
2. van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, et al. Mycobacterium ulcerans disease. Bull World Health Organ 2005; 83:785–791. 3. Ji B, Chauffour A, Robert J, Lefrancois S, Jarlier V. Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice. Antimicrob Agents Chemother 2007; 51:3737–3739. 4. Alffenaar JWC, Nienhuis WA, de Velde F, Zuur AT, Wessels AMA, Almeida D, et al. Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection. Antimicrob Agents Chemother 2010; 54:3878–3883. 5. Sarfo FS, Phillips R, Asiedu K, Ampadu E, Bobi N, Adentwe E, et al. Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 2010; 54:3678–3685. 6. Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010; 375:664–672.
DOI:10.1097/QAD.0000000000000146
Fecal microbiota transplantation for Clostridium difficile-associated colitis in a severely immunocompromized critically ill AIDS patient: a case report In June 2013, a 54-year-old male patient was admitted to our hospital with acute renal failure and metabolic acidosis due to exsiccosis. The underlying illness was pseudomembraneous colitis, as determined by endoscopy. This was complicated by secondary peritonitis with paralytic ileus. Additionally, we found severe necrotizing inflammation of the distal esophagus. The patient was referred to the intensive care unit (ICU) because of instable clinical status. In the work-up, Clostridium difficile antigen and toxins A and B were found in stool, Candida albicans was grown in blood culture, and ascites fluid revealed Candida glabrata, Pseudomonas aeruginosa, and vancomycin-resistant enterococci (VRE). From esophageal biopsies, cytomegalovirus (CMV) and human herpes virus (HSV) type 1 PCR were positive. HIV infection was diagnosed in 2005, at that time the patient suffered from CMV and HIV encephalitis, wasting syndrome, giardiasis, and Candida stomatitis. After initiation of combination antiretroviral therapy (cART), an immune reconstitution inflammatory syndrome occurred. In 2009, he developed pneumonia and Candida esophagitis. In 2010, a first episode of C. difficile-associated colitis (CDAC) was diagnosed. Further disease episodes were pneumonia with consecutive CDAC, psychosis, psoriasis inversa, HSV proctitis, and renal impairment under tenofovir treatment. Medical therapy on admission consisted of abacavir, lamivudine, darunavir, ritonavir, mirtazapin, olanzapin, allopurinol, calcitriol, L-thyroxin, biperiden, and propranolol. CD4þ cell count was 54/ml (17%), HIV viral load was 2480 copies/ml.
The following antimicrobial drugs were applied: metronidozol, vancomycin, fidaxomycin, ciprofloxazin, meropenem, tigecyclin, caspofungin, and aciclovir. cART was maintained continuously. Within few days, the course of disease was complicated by aspiration pneumonia requiring mechanical ventilation and agranulocytosis, probably due to allopurinol, propranolol, or metamizol. These measures were accompanied by standard ICU management. After 16 days, the patient had recovered to an extent that permitted movement to peripheral ward. Unfortunately, after 23 days, septicemia caused by VRE with severe exacerbation of CDAC made another course of ICU treatment necessary. Whereas the VRE infection improved, toxic megacolon developed despite of maximum therapy of CDAC. Therefore, the patient was treated with two stool transplantations, 10 days apart, taken from the mother. After exclusion of current infections in the donor, the fecal transplantation was administered via intestinal tube in one case and colonoscopy in the other. In the following week, clinical situation improved consistently, and pseudomembraneous colitis dissolved completely thereafter. An intermittent infection of central venous catheter due to P. aeruginosa and Streptococcus parasanguinis was cured. The patient could be discharged from hospital after another 9 days without evidence of ongoing C. difficile infection. By that time, CD4þ cell count had risen from 104/ml (9%) on the day of first transplantation to 306/ml (15%) with a viral load below the detection limit of 20/ml. We present a patient with severe immunosuppression suffering from numerous life-threatening diseases
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including fulminant CDAC with complicating peritonitis and bowel atony. After transient improvement, toxic megacolon developed, leaving the only standard treatment option of complete resection. Due to inadequate clinical condition for surgery, we proposed stool transplantation alternatively, which the patient and his family opted for. To our great pleasure, the patient’s state improved substantially, colitis resolved completely, and discharge to his home was possible. Moreover, CD4þ cell count increased rapidly and suppression of viral replication was maintained. Current treatment strategies of CDAC include discontinuation of systemic antibiotics and administration of predominantly topic anti-infectives against C. difficile. Common drugs are metronidazol and vancomycin. As in the presented case, the infection has a high recurrence rate. Recently, fidaxomycin was approved with data showing good efficacy in this context [1]. Other approaches are application of prebiotics and, as a new option, fecal transplantation. The latter was shown to be effective in the majority of HIV-negative patients [2,3]. Currently, no evidence has been published for HIVpositive patients and, even more relevant, for patients with severe immunosuppression. The presented case shows that stool transplantation may be a treatment option in HIV-positive patients, as no side effect could be detected in the weeks after. However, further experience is needed to estimate the safety of this approach. As C. difficile infections have been described in this patient group [4], it is necessary to have the opportunity to apply all modalities of therapy due to the significant mortality of CDAC. In this context, our case may serve as an example for the situation of critical illness. In summary, we present the case of a 54-year-old man with far progressed immunosuppression in poor clinical
condition who recovered from fulminant CDAC by stool transplantation. To our knowledge, this is the first case of fecal microbiota transplantation in an AIDS patient.
Acknowledgements Conflicts of interest There are no conflicts of interest Marko Schu¨nemann and Mark Oette Correspondence to Mark Oette, MD, Augustinerinnen Hospital, Clinic for General Medicine, Gastroenterology, and Infectious Diseases, Jakobstrasse 27–31, 50678, Cologne, Germany. E-mail: [email protected] Received: 3 November 2013; revised: 8 November 2013; accepted: 8 November 2013.
References 1. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. OPT-80-004 Clinical Study Group. Fidaxomycin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, noninferiority, randomized controlled trial. Lancet Infect Dies 2012; 12:281–289. 2. Rohlke F, Stollmann N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Ther Adv Gastroenterol 2012; 5:403–420. 3. Kleger A, Schnell J, Essig A, Wagner M, Bommer M, Seufferlein T, et al. Case report: fecal transplant in refractory Clostridium difficile colitis. Dtsch Arztebl Int 2013; 110:108–115. 4. Haines CF, Moore RD, Bartlett JG, Sears CL, Cosgrove SE, Caroll K, et al. Clostridium difficile in a HIV-infected cohort: incidence, risk factors, and clinical outcomes. AIDS 2013; 27:2799–2807.
DOI:10.1097/QAD.0000000000000148
On the speculations about the causes of increased condom use in Africa We have read with interest the letter about increased use of condoms by Catholics in some countries from subSaharan Africa during Pope Benedict XVI’s tenure [1]. The author suggests that this increase could be the result of the Pope’s statement about condom use in November 2010 [2,3]. But this assumption is not supported by the data provided in De Neve’s letter. In addition to methodological problems common to descriptive studies or ecological analyses, De Neve’s study presents other important limitations which have not been addressed. Firstly, the author only compares data about condom use from 2004, 2005 or 2006 (depending on the country) with data from 2011. We do not know which factors other than the Pope’s statement may have influenced
condom use in that period. In fact, according to the last UNAIDS (The Joint United Nations Programme on HIVand AIDS) report, other preventive measures such as HIV testing, voluntary male circumcision, reduction in the number of sexual partners, delay in sexual debut and also condom use in the last sexual relationship, have increased in many countries during the past decade, including African countries [4]. In addition, De Neve does not provide enough data to evaluate the tendency in condom use before the Pope’s statement in 2010. For example, in Mozambique, from 2003 to 2009, condom use among people with more than one sexual partner rose, and so did condom use during last paid sex in the same period [5].
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Furthermore, the Pope’s statement about condom use was published in November 2010, but the data from the 2011 Demographic Health Surveys in Rwanda and Zimbabwe were collected from September 2010 to March 2011. This invalidates the idea that the Pope may have influenced the use of condoms in these countries. In the other countries, data were collected from January to August 2011 (Cameroon) and from June to November 2011 (Mozambique and Uganda). It is still not reasonable to think that the Pope’s message could have such a big impact in Africans’ sexual behavior in that short period of time. Also, it has to be pointed out that, according to De Neve’s letter, condom use among Catholics was similar to other religious groups, and that the increase in condom use was not specific to Catholics. In fact, Protestants, who do not follow the Pope’s teachings, also showed an increase in condom use (see Fig. 1 in De Neve’s letter). Both facts show a lack of specificity in the association between the Pope’s statement and the behavior change among Catholic Africans. Moreover, in Uganda, when the reason for not using a condom at last sex was asked in the AIDS National Survey, only 1.5% of men and 1.4% of women reported religious beliefs [6]. In conclusion, there is no evidence to say that increase in condom use in some African countries could be related to Pope Benedict XVI’s message, as De Neve suggests. Rigorous scientific studies are needed to assess the impact of prevention campaigns in a really dramatic health problem such as the HIV pandemic.
Acknowledgements Conflicts of interest There are no conflicts of interest.
Alfonso Osorioa,c, Silvia Carlosb,c and Cristina Lopezdel Burgob,c, aDepartment of Education,, bDepartment of Preventive Medicine and Public Health,, and c Institute for Culture and Society, University of Navarra, Campus Universitario, Pamplona, Navarra, Spain. Correspondence to Cristina Lopez-del Burgo, University of Navarra, Campus Universitario, 31009 Pamplona, Navarra, Spain. Tel: +34948425600; e-mail: [email protected], [email protected] Received: 5 November 2013; revised: 13 November 2013; accepted: 13 November 2013.
References 1. De Neve J. ‘Pope as prevention’? Condom use by Catholics increased in five HIV endemic countries in sub-Saharan Africa during Pope Benedict XVI’s tenure. AIDS 2013; 27: 2825–2830. 2. Seewald P, Pope Benedict XVI. Light of the world: the Pope, the Church and the signs of the times. San Francisco: Ignatius Press; 2010. 3. Congregation for the Doctrine of the Faith. On the banalization of sexuality. Regarding certain interpretations of ‘Light of the World’. 2010. http://goo.gl/i6RRxb. [Accessed 4 November 2013]. 4. UNAIDS report on the global AIDS epidemic 2013. Geneva: UNAIDS; 2013. 5. Ministe´rio da Sau´de Moc¸ambique. INSIDA 2009 Relato´rio Final. Maputo, Moc¸ambique: INSIDA; 2010. 6. Uganda HIV/AIDS Sero-Behavioural Survey, 2004–2005. Calverton, Maryland, USA: Ministry of Health and ORC Macro; 2006.
DOI:10.1097/QAD.0000000000000153
Paclitaxel for relapsed or recurrent HIV-associated pediatric Kaposi’s sarcoma In sub-Saharan Africa, Kaposi’s sarcoma remains a common pediatric HIV-related malignancy with primary treatment consisting of antiretroviral therapy (ART) in addition to chemotherapy with differing combinations of adriamycin, bleomycin, and vincristine (ABV) [1–3]. Due to resource limitations, salvage therapy is lacking, and patients who relapse or are refractory to therapy often have no further treatment options. Paclitaxel has been noted as an effective salvage agent in adult HIV patients. Here, we present the first report on two pediatric patients. The first patient, a 12-year-old HIV-positive male, presented to Princess Marina Hospital, the country-wide referral hospital in Gaborone, Botswana, with severe wasting, having recently started both tuberculosis (TB)
therapy 2 months prior and ART 2 weeks prior. His ART therapy consisted of stavudine (d4T), lamivudine (3TC), and efavirenz (EFV). Since ART initiation, he developed lesions consistent with Kaposi’s sarcoma on his left thumb and bilateral feet. He additionally presented with increased work of breathing and was found to have a large pericardial effusion. With the worsening symptoms after starting ART, both TB and Kaposi’s sarcoma-associated immune reconstitution inflammatory syndrome (IRIS) were diagnostic considerations. Pericardial fluid was sent for acid-fast bacilli and cytology, both of which were negative. Due to clinical suspicion of Kaposi’s sarcomaIRIS based on the skin lesions and reports of isolated pericardial effusion as a symptom of Kaposi’s sarcoma, we began therapy with bleomycin and vincristine (BV)
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Fig. 1. Improvement in Kaposi’s sarcoma pulmonary involvement after one cycle of paclitaxel.
omitting doxorubicin due to concomitant cytopenias thought secondary to bone marrow involvement or suppression from Kaposi’s sarcoma [4,5]. Repeat echocardiogram after one cycle of BV showed significant improvement in the pericardial effusion, and after two additional weekly BV cycles, the patient’s cytopenias resolved. He was then switched to every 3-week ABV therapy. He unfortunately proved refractory with development of significant right-sided lung involvement which worsened over two cycles of ABV. He also developed peripheral neuropathy, likely due to the combination of vincristine and d4T, so d4Twas switched to abacavir (ABC). With disease progression, he was changed to paclitaxel for salvage, receiving 150 mg/m2 over 3 h with oral dexamethasone premedication 12 and 6 h prior to infusion. After one cycle, he showed dramatic improvement in his lung involvement (Fig. 1) and had no significant toxicity to therapy. Sadly, after the second paclitaxel cycle, he again showed signs of progression and passed away from respiratory symptoms. The second patient, an HIV-positive 8-year-old male on ART, presented with new respiratory symptoms and an oxygen requirement after twice previously being treated for Kaposi’s sarcoma with six cycles of ABV. His ART regimen consisted of zidovidine (AZT), 3TC, and EFV. The first ABV treatment course 2 years prior was given for isolated Kaposi’s sarcoma skin involvement, whereas the second course occurred a year later with pulmonary relapse. Due to this second pulmonary relapse, he was started on paclitaxel salvage therapy at a dose of 150 mg/m2 every 3 weeks, again as a 3-h infusion with oral dexamethasone premedication. After the first cycle, he showed clinical improvement with resolution of his oxygen requirement, although without significant change in his chest radiograph. He continued on every 3-week paclitaxel and achieved disease stabilization with no noted therapeutic toxicity. Although he did not have any significant myelosuppression, he was prophylactically switched from AZT to ABC. With continued disease stability, he was adjusted to every 4-week paclitaxel therapy for familial convenience and has remained stable for 12 months to date. Paclitaxel has shown both in-vitro and in-vivo evidence of activity against Kaposi’s sarcoma due to inhibition of
Bcl-2 antiapoptotic effects in addition to effects on microtubule depolymerization and angiogenesis [6,7]. Adult studies have shown benefit in HIV-associated Kaposi’s sarcoma utilizing different treatment schedules, doses of 100–175 mg/m2 every 2–3 weeks, with neutropenia being the most common toxicity [8–12]. Vaz et al. [13] recently reported on 28 Mozambican children given paclitaxel as first-line therapy after ART initiation at a dose of 75 mg/m2 at 4-week intervals for six cycles. No grade III/IV myelosuppression was seen in our two patients. Two reports in adults have shown severe paclitaxel toxicity due to deceased metabolism with concurrent use of protease inhibitors [14,15]. Larger studies have failed to show any significant interaction [11,16]. Additionally, potential interaction between AZT and chemotherapy must be considered. Our cases highlight the safety and efficacy of paclitaxel in pediatric HIV-associated Kaposi’s sarcoma that has relapsed or is refractory to standard therapy. As African countries move towards further therapies and the addition of salvage regimens, paclitaxel should be acknowledged as a plausible and reasonably inexpensive agent in pediatric patients.
Acknowledgements Conflicts of interest There are no conflicts of interest. Shoba Reddy-Holdcrafta, Parth S. Mehtab and Anurag K. Agrawalb, aTexas Children’s Hospital, and bTexas Children’s Cancer and Hematology Centers, Texas Children’s Hospital Global Health Service Corps, Botswana-Baylor Children’s Clinical Center of Excellence, Princess Marina Hospital, Texas, USA. Correspondence to Parth S. Mehta, MD, Texas Children’s Cancer and Hematology Centers, 1102 Bates Street, Feigin Center 1025.08, Houston, TX 77030, USA. Tel: +1 832 227 1061; fax: +1 832 227 1096; e-mail: [email protected]
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Received: 6 November 2013; revised: 14 November 2013; accepted: 14 November 2013.
References 1. Martellotta F, Berretta M, Vaccher E, Schioppa O, Zanet E, Tirelli U. AIDS-related Kaposi’s sarcoma: state of the art and therapeutic strategies. Curr HIV Res 2009; 7:634–638. 2. Gantt S, Kakuru A, Wald A, Walusansa V, Corey L, Casper C, Orem J. Clinical presentation and outcome of epidemic Kaposi sarcoma in Ugandan children. Pediatr Blood Cancer 2010; 54:670–674. 3. Stefan DC, Stones DK, Wainwright L, Newton R. Kaposi sarcoma in South African children. Pediatr Blood Cancer 2011; 56:392–396. 4. Stotka JL, Good CB, Downer WR, Kapoor WN. Pericardial effusion and tamponade due to Kaposi’s sarcoma in acquired immunodeficiency syndrome. Chest 1989; 95:1359–1361. 5. Reynolds MM, Hecht SR, Berger M, Kolokathis A, Horowitz SF. Large pericardial effusions in the acquired immunodeficiency syndrome. Chest 1992; 102:1746–1747. 6. Sgadari C, Toschi E, Palladino C, Barillari G, Carlei D, Cereseto A. Mechanism of paclitaxel activity in Kaposi’s sarcoma. J Immunol 2000; 165:509–517. 7. Dhillon T, Stebbing J, Bower M. Paclitaxel for AIDS-associated Kaposi’s sarcoma. Expert Rev Anticancer Ther 2005; 5:215–219. 8. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet 1995; 346:26–28. 9. Welles L, Saville MW, Lietzau J, Pluda JM, Wyvill KM, Feuerstein I. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 1998; 16:1112–1121.
10. Gill PS, Tulpule A, Espina BM, Cabriales S, Bresnahan J, Ilaw M. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999; 17:1876– 1883. 11. Tulpule A, Groopman J, Saville MW, Harrington W Jr, Friedman-Kien A, Espina BM. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002; 95:147–154. 12. Stebbing J, Wildfire A, Portsmouth S, Powles T, Thirlwell C, Hewitt P. Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations. Ann Oncol 2003; 14:1660–1666. 13. Vaz P, Macassa E, Jani I, Thome B, Mahagaja E, Madede T. Treatment of Kaposi sarcoma in human immunodeficiency virus-1-infected Mozambican children with antiretroviral drugs and chemotherapy. Pediatr Infect Dis J 2011; 30:891– 893. 14. Hurwitz CA, Relling MV, Weitman SD, Ravindranath Y, Vietti TJ, Strother DR. Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study. J Clin Oncol 1993; 11:2324–2329. 15. Woo MH, Relling MV, Sonnichsen DS, Rivera GK, Pratt CB, Pui CH. Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. Clin Cancer Res 1999; 5:543–549. 16. Cianfrocca M, Lee S, Von Roenn J, Rudek MA, Dezube BJ, Krown SE, Sparano JA. Pilot study evaluating the interaction between paclitaxel and protease inhibitors in patients with human immunodeficiency virus-associated Kaposi’s sarcoma: an Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial. Cancer Chemother Pharmacol 2011; 68:827–833.
DOI:10.1097/QAD.0000000000000157
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Oral treatment for patients with Buruli ulcer co-infected with HIV: think twice In their opinion article, O’Brien et al. [1] argue that moxifloxacin (MFX) is preferable to clarithromycin (CLA) as a companion drug to rifampicin (RIF) when treating Buruli ulcer with an oral regimen in HIV-coinfected patients. Fortunately, HIV is not the driving force in the emergence of Buruli ulcer. Buruli ulcer mainly affects children, and the highest Buruli ulcer case rates are observed in rural areas of West Africa where HIV prevalence is low [2]. We concur that oral therapy is highly desirable. However, we believe that the combination of RIF and CLA is currently the better alternative. In the mouse model, there were clear indications that MFX was inferior to CLA either given alone or in combination with RIF [3]. The authors argue that anefavirenz (EFV) containing combination antiretroviral therapy, in combination with RIF, would induce CYP3A4-mediated metabolism of CLA, potentially leading to sub-therapeutic concentrations of CLA. The interaction of CYP3A4 inducers with CLA is indeed a concern. Pharmacokinetic data in Buruli ulcer patients treated with RIF-CLA combination show that a dosage of 7.5 mg/kg already gives median concentrations above the minimum inhibitory concentration of Mycobacterium ulcerans [4] resulting in cure of Buruli ulcer in nearly all patients [5,6]. However, the CLA dosage can safely be doubled to 15 mg/kg, and administered once-daily with an extended release formulation, which is likely to give therapeutic plasma concentrations, even in the presence of CYP3A4 induction; this approach is currently utilized in an ongoing WHO-sponsored clinical trial in West Africa (http:// www.clinicaltrials.gov/ct2/show/NCT01659437 NLM Identifier: NCT01659437). Next, the authors argue that the combination of MFX and RIF would be better suited to treat a possible concurrent tuberculosis (TB)-infection. Though theoretically possible, Buruli ulcer-TB co-infection is uncommon as O’Brien et al. [1] admit; indeed, no single case of Buruli ulcer-TB-HIV co-infection has ever been reported in the literature. Buruli ulcer is a predominantly rural disease, whereas TB is more prevalent in urban areas. Should an HIV-positive patient present with both manifest TB and Buruli ulcer, we propose that initial therapy be directed at TB and HIV only. In such extremely rare cases, a MFX and RIF containing anti-TB regimen will indeed likely suffice to treat Buruli ulcer as well; the larger risk for patients with this triple infection would clearly be HIV and TB, not Buruli ulcer.
Treatment with MFX and RIF for 8 weeks is not an established therapy for the treatment of latent TB and certainly not for the treatment of active TB. We rather propose that latent TB in HIV-infected patients is viewed as a separate entity, which needs proper diagnosis and treatment according to local and WHO guidelines. The authors mention the risk of the development of resistance of Mycobacterium tuberculosis during treatment with MFX. Other concerns with the use of MFX instead of CLA are the high costs, low availability and development of resistance amongst Gram-negative bacteria. In addition, it is contra-indicated in those under 18 years, the age group most affected by Buruli ulcer. In conclusion, we believe that there is currently no compelling reason to introduce MFX as a first-line drug for the treatment of HIV-positive Buruli ulcer patients. Priorities in research and treatment in Buruli ulcer cannot be copied from TB. Antimicrobial treatment is only part of the treatment in Buruli ulcer. Considering the median time to healing of 12–20 months [5,6], most of the healing takes place in the period after drug treatment, when local wound care and possibly, surgical interventions are important – not drug treatment. The need to start with combination antiretroviral therapy (cART) during the first 8 weeks of drug treatment for Buruli ulcer should be balanced with the risk of compliance problems and increased risks of side-effects. Vertical control programs may further limit the early start of cART in many Buruli ulcer centers. We propose that the pharmacokinetics of extended release CLA at 15 mg/kg in combination with RIF and EFV be studied in a small series of Buruli ulcer-HIV co-infected patients, and that the available research funding is directed at firmly establishing the efficacy and safety of the combination of RIF and CLA as oral therapy for Buruli ulcer.
Acknowledgements Conflicts of interest There are no conflicts of interest. Sandor Klisa, Tjip S. van der Werf a,b, Richard O. Phillipsc,d, Fred S. Sarfoc, Mark Wansbrough-Jonese and Ymkje Stienstraa, aDepartment of Internal Medicine – Infectious Diseases, bDepartment of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, cKomfo Anokye Teaching Hospital,
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Kwame Nkrumah University of Science and Technology, Kumasi, Ghana, and eSt George’s University of London, London, UK. Correspondence to Sandor Klis, University Medical Center Groningen, PO Box 30 001,9700 RB Groningen, the Netherlands. E-mail: [email protected] Received: 6 November 2013; revised: 8 November 2013; accepted: 8 November 2013.
References 1. O’Brien DP, Comte E, Ford N, Christinet V, Cros du P. Moxifloxacin for Buruli ulcer/HIV coinfected patients: kill two birds with one stone? AIDS 2013; 27:2177–2179.
2. van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, et al. Mycobacterium ulcerans disease. Bull World Health Organ 2005; 83:785–791. 3. Ji B, Chauffour A, Robert J, Lefrancois S, Jarlier V. Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice. Antimicrob Agents Chemother 2007; 51:3737–3739. 4. Alffenaar JWC, Nienhuis WA, de Velde F, Zuur AT, Wessels AMA, Almeida D, et al. Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection. Antimicrob Agents Chemother 2010; 54:3878–3883. 5. Sarfo FS, Phillips R, Asiedu K, Ampadu E, Bobi N, Adentwe E, et al. Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 2010; 54:3678–3685. 6. Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010; 375:664–672.
DOI:10.1097/QAD.0000000000000146
Fecal microbiota transplantation for Clostridium difficile-associated colitis in a severely immunocompromized critically ill AIDS patient: a case report In June 2013, a 54-year-old male patient was admitted to our hospital with acute renal failure and metabolic acidosis due to exsiccosis. The underlying illness was pseudomembraneous colitis, as determined by endoscopy. This was complicated by secondary peritonitis with paralytic ileus. Additionally, we found severe necrotizing inflammation of the distal esophagus. The patient was referred to the intensive care unit (ICU) because of instable clinical status. In the work-up, Clostridium difficile antigen and toxins A and B were found in stool, Candida albicans was grown in blood culture, and ascites fluid revealed Candida glabrata, Pseudomonas aeruginosa, and vancomycin-resistant enterococci (VRE). From esophageal biopsies, cytomegalovirus (CMV) and human herpes virus (HSV) type 1 PCR were positive. HIV infection was diagnosed in 2005, at that time the patient suffered from CMV and HIV encephalitis, wasting syndrome, giardiasis, and Candida stomatitis. After initiation of combination antiretroviral therapy (cART), an immune reconstitution inflammatory syndrome occurred. In 2009, he developed pneumonia and Candida esophagitis. In 2010, a first episode of C. difficile-associated colitis (CDAC) was diagnosed. Further disease episodes were pneumonia with consecutive CDAC, psychosis, psoriasis inversa, HSV proctitis, and renal impairment under tenofovir treatment. Medical therapy on admission consisted of abacavir, lamivudine, darunavir, ritonavir, mirtazapin, olanzapin, allopurinol, calcitriol, L-thyroxin, biperiden, and propranolol. CD4þ cell count was 54/ml (17%), HIV viral load was 2480 copies/ml.
The following antimicrobial drugs were applied: metronidozol, vancomycin, fidaxomycin, ciprofloxazin, meropenem, tigecyclin, caspofungin, and aciclovir. cART was maintained continuously. Within few days, the course of disease was complicated by aspiration pneumonia requiring mechanical ventilation and agranulocytosis, probably due to allopurinol, propranolol, or metamizol. These measures were accompanied by standard ICU management. After 16 days, the patient had recovered to an extent that permitted movement to peripheral ward. Unfortunately, after 23 days, septicemia caused by VRE with severe exacerbation of CDAC made another course of ICU treatment necessary. Whereas the VRE infection improved, toxic megacolon developed despite of maximum therapy of CDAC. Therefore, the patient was treated with two stool transplantations, 10 days apart, taken from the mother. After exclusion of current infections in the donor, the fecal transplantation was administered via intestinal tube in one case and colonoscopy in the other. In the following week, clinical situation improved consistently, and pseudomembraneous colitis dissolved completely thereafter. An intermittent infection of central venous catheter due to P. aeruginosa and Streptococcus parasanguinis was cured. The patient could be discharged from hospital after another 9 days without evidence of ongoing C. difficile infection. By that time, CD4þ cell count had risen from 104/ml (9%) on the day of first transplantation to 306/ml (15%) with a viral load below the detection limit of 20/ml. We present a patient with severe immunosuppression suffering from numerous life-threatening diseases
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including fulminant CDAC with complicating peritonitis and bowel atony. After transient improvement, toxic megacolon developed, leaving the only standard treatment option of complete resection. Due to inadequate clinical condition for surgery, we proposed stool transplantation alternatively, which the patient and his family opted for. To our great pleasure, the patient’s state improved substantially, colitis resolved completely, and discharge to his home was possible. Moreover, CD4þ cell count increased rapidly and suppression of viral replication was maintained. Current treatment strategies of CDAC include discontinuation of systemic antibiotics and administration of predominantly topic anti-infectives against C. difficile. Common drugs are metronidazol and vancomycin. As in the presented case, the infection has a high recurrence rate. Recently, fidaxomycin was approved with data showing good efficacy in this context [1]. Other approaches are application of prebiotics and, as a new option, fecal transplantation. The latter was shown to be effective in the majority of HIV-negative patients [2,3]. Currently, no evidence has been published for HIVpositive patients and, even more relevant, for patients with severe immunosuppression. The presented case shows that stool transplantation may be a treatment option in HIV-positive patients, as no side effect could be detected in the weeks after. However, further experience is needed to estimate the safety of this approach. As C. difficile infections have been described in this patient group [4], it is necessary to have the opportunity to apply all modalities of therapy due to the significant mortality of CDAC. In this context, our case may serve as an example for the situation of critical illness. In summary, we present the case of a 54-year-old man with far progressed immunosuppression in poor clinical
condition who recovered from fulminant CDAC by stool transplantation. To our knowledge, this is the first case of fecal microbiota transplantation in an AIDS patient.
Acknowledgements Conflicts of interest There are no conflicts of interest Marko Schu¨nemann and Mark Oette Correspondence to Mark Oette, MD, Augustinerinnen Hospital, Clinic for General Medicine, Gastroenterology, and Infectious Diseases, Jakobstrasse 27–31, 50678, Cologne, Germany. E-mail: [email protected] Received: 3 November 2013; revised: 8 November 2013; accepted: 8 November 2013.
References 1. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. OPT-80-004 Clinical Study Group. Fidaxomycin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, noninferiority, randomized controlled trial. Lancet Infect Dies 2012; 12:281–289. 2. Rohlke F, Stollmann N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Ther Adv Gastroenterol 2012; 5:403–420. 3. Kleger A, Schnell J, Essig A, Wagner M, Bommer M, Seufferlein T, et al. Case report: fecal transplant in refractory Clostridium difficile colitis. Dtsch Arztebl Int 2013; 110:108–115. 4. Haines CF, Moore RD, Bartlett JG, Sears CL, Cosgrove SE, Caroll K, et al. Clostridium difficile in a HIV-infected cohort: incidence, risk factors, and clinical outcomes. AIDS 2013; 27:2799–2807.
DOI:10.1097/QAD.0000000000000148
On the speculations about the causes of increased condom use in Africa We have read with interest the letter about increased use of condoms by Catholics in some countries from subSaharan Africa during Pope Benedict XVI’s tenure [1]. The author suggests that this increase could be the result of the Pope’s statement about condom use in November 2010 [2,3]. But this assumption is not supported by the data provided in De Neve’s letter. In addition to methodological problems common to descriptive studies or ecological analyses, De Neve’s study presents other important limitations which have not been addressed. Firstly, the author only compares data about condom use from 2004, 2005 or 2006 (depending on the country) with data from 2011. We do not know which factors other than the Pope’s statement may have influenced
condom use in that period. In fact, according to the last UNAIDS (The Joint United Nations Programme on HIVand AIDS) report, other preventive measures such as HIV testing, voluntary male circumcision, reduction in the number of sexual partners, delay in sexual debut and also condom use in the last sexual relationship, have increased in many countries during the past decade, including African countries [4]. In addition, De Neve does not provide enough data to evaluate the tendency in condom use before the Pope’s statement in 2010. For example, in Mozambique, from 2003 to 2009, condom use among people with more than one sexual partner rose, and so did condom use during last paid sex in the same period [5].
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Furthermore, the Pope’s statement about condom use was published in November 2010, but the data from the 2011 Demographic Health Surveys in Rwanda and Zimbabwe were collected from September 2010 to March 2011. This invalidates the idea that the Pope may have influenced the use of condoms in these countries. In the other countries, data were collected from January to August 2011 (Cameroon) and from June to November 2011 (Mozambique and Uganda). It is still not reasonable to think that the Pope’s message could have such a big impact in Africans’ sexual behavior in that short period of time. Also, it has to be pointed out that, according to De Neve’s letter, condom use among Catholics was similar to other religious groups, and that the increase in condom use was not specific to Catholics. In fact, Protestants, who do not follow the Pope’s teachings, also showed an increase in condom use (see Fig. 1 in De Neve’s letter). Both facts show a lack of specificity in the association between the Pope’s statement and the behavior change among Catholic Africans. Moreover, in Uganda, when the reason for not using a condom at last sex was asked in the AIDS National Survey, only 1.5% of men and 1.4% of women reported religious beliefs [6]. In conclusion, there is no evidence to say that increase in condom use in some African countries could be related to Pope Benedict XVI’s message, as De Neve suggests. Rigorous scientific studies are needed to assess the impact of prevention campaigns in a really dramatic health problem such as the HIV pandemic.
Acknowledgements Conflicts of interest There are no conflicts of interest.
Alfonso Osorioa,c, Silvia Carlosb,c and Cristina Lopezdel Burgob,c, aDepartment of Education,, bDepartment of Preventive Medicine and Public Health,, and c Institute for Culture and Society, University of Navarra, Campus Universitario, Pamplona, Navarra, Spain. Correspondence to Cristina Lopez-del Burgo, University of Navarra, Campus Universitario, 31009 Pamplona, Navarra, Spain. Tel: +34948425600; e-mail: [email protected], [email protected] Received: 5 November 2013; revised: 13 November 2013; accepted: 13 November 2013.
References 1. De Neve J. ‘Pope as prevention’? Condom use by Catholics increased in five HIV endemic countries in sub-Saharan Africa during Pope Benedict XVI’s tenure. AIDS 2013; 27: 2825–2830. 2. Seewald P, Pope Benedict XVI. Light of the world: the Pope, the Church and the signs of the times. San Francisco: Ignatius Press; 2010. 3. Congregation for the Doctrine of the Faith. On the banalization of sexuality. Regarding certain interpretations of ‘Light of the World’. 2010. http://goo.gl/i6RRxb. [Accessed 4 November 2013]. 4. UNAIDS report on the global AIDS epidemic 2013. Geneva: UNAIDS; 2013. 5. Ministe´rio da Sau´de Moc¸ambique. INSIDA 2009 Relato´rio Final. Maputo, Moc¸ambique: INSIDA; 2010. 6. Uganda HIV/AIDS Sero-Behavioural Survey, 2004–2005. Calverton, Maryland, USA: Ministry of Health and ORC Macro; 2006.
DOI:10.1097/QAD.0000000000000153
Paclitaxel for relapsed or recurrent HIV-associated pediatric Kaposi’s sarcoma In sub-Saharan Africa, Kaposi’s sarcoma remains a common pediatric HIV-related malignancy with primary treatment consisting of antiretroviral therapy (ART) in addition to chemotherapy with differing combinations of adriamycin, bleomycin, and vincristine (ABV) [1–3]. Due to resource limitations, salvage therapy is lacking, and patients who relapse or are refractory to therapy often have no further treatment options. Paclitaxel has been noted as an effective salvage agent in adult HIV patients. Here, we present the first report on two pediatric patients. The first patient, a 12-year-old HIV-positive male, presented to Princess Marina Hospital, the country-wide referral hospital in Gaborone, Botswana, with severe wasting, having recently started both tuberculosis (TB)
therapy 2 months prior and ART 2 weeks prior. His ART therapy consisted of stavudine (d4T), lamivudine (3TC), and efavirenz (EFV). Since ART initiation, he developed lesions consistent with Kaposi’s sarcoma on his left thumb and bilateral feet. He additionally presented with increased work of breathing and was found to have a large pericardial effusion. With the worsening symptoms after starting ART, both TB and Kaposi’s sarcoma-associated immune reconstitution inflammatory syndrome (IRIS) were diagnostic considerations. Pericardial fluid was sent for acid-fast bacilli and cytology, both of which were negative. Due to clinical suspicion of Kaposi’s sarcomaIRIS based on the skin lesions and reports of isolated pericardial effusion as a symptom of Kaposi’s sarcoma, we began therapy with bleomycin and vincristine (BV)
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Fig. 1. Improvement in Kaposi’s sarcoma pulmonary involvement after one cycle of paclitaxel.
omitting doxorubicin due to concomitant cytopenias thought secondary to bone marrow involvement or suppression from Kaposi’s sarcoma [4,5]. Repeat echocardiogram after one cycle of BV showed significant improvement in the pericardial effusion, and after two additional weekly BV cycles, the patient’s cytopenias resolved. He was then switched to every 3-week ABV therapy. He unfortunately proved refractory with development of significant right-sided lung involvement which worsened over two cycles of ABV. He also developed peripheral neuropathy, likely due to the combination of vincristine and d4T, so d4Twas switched to abacavir (ABC). With disease progression, he was changed to paclitaxel for salvage, receiving 150 mg/m2 over 3 h with oral dexamethasone premedication 12 and 6 h prior to infusion. After one cycle, he showed dramatic improvement in his lung involvement (Fig. 1) and had no significant toxicity to therapy. Sadly, after the second paclitaxel cycle, he again showed signs of progression and passed away from respiratory symptoms. The second patient, an HIV-positive 8-year-old male on ART, presented with new respiratory symptoms and an oxygen requirement after twice previously being treated for Kaposi’s sarcoma with six cycles of ABV. His ART regimen consisted of zidovidine (AZT), 3TC, and EFV. The first ABV treatment course 2 years prior was given for isolated Kaposi’s sarcoma skin involvement, whereas the second course occurred a year later with pulmonary relapse. Due to this second pulmonary relapse, he was started on paclitaxel salvage therapy at a dose of 150 mg/m2 every 3 weeks, again as a 3-h infusion with oral dexamethasone premedication. After the first cycle, he showed clinical improvement with resolution of his oxygen requirement, although without significant change in his chest radiograph. He continued on every 3-week paclitaxel and achieved disease stabilization with no noted therapeutic toxicity. Although he did not have any significant myelosuppression, he was prophylactically switched from AZT to ABC. With continued disease stability, he was adjusted to every 4-week paclitaxel therapy for familial convenience and has remained stable for 12 months to date. Paclitaxel has shown both in-vitro and in-vivo evidence of activity against Kaposi’s sarcoma due to inhibition of
Bcl-2 antiapoptotic effects in addition to effects on microtubule depolymerization and angiogenesis [6,7]. Adult studies have shown benefit in HIV-associated Kaposi’s sarcoma utilizing different treatment schedules, doses of 100–175 mg/m2 every 2–3 weeks, with neutropenia being the most common toxicity [8–12]. Vaz et al. [13] recently reported on 28 Mozambican children given paclitaxel as first-line therapy after ART initiation at a dose of 75 mg/m2 at 4-week intervals for six cycles. No grade III/IV myelosuppression was seen in our two patients. Two reports in adults have shown severe paclitaxel toxicity due to deceased metabolism with concurrent use of protease inhibitors [14,15]. Larger studies have failed to show any significant interaction [11,16]. Additionally, potential interaction between AZT and chemotherapy must be considered. Our cases highlight the safety and efficacy of paclitaxel in pediatric HIV-associated Kaposi’s sarcoma that has relapsed or is refractory to standard therapy. As African countries move towards further therapies and the addition of salvage regimens, paclitaxel should be acknowledged as a plausible and reasonably inexpensive agent in pediatric patients.
Acknowledgements Conflicts of interest There are no conflicts of interest. Shoba Reddy-Holdcrafta, Parth S. Mehtab and Anurag K. Agrawalb, aTexas Children’s Hospital, and bTexas Children’s Cancer and Hematology Centers, Texas Children’s Hospital Global Health Service Corps, Botswana-Baylor Children’s Clinical Center of Excellence, Princess Marina Hospital, Texas, USA. Correspondence to Parth S. Mehta, MD, Texas Children’s Cancer and Hematology Centers, 1102 Bates Street, Feigin Center 1025.08, Houston, TX 77030, USA. Tel: +1 832 227 1061; fax: +1 832 227 1096; e-mail: [email protected]
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Received: 6 November 2013; revised: 14 November 2013; accepted: 14 November 2013.
References 1. Martellotta F, Berretta M, Vaccher E, Schioppa O, Zanet E, Tirelli U. AIDS-related Kaposi’s sarcoma: state of the art and therapeutic strategies. Curr HIV Res 2009; 7:634–638. 2. Gantt S, Kakuru A, Wald A, Walusansa V, Corey L, Casper C, Orem J. Clinical presentation and outcome of epidemic Kaposi sarcoma in Ugandan children. Pediatr Blood Cancer 2010; 54:670–674. 3. Stefan DC, Stones DK, Wainwright L, Newton R. Kaposi sarcoma in South African children. Pediatr Blood Cancer 2011; 56:392–396. 4. Stotka JL, Good CB, Downer WR, Kapoor WN. Pericardial effusion and tamponade due to Kaposi’s sarcoma in acquired immunodeficiency syndrome. Chest 1989; 95:1359–1361. 5. Reynolds MM, Hecht SR, Berger M, Kolokathis A, Horowitz SF. Large pericardial effusions in the acquired immunodeficiency syndrome. Chest 1992; 102:1746–1747. 6. Sgadari C, Toschi E, Palladino C, Barillari G, Carlei D, Cereseto A. Mechanism of paclitaxel activity in Kaposi’s sarcoma. J Immunol 2000; 165:509–517. 7. Dhillon T, Stebbing J, Bower M. Paclitaxel for AIDS-associated Kaposi’s sarcoma. Expert Rev Anticancer Ther 2005; 5:215–219. 8. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet 1995; 346:26–28. 9. Welles L, Saville MW, Lietzau J, Pluda JM, Wyvill KM, Feuerstein I. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 1998; 16:1112–1121.
10. Gill PS, Tulpule A, Espina BM, Cabriales S, Bresnahan J, Ilaw M. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999; 17:1876– 1883. 11. Tulpule A, Groopman J, Saville MW, Harrington W Jr, Friedman-Kien A, Espina BM. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002; 95:147–154. 12. Stebbing J, Wildfire A, Portsmouth S, Powles T, Thirlwell C, Hewitt P. Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations. Ann Oncol 2003; 14:1660–1666. 13. Vaz P, Macassa E, Jani I, Thome B, Mahagaja E, Madede T. Treatment of Kaposi sarcoma in human immunodeficiency virus-1-infected Mozambican children with antiretroviral drugs and chemotherapy. Pediatr Infect Dis J 2011; 30:891– 893. 14. Hurwitz CA, Relling MV, Weitman SD, Ravindranath Y, Vietti TJ, Strother DR. Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study. J Clin Oncol 1993; 11:2324–2329. 15. Woo MH, Relling MV, Sonnichsen DS, Rivera GK, Pratt CB, Pui CH. Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. Clin Cancer Res 1999; 5:543–549. 16. Cianfrocca M, Lee S, Von Roenn J, Rudek MA, Dezube BJ, Krown SE, Sparano JA. Pilot study evaluating the interaction between paclitaxel and protease inhibitors in patients with human immunodeficiency virus-associated Kaposi’s sarcoma: an Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial. Cancer Chemother Pharmacol 2011; 68:827–833.
DOI:10.1097/QAD.0000000000000157
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