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Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi.

ABSTRACT: HIV-associated Kaposi sarcoma (HIV-KS) is the most common cancer in Malawi. In 2008, the non-governmental organization, Partners In Health, and the Ministry of Health established the Neno Kaposi Sarcoma Clinic (NKSC) to treat HIV-KS in rural Neno district. We aimed to evaluate 12-month clinical outcomes and retention in care for HIV-KS patients in the NKSC, and to describe our implementation model, which featured protocol-guided chemotherapy, integrated antiretroviral therapy (ART) and psychosocial support delivered by community health workers.We conducted a retrospective cohort study using routine clinical data from 114 adult HIV-KS patients who received ART and ?1 chemotherapy cycle in the NKSC between March 2008 and February 2012.At enrolment 97% of patients (n/N=103/106) had advanced HIV-KS (stage T1). Most patients were male (n/N=85/114, 75%) with median age 36 years (interquartile range, IQR: 29-42). Patients started ART a median of 77 days prior to chemotherapy (IQR: 36-252), with 97% (n/N=105/108) receiving nevirapine/lamivudine/stavudine. Following standardized protocols, we treated 20 patients (18%) with first-line paclitaxel and 94 patients (82%) with bleomycin plus vincristine (BV). Of the 94 BV patients, 24 (26%) failed to respond to BV requiring change to second-line paclitaxel. A Division of AIDS grade 3/4 adverse event occurred in 29% of patients (n/N=30/102). Neutropenia was the most common grade 3/4 event (n/N=17/102, 17%). Twelve months after chemotherapy initiation, 83% of patients (95% CI: 74-89%) were alive, including 88 (77%) retained in care. Overall survival (OS) at 12 months did not differ by initial chemotherapy regimen (p=0.6). Among patients with T1 disease, low body mass index (BMI) (adjusted hazard ratio, aHR=4.10, 95% CI: 1.06-15.89) and 1 g/dL decrease in baseline haemoglobin (aHR=1.52, 95% CI: 1.03-2.25) were associated with increased death or loss to follow-up at 12 months.The NKSC model resulted in infrequent adverse events, low loss to follow-up and excellent OS. Our results suggest it is safe, effective and feasible to provide standard-of-care chemotherapy regimens from the developed world, integrated with ART, to treat HIV-KS in rural Malawi. Baseline BMI and haemoglobin may represent important patient characteristics associated with HIV-KS survival in rural sub-Saharan Africa.

SUBMITTER: Herce ME

PROVIDER: S-EPMC4450240 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi.

Herce Michael E ME Kalanga Noel N Wroe Emily B EB Keck James W JW Chingoli Felix F Tengatenga Listern L Gopal Satish S Phiri Atupere A Mailosi Bright B Bazile Junior J Beste Jason A JA Elmore Shekinah N SN Crocker Jonathan T JT Rigodon Jonas J

Journal of the International AIDS Society 20150529

<h4>Introduction</h4>HIV-associated Kaposi sarcoma (HIV-KS) is the most common cancer in Malawi. In 2008, the non-governmental organization, Partners In Health, and the Ministry of Health established the Neno Kaposi Sarcoma Clinic (NKSC) to treat HIV-KS in rural Neno district. We aimed to evaluate 12-month clinical outcomes and retention in care for HIV-KS patients in the NKSC, and to describe our implementation model, which featured protocol-guided chemotherapy, integrated antiretroviral therap ...[more]

PMID: 26028156

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Project description:PurposeIn sub-Saharan Africa, Kaposi sarcoma (KS) is the most common HIV-associated cancer. KS causes substantial morbidity, and treatment goals should emphasize quality of life (QOL). Antiretroviral therapy (ART) is indicated, and early chemotherapy significantly improves tumor regression. The effect of ART alone or with chemotherapy on QOL in treatment-naïve South Africans with HIV-associated KS was assessed.MethodsKAART (Kaposi Sarcoma AIDS Anti-Retroviral Therapy) is a randomized, controlled, open-label trial of ART versus ART plus chemotherapy. Crossover between arms was allowed for patients with progressive disease. Eighty-nine percent of patients had advanced tumor burden. Within KAART, QOL measured by European Organization for Research and Treatment of Cancer-QLQ-C30 questionnaire evaluated functional and symptom domains and global QOL. Intragroup changes between baseline and month 12 (Wilcoxon rank sign test), changes between the arms (Mann-Whitney test), and the relationship between responses, determined by AIDS Clinical Trial Group criteria and QOL measures (Kruskal-Wallis test), were evaluated. P values < .01 were considered significant.ResultsQOL information was available for 111 of 112 patients. Significant improvements over 12 months were seen in global health status and functional scales (emotional, cognitive, and social scales; not physical and role function). Most symptom scales (fatigue, pain, dyspnea, insomnia, appetite, diarrhea, and constipation) also showed significant improvement. There were no statistically significant changes between arms in intention-to-treat analysis. Patients showing a response to the tumor (complete or partial) reported significantly increased global QOL ( P < .001), pain relief, and improved role functioning. Adherence, adverse events, HIV viral load, and CD4 count did not correlate with global QOL.ConclusionAfrican patients with HIV-associated KS derive a significant benefit in QOL from ART and tumor regression.

Project description:BACKGROUND:The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes. METHODS:We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50-100 mg for 1-21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life. RESULTS:Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%-43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients. CONCLUSIONS:HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.

Project description:BackgroundAIDS-related Kaposi sarcoma (AIDS-KS), a common malignancy in Kenya is associated with high morbidity and mortality. AIDS-KS is treated using bleomycin and vincristine (BV) plus or minus doxorubicin in most low resource settings, with response rates ranging from 24.8 to 87%. Survival in low resource settings has not been well documented. We report the three-year survival in a cohort of seventy patients referred to Moi Teaching and Referral Hospital (MTRH).MethodsStudy participants are part of a randomized phase IIA trial on the use of gemcitabine compared to bleomycin plus vincristine for the treatment of Kaposi sarcoma after combination antiretroviral therapy (cART) in Western Kenya. All patients were followed for three years in MTRH. Survival was determined by three monthly physical examination and analysed using Kaplan-Meier method, while possible determinants of survival such as baseline characteristics, type of chemotherapy, initial CD4 counts, age at enrolment, gender and early response to chemotherapy were analysed using univariate and multivariate Cox regression.ResultsParticipants were aged between 19 and 70?years with 56% being male. The median CD4 count was 224 cells/?l, median duration of HIV diagnosis was 12.0?months and median duration of KS lesions after histology diagnosis before initiating chemotherapy was 4.8?weeks. At three years, 60 (85.7%) patients were alive. Six of those who died were under treatment with BV while four with gemcitabine. There was no difference in the probability of survival between the patients on either treatment arm (HR?=?0.573 [95% C. I 0.143, 2.292; p?=?0.4311]). Additionally, the hazard ratio (HR) for response after six weeks, age at enrolment and gender indicated that they were not significant determinants of survival. Patients with normal CD4 cell counts (>?=?500/?l), had a HR of 0.401(0.05,3.23; p?=?0.391), suggesting better survival.ConclusionsPatients with AIDS-KS treated with combined antiretroviral drugs had excellent three-year survival regardless of whether they were treated with BV or gemcitabine as first line therapy. An initial CD4 cell count of >?=?500/?l appeared to improve survival while gender, age and early response to chemotherapy were not predictors of survival after three years.Trial registrationNumber PACTR201510001.

Project description:ImportanceStudies performed in the 1980s and early 1990s have shown that people who develop Kaposi sarcoma (KS) are at higher risk of developing other cancers. The demographics of those affected with human immunodeficiency virus (HIV)/AIDS and KS have changed, and individuals with HIV/AIDS and KS now live longer.ObjectivesTo test the hypothesis that the secondary cancers developing in patients with KS have changed in recent years and to assess the risk of secondary cancers after KS in different periods.Design, setting, and participantsLongitudinal data from 9 cancer registries in the Surveillance, Epidemiology, and End Results (SEER) database were used to identify cases of KS diagnosed from January 1973 to December 2013. The dates of the analysis were November 2016 to February 2017.Main outcomes and measuresThe primary outcome was the development of secondary cancers in individuals with KS. Secondary cancers were considered only if diagnosed 2 months after a diagnosis of KS. Standardized incidence ratios (SIRs) were calculated for the development of new secondary cancers in the pre-AIDS era (1973-1979), pre-highly active antiretroviral therapy (HAART) era (1980-1995), and HAART era (1996-2013). Stratified analysis was then performed on a subset of the cases diagnosed from 1996 to 2013 based on age at diagnosis (<65 and ≥65 years), latency period between KS and the development of secondary cancers (1 year, 2-5 years, >5 to 10 years, and >10 years), and registries with higher vs lower reported rates of HIV/AIDS.ResultsAmong 14 905 individuals with diagnosed KS, 13 721 (92.1%) were younger than 65 years at the time of diagnosis, and 14 356 (96.3%) were male. From 1980 to 1995, SIRs were 2.01 (95% CI, 1.00-3.60) for cancer of the rectum, 49.70 (95% CI, 33.53-70.94) for cancer of the anus, 4.98 (95% CI, 2.79-8.22) for cancer of the liver, 13.70 (95% CI, 2.82-40.03) for cancer of the cervix, 6.40 (95% CI, 2.76-12.60) for Hodgkin lymphoma, and 48.97 (95% CI, 44.85-53.36) for non-Hodgkin lymphoma. From 1996 to 2013, cancer of the anus, Hodgkin lymphoma, non-Hodgkin lymphoma, and cancer of the liver remained associated with KS, with the addition of the following significant SIRs: 6.99 (95% CI, 3.20-13.27) for cancer of the tongue, 10.28 (95% CI, 1.24-37.13) for cancer of the penis, and 17.62 (95% CI, 3.63-51.49) for acute lymphocytic leukemia. The SIR of developing any tumor after KS decreased significantly from 3.36 to 1.94 from the pre-HAART era to the HAART era.Conclusions and relevanceThere has been a significant decline in the overall risk of secondary cancers after KS. Certain cancers, including acute lymphocytic leukemia, cancer of the tongue, and cancer of the penis, are increasingly becoming more common in the HAART era compared with the pre-HAART era. Close monitoring and screening for these secondary cancers is desirable in patients with KS.

Project description:Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.

Dataset Information

Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi.

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Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi.

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