Dataset Information

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

ABSTRACT:

Background

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.

Methods

In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779.

Findings

Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases).

Interpretation

ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment.

Funding

UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

SUBMITTER: DART Trial Team

PROVIDER: S-EPMC2805723 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

Mugyenyi P P Walker A S AS Hakim J J Munderi P P Gibb D M DM Kityo C C Reid A A Grosskurth H H Darbyshire J H JH Ssali F F Bray D D Katabira E E Babiker A G AG Gilks C F CF Grosskurth H H Munderi P P Kabuye G G Nsibambi D D Kasirye R R Zalwango E E Nakazibwe M M Kikaire B B Nassuna G G Massa R R Fadhiru K K Namyalo M M Zalwango A A Generous L L Khauka P P Rutikarayo N N Nakahima W W Mugisha A A Todd J J Levin J J Muyingo S S Ruberantwari A A Kaleebu P P Yirrell D D Ndembi N N Lyagoba F F Hughes P P Aber M M Lara A Medina AM Foster S S Amurwon J J Wakholi B Nyanzi BN Whitworth J J Wangati K K Amuron B B Kajungu D D Nakiyingi J J Omony W W Fadhiru K K Nsibambi D D Khauka P P Mugyenyi P P Kityo C C Ssali F F Tumukunde D D Otim T T Kabanda J J Musana H H Akao J J Kyomugisha H H Byamukama A A Sabiiti J J Komugyena J J Wavamunno P P Mukiibi S S Drasiku A A Byaruhanga R R Labeja O O Katundu P P Tugume S S Awio P P Namazzi A A Bakeinyaga G T GT Katabira H H Abaine D D Tukamushaba J J Anywar W W Ojiambo W W Angweng E E Murungi S S Haguma W W Atwiine S S Kigozi J J Namale L L Mukose A A Mulindwa G G Atwiine D D Muhwezi A A Nimwesiga E E Barungi G G Takubwa J J Murungi S S Mwebesa D D Kagina G G Mulindwa M M Ahimbisibwe F F Mwesigwa P P Akuma S S Zawedde C C Nyiraguhirwa D D Tumusiime C C Bagaya L L Namara W W Kigozi J J Karungi J J Kankunda R R Enzama R R Latif A A Hakim J J Robertson V V Reid A A Chidziva E E Bulaya-Tembo R R Musoro G G Taziwa F F Chimbetete C C Chakonza L L Mawora A A Muvirimi C C Tinago G G Svovanapasis P P Simango M M Chirema O O Machingura J J Mutsai S S Phiri M M Bafana T T Chirara M M Muchabaiwa L L Muzambi M M Mutowo J J Chivhunga T T Chigwedere E E Pascoe M M Warambwa C C Zengeza E E Mapinge F F Makota S S Jamu A A Ngorima N N Chirairo H H Chitsungo S S Chimanzi J J Maweni C C Warara R R Matongo M M Mudzingwa S S Jangano M M Moyo K K Vere L L Mdege N N Machingura I I Katabira E E Ronald A A Kambungu A A Lutwama F F Mambule I I Nanfuka A A Walusimbi J J Nabankema E E Nalumenya R R Namuli T T Kulume R R Namata I I Nyachwo L L Florence A A Kusiima A A Lubwama E E Nairuba R R Oketta F F Buluma E E Waita R R Ojiambo H H Sadik F F Wanyama J J Nabongo P P Oyugi J J Sematala F F Muganzi A A Twijukye C C Byakwaga H H Ochai R R Muhweezi D D Coutinho A A Etukoit B B Gilks C C Boocock K K Puddephatt C C Grundy C C Bohannon J J Winogron D D Gibb D M DM Burke A A Bray D D Babiker A A Walker A S AS Wilkes H H Rauchenberger M M Sheehan S S Spencer-Drake C C Taylor K K Spyer M M Ferrier A A Naidoo B B Dunn D D Goodall R R Darbyshire J H JH Peto L L Nanfuka R R Mufuka-Kapuya C C Kaleebu P P Pillay D D Robertson V V Yirrell D D Tugume S S Chirara M M Katundu P P Ndembi N N Lyagoba F F Dunn D D Goodall R R McCormick A A Lara A Medina AM Foster S S Amurwon J J Wakholi B Nyanzi BN Kigozi J J Muchabaiwa L L Muzambi M M Weller I I Babiker A A Bahendeka S S Bassett M M Wapakhabulo A Chogo AC Darbyshire J H JH Gazzard B B Gilks C C Grosskurth H H Hakim J J Latif A A Mapuchere C C Mugurungi O O Mugyenyi P P Burke C C Jones S S Newland C C Pearce G G Rahim S S Rooney J J Smith M M Snowden W W Steens J-M JM Breckenridge A A McLaren A A Hill C C Matenga J J Pozniak A A Serwadda D D Peto T T Palfreeman A A Borok M M Katabira E E

Lancet (London, England) 20091208 9709

<h4>Background</h4>HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.<h4>Methods</h4>In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD ...[more]

PMID: 20004464

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Project description:BackgroundDespite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated.MethodsCost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12-weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial.Results3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm(3)) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95%CI:685,845], translating into an adjusted incremental cost of $7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent cost-drivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below $3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term.ConclusionsThere is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test.

Project description:IntroductionSouth Africa is considered highly endemic for hepatitis A virus (HAV) although few seroprevalence studies have been conducted over the past two decades. The World Health Organization recommends integrating HAV vaccination into national childhood immunization schedules where there is transition from high to intermediate endemicity. As a means of gauging age-specific rates of infection, we report HAV seroprevalence rates among specimens tested for HAV serology within South Africa's public health sector from 2005-2015.Materials and methodsHepatitis A serology results (Anti-HAV IgM, IgG and total antibody) from 2005-2015 were extracted from South Africa's National Health Laboratory Service's Corporate Data Warehouse (NHLS CDW), the central data repository of all laboratory test-sets within the public health sector. Results were extracted according to test-set, result, date of testing, health facility, name, surname, age, and sex. Anti-HAV IgG results were merged with total antibody results to reflect anti-HAV seroprevalence. Testing volume, positivity rates and age-specific anti-HAV seroprevalence rates by year and geographic distribution are described.Results and discussionA total of 501 083 HAV IgM results were retrieved, of which 16 423 (3.3%) were positive, 484 259 (96.6%) negative and 401 (0.1%) equivocal; and 34 710 HAV total antibody/IgG tests of which 30 675 (88.4%) were positive, 4 020 (11.6%) negative and 15 equivocal. Whereas IgM positivity was highest among the 1-4 year age group (33.5%) and lowest among patients >45 years (<0.5%), total antibody positivity ranged from its lowest level of 52.7% in the 1-4 year age group increasing to levels of >90% only after 25 years of age.ConclusionAnti-HAV total antibody testing within the South African public health sector demonstrates seroprevalence rates reach levels >90% only in adulthood, suggesting South Africa could be in transition from high to intermediate endemicity. Prospective studies with geographically representative sampling are required to confirm these findings and evaluate provincial and urban/rural heterogeneity.

Project description:ImportancePrevious studies have shown that uniform pathologic review of all splenectomy surgical specimens reveals new clinically actionable diagnoses only in a minority of cases.ObjectiveTo examine whether the aggregate of clinical, laboratory, imaging, and pathologic preoperative data is associated with a clinically beneficial pathologic study for routine splenectomy surgical specimens.Design, setting, and participantsThis single-center retrospective cohort study included all patients who underwent splenectomy from January 1, 2013, through December 31, 2018, at a single center. Clinical, imaging, and pathologic data were extracted from the institution's electronic medical records system. Data analysis was conducted from June to November 2020.ExposuresUndergoing splenectomy for trauma or diagnostic or therapeutic indications.Main outcomes and measuresSpleen pathology study resulting in a new medical diagnosis or change in medical management.ResultsOverall, 90 patients (53 [59%] men) with a median (range) age of 59 (19-90) years underwent splenectomy for therapeutic purposes in 41 patients (45%), trauma in 24 patients (27%), diagnostic purposes in 15 patients (17%), and combined therapeutic and diagnostic purposes in 9 patients (10%). In 14 patients (15%) a new malignant neoplasm was found, and in 8 patients (9%), a new nonneoplastic medical condition was diagnosed. A new pathologic diagnosis resulted in change in medical management in 16 patients (18%). In patients without a prior diagnosis of cancer, 41 of 56 pathology biopsies (73%) were found to be normal whereas in 7 biopsies (13%), a new diagnosis of a hematologic malignant neoplasm was revealed (P < .001). Patients with clinical splenomegaly were significantly more likely to have a new pathologic diagnosis of cancer compared with patients without splenomegaly (15 of 26 [58%] vs 4 of 64 [7%]; P < .001). In 39 of 43 patients (91%) with normal presurgery imaging studies, normal spleen pathology was revealed, whereas in 14 of 17 patients (82%) with abnormal imaging studies, a new hematological malignant neoplasm was diagnosed following pathologic review of the spleen specimen (P < .001). Patients with gross abnormalities on macroscopic examination had a significantly increased likelihood of a hematological cancer diagnosis (17 of 40 [43%]) and a solid cancer diagnosis (4 [10%]) compared with patients with grossly normal specimens (4 of 49 [8%]; P < .001).Conclusions and relevanceIn this cohort study, routine pathologic review of spleen specimens was clinically beneficial in patients with splenomegaly, abnormal imaging results, a prior diagnosis of cancer, and with grossly abnormal spleens.

Project description:Same-day initiation (SDI) of antiretroviral therapy (ART) has been recommended to improve ART programme outcomes in South Africa since August 2017. This study assessed implementation of SDI over time in two South African districts, describing the characteristics of same-day initiators and evaluating the impact of SDI on retention in ART care. Routine data were analysed for HIV-infected adults who were newly initiating ART in Johannesburg or Mopani Districts between October 2017 and June 2018. Characteristics of same-day ART initiators were compared to later initiators, and losses to follow-up (LTFU) to six months were assessed using Kaplan Meier survival analysis and multivariate logistic regression. The dataset comprised 32 290 records (29 964 from Johannesburg and 2 326 from Mopani). The overall rate of SDI was 40.4% (n = 13 038), increasing from 30.3% in October 2017 to 54.2% in June 2018. Same-day ART initiators were younger, more likely to be female and presented with less advanced clinical disease than those initiating treatment at later times following diagnosis (p<0.001 for all). SDI was associated with disengagement from care: LTFU was 30.1% in the SDI group compared to 22.4%, 19.8% and 21.9% among clients initiating ART 1-7 days, 8-21 days and ≥22 days after HIV diagnosis, respectively (p<0.001). LTFU was significantly more likely among clients in Johannesburg versus Mopani (adjusted odds ratio (aOR) = 1.43, p<0.001) and among same-day versus later initiators (aOR = 1.45, p<0.001), while increasing age reduced LTFU (aOR = 0.97, p<0.001). In conclusion, SDI has increased over time as per national guidelines, but there is serious concern regarding the reduced rate of retention among same-day initiators. Nevertheless, SDI may result in a net programmatic benefit provided that interventions are implemented to support client readiness for treatment and ongoing engagement in ART care, particularly among younger adults in large ART programmes such as Johannesburg.

Project description:BACKGROUND:For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS:A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS:Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION:In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING:National Institutes of Health.

Project description:BackgroundExpanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients.MethodsThis randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per microL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1.40. This study is registered with ClinicalTrials.gov, number NCT00255840.Findings408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1.09 (95% CI 0.89-1.33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60-144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively.InterpretationNurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART.FundingNational Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases.

Dataset Information

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

Background

Methods

Findings

Interpretation

Funding

Publications

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

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