Study design

Recruitment began Feb 15, 2005, and ended Dec 19, 2006, and follow-up continued until Jan 31, 2009. Numbers of patients eligible for antiretroviral therapy were not known in advance—participants were identified after they were tested for CD4-cell counts and clinically assessed. The catchment area was divided into nine strata according to ratio of urban and rural participants and approximate distance from a central point to the TASO Jinja clinic. In every stratum, an even number of clusters (geographical areas) were defined for randomisation along subdistrict boundaries, or, in the case of a few large subdistricts, by known barriers within the subdistrict. Clusters in every stratum had a similar estimated number of people with HIV who were registered at TASO Jinja. Distribution of strata and clusters was as follows: (1) four clusters in urban areas or near the TASO Jinja facility; (2) eight in periurban intermediate distance; (3) eight in rural and far; (4) four in Kamuli district; (5) four in Mukono district near; (6) six in Mukono district far; (7) six in Mayuge district; (8) two in Iganga district near; and (9) two in Iganga district far. Strata and clusters were devised by two people with knowledge of the area (one TASO staff member and one researcher) and cross-checked independently by two other people on two separate occasions.

For all patients, antiretroviral therapy was started at the TASO Jinja clinic, and thereafter patients received care according to the treatment to which their residential area had been assigned. After giving consent, patients were enrolled into the study by research staff, and their addresses were confirmed from TASO records. At every clinic visit, research staff interviewed participants in privacy in a separate building soon after their arrival and before they saw TASO staff.¹⁹

Randomisation

Clusters in each strata were allocated to either home-based or facility-based care by drawing cards from a concealed box. The cards were sealed in advance and labelled with the stratum number by the trial coordinator and TASO senior medical officer who organised the allocation event and placed the cards into the box for each stratum. Cards were drawn by two patient representatives, a TASO medical officer, TASO counsellor, and TASO field officer, each taking turns. This process was done in the presence of senior TASO staff, researchers, and local public health representatives.

Models of care

The trial was done in conditions similar to those of actual health services, with TASO staff responsible for service delivery.¹⁹ Numbers of counsellors, nurses, and laboratory and pharmacy staff in Jinja were similar to those at other TASO centres. The clinic had five medical officers but the number present usually varied between two and four, with some support from local part-time physicians during the trial. Most medical officers were newly qualified. Clinical staff were trained on antiretroviral therapy and supported by a senior medical officer.

For the home-based group, trained field officers travelling on motorcycles visited patients at home every month to deliver drugs, monitor participants with a checklist that included signs and symptoms of drug toxicity or disease progression, and provide adherence support. Most field officers had degree qualifications or college diplomas and underwent 4 weeks of intensive training at the start of the study and yearly refresher courses thereafter about the principles of antiretroviral therapy and adherence support. They were supported at the TASO clinic by counsellors and medical officers.

Field officers referred patients to a physician or counsellor at the TASO clinic when they judged referral to be necessary. They had mobile phones and could contact physicians when unsure about referral. At the end of every day, a medical officer reviewed the notes made by field officers and, when needed, asked officers to return to the patient's home to refer them. Patients who were not at home for their monthly appointment were visited again—usually the next day. If they were absent again, fieldworkers left a message for them to come to the clinic. All patients were invited to the clinic for routine reviews by a medical officer and a counsellor at 2 and 6 months after starting therapy and every 6 months thereafter. Drugs were not dispensed during clinic visits for those allocated to home-based case. Before antiretroviral therapy started, TASO offered free voluntary counselling and testing in the home to household members of participants. This offer was repeated during home visits for drug delivery for those who were absent previously.

In the facility-based group, patients obtained drugs every month from the clinic and had routine reviews with a medical officer and counsellor that were scheduled at 2 and 3 months after start of treatment and every 3 months thereafter. Apart from scheduled reviews, patients were assessed during clinic visits by a nurse and referred to a doctor when necessary. When an appointment was missed, patients were followed up at home by a field officer (if patients had given permission for home visits), usually after 2–3 days, and reminded to attend clinic. Participants were also given vouchers for their household for free voluntary counselling and testing at TASO Jinja. Patients in both groups were asked to come to the clinic any time that they felt unwell. They were also given a telephone number to call for advice. In exceptional cases, and when TASO resources allowed, home care was provided by a team, including a physician, to patients who were bedridden. No financial or other incentives were provided to patients or staff and TASO clinical management procedures were identical for trial and non-trial participants.

Procedures

Independent research staff assessed adherence.¹⁹ Patients in both groups were interviewed during routine clinical and counselling visits at 2 months and 6 months after starting therapy and then every 6 months. Questionnaires were translated into the local language, Luganda, and then back into English by an independent person, and cross-checked by another researcher who was not involved with the trial.

Clinical data were transcribed from patient notes. A change to a second-line regimen was decided by a TASO case conference, consisting of physicians and counsellors, and was made when a patient had one of the following criteria: (1) new or recurrent WHO clinical stage IV or advanced stage III disease; (2) clinical deterioration (eg, weight loss) and two or more consecutive CD4-cell counts less than baseline, or a fall to 50% less than peak CD4-cell count attained after the start of antiretroviral therapy; or (3) CD4-cell counts persistently fewer than 100 cells per μL. Survival status was established through home follow-ups or hospital records, dependent on where deaths took place. We established the status of participants who withdrew from TASO records.

CD4-cell counts were monitored by TASO staff every 6 months for all patients as part of their clinical care. CD4-positive cells were measured with TriTEST reagents (Becton-Dickenson, Franklin Lakes, NJ, USA), according to an inhouse dual-platform protocol and MultiSET and Attractors software (version 2.2) with a FACScan flow cytometer (Becton-Dickinson, Franklin Lakes, NJ, USA). Additional blood was taken to measure plasma viral load, but this testing was for research reasons and done in batches later. Plasma was separated within 2 h and stored immediately at −80°C. HIV-1 RNA was tested with the VERSANT RNA 3.0 (Bayer, Bayer HealthCare, NY, USA) assay (with a lower limit of detection of 50 copies per mL) for baseline samples, and the Amplicor MONITOR 1.5 (Roche, Roche Molecular Systems, NJ, USA) for other samples (400 per copies per mL). After we established close correlation between results of the two assays, the Amplicor assay was used to keep costs to a minimum.

Our economic analysis took a societal perspective and included recurrent and capital costs incurred by the provider, transport and other related costs, and income lost by patients while accessing care. We reported all costs in 2008 US$;themeanexchangeratefrom2005to2008was1732Ugandanshillingsto$1. Cost data and all data for care provided by TASO were obtained from TASO accounts. We used three steps to allocate costs. First, we established the proportion of all TASO clients who were receiving antiretroviral therapy. Second, we calculated the percentage of TASO clients on therapy who entered the trial. Both percentages changed over time, rising initially as numbers of patients who were put on therapy increased, and then falling when recruitment stopped. To capture this dynamic situation, we gathered and aggregated monthly cost data every 6 months, and converted data to US$ with the prevailing exchange rate, with adjustment for inflation.

Third, we allocated costs to facility and home groups. When possible, we used actual service data—eg, information about numbers of doctor visits was used to allocate staff time. We assigned antiretroviral therapy costs proportionally by patient numbers in both groups for that period. Drug prices included purchase cost, insurance, and freight to Uganda and were adjusted to account for substantial price reductions that occurred early in the project. We established costs incurred by patients through a questionnaire.

Health-services costs consisted of: staff costs (doctors, field officers, cousellors, and other staff), transport (motorcycle and vehicle costs of fuel and maintenance, and other transport costs); all drugs; laboratory and clinical expenses (radiograph, ultrasound, and laboratory and CD4 tests); sensitisation (AIDS education via radio, other media, and drama); training, teambuilding, and workshops; utilities (electricity, telephone, postage, and security), supervision and overheads (stationery, repairs, overheads, and supervision costs), and capital costs (buildings, furniture, vehicles, equipment, and inventory). Buildings depreciated over 50 years and other elements 5 years (eg, The AIDS Support Organisation practice). Patient costs consisted of: cost of transport (including transport of medicine companion), childcare, and lunches, if applicable, median weighted by proportion ($2·88forwomenand$3·46 for men); and lost work time, estimated 1 day for clinic visits and 0·5 days for home visits, valued at Uganda mean per head gross domestic product from 2005–08 (World Bank data) for 300 working days per year.

The primary endpoint was rate of virological failure, defined as time (starting from 6 months) to a plasma RNA viral load of more than 500 copies per mL. The secondary outcome measures were time to either detectable plasma viral load of more than 500 copies per mL at any visit from 12 months onwards in patients with viral loads of fewer than 500 copies per mL at 6 months, or an increase of 1000 copies per mL between two consecutive tests in those not achieving a viral load of fewer than 500 copies per mL at 6 months. Other secondary outcomes were all-cause mortality; virological failure as defined in the primary outcome or death; time to first admission; death, admission, or change to second-line antiretroviral therapy; outpatient attendance; adherence during the previous 28 days (measured with a standardised questionnaire); and costs incurred by the health service and patients.

Statistical analysis

We designed the study as an equivalence trial. Virological failure time was taken as halfway between the last measure of RNA of 500 copies per mL or fewer and the first of more than 500 copies per mL. Testing was repeated in patients who had viral loads between 500 and 1000 copies per mL to exclude the possibility of small transient increases. We assumed that in one group the rate of virological failure during follow-up would be about 20%,^20–22 and that the other group could be regarded as equivalent if the rate of virological failure did not exceed 20% by more than 9%—ie, 29% or less. Thus, the upper limit of our equivalence interval was 29/20 or 1·45, and by symmetry the lower limit was 20/29 or 0·69. A sample size of 20 clusters per group with a total of 1200 participants gave more than 95% power to show equivalence, on the assumption of a between-cluster coefficient of variation of 0·2.

Analysis was by intention to treat, in which all participants were regarded as randomly assigned to the group corresponding to the cluster in which they lived. Analyses were done for the individual by fitting generalised linear mixed models with a log-link and poisson distribution, with every patient contributing an outcome of 1 if they had virological failure and 0 if they did not. The model had fixed terms for study regions, baseline CD4-cell counts (categorised as a four-level factor with counts of 0–49, 50–99, 100–149, and 150 or more cells per μL), and study groups, with the log of exposure time included as an offset variable, and a random term for study cluster. The model was fitted with the assumption that the random cluster effects followed a γ distribution. For the primary endpoint, exposure time was calculated from the 6-month visit to midway between the last date on which the patient did not have virological failure and the date of virological failure. For other endpoints, exposure time was calculated from enrolment. Those who withdrew or were lost to follow-up before 12 months were excluded from the primary endpoint analysis, and for other endpoints they were censored on the last date seen.

SJ, HG, AC, JM, and RB were the principal investigators, wrote the protocol, and supervised implementation of the study. SJ was the main author. SF wrote the protocols for the costs component and with RK analysed these data. JL analysed data for the primary and secondary endpoints. BA, GN, JB, and CN were responsible for coordination of field and clinical activities and data collection. NN was responsible for the virology testing and contributed to interpretation of laboratory data. AO and JWT gave input into study implementation and interpretation of findings. All authors contributed to writing of the report and have seen and approved the final version of the report.

Data and safety monitoring board members are indicated by an asterisk. Medical Research Council and Uganda Virus Research Institute Research Unit on AIDS (Entebbe, Uganda) T Eliatu, P Kaleebu, E Tugumisirize, B Wolff, P Munderi*, S Muyingo*, J Todd*; The AIDS Support Organisation (Kampala, Uganda) B Etukoit, S Khanakhwa, J Luzze, E Mugalanzi; Ministry of Health AIDS control programme (Kampala, Uganda) E Madraa; Jinja District Hospital (Uganda) E Habyara; Makerere University, Kampala (Uganda) J Freers*.

We declare that we have no conflicts of interest.