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

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.

HIV-1 epidemic trends in rural south-west Uganda over a 10-year period.

The objective of this study was to examine the epidemic trends of HIV-1 infection in a rural population cohort in Uganda followed for 10 years. The methods used were to assess incidence and prevalence trends in adults in this longitudinal cohort study. The results showed that incidence of infection has fallen significantly in all adults, and separately in males, females, young adults and older adults over the course of the study period. There was also a reduction in prevalence, especially in young men and women. There was some evidence of a cohort effect in women. The conclusions are that this study provides the first evidence of a falling incidence in a rural general population in Africa. This was an observational cohort exposed to national health education messages, giving hope that similar campaigns elsewhere in Africa could be used effectively in efforts to control the HIV epidemic.

Generalizability of population-based studies on AIDS: a comparison of newly and continuously surveyed villages in rural southwest Uganda.

BACKGROUND: Population-based studies are thought to provide generalizable epidemiological data on the human immunodeficiency virus type 1 (HIV-1) epidemic. However, longitudinal studies are susceptible to bias from added attention caused by study activities. We compare HIV-1 prevalence in previously and newly surveyed villages in rural southwest Uganda. METHODS: The study population resided in 25 neighbouring villages, of which 15 have been surveyed for 10 years. Respondents (>/=13 years) provided socio-demographic and sexual behaviour data and a blood sample for HIV-1 serology in private after informed consent. We tested the independent effect of residency: (1) original versus new villages; (2) proximity to main road; and (3) proximity to trading centre on HIV-1 serostatus of respondents using multivariate logistic regression. RESULTS: There were 8,990 adults censused, 68.3% were from the original villages, 48.2% were males and 6111 (68.0%) were interviewed and had definite HIV-1 serostatus. The HIV-1 prevalence was 6.1% overall, 5.7% in the new, and 6.4% in the original villages (P = 0.25). Residency in the new or original villages did not independently predict HIV-1 serostatus of respondents (P = 0.46). Independent predictors of HIV-1 serostatus were education (primary or higher, odds ratio [OR] = 1.7 and 1.4, respectively), being separated or widowed OR = 4.2, reported previous use of a condom OR = 1.8, or reported genital ulceration OR = 3.3, and age group 25-34 and 35-44 years OR = 5.8 and OR = 4.8 (all P

Evaluation of E-optotypes as a screening test and the prevalence and causes of visual loss in a rural population in SW Uganda.

BACKGROUND: Few population-based eye surveys have been conducted in sub-Saharan Africa, limiting the quality of epidemiological information on visual loss from Africa. In the present paper, we describe the prevalence of visual loss in rural Uganda and the screening accuracy of E-optotypes when used by non-medical staff. METHODS: Residents of 15 neighbouring villages were screened for visual loss (<6/18 in either eye) using Snellen's E-optotypes. Individuals who failed were initially referred to an ophthalmic clinical officer (OCO), who retested visual acuity and subsequently referred to an ophthalmologist to determine the cause of visual loss. Subjects from two villages (248 individuals) who passed visual acuity screening were re-examined by the OCO to estimate the accuracy of the screening procedure. RESULTS: Of the 4076 adults (aged 13 years and over, 69.3% of the censused population) who participated, 191 (4.7%) failed the vision screening criteria and 648 (15.9%) had non-vision impairing conditions. The prevalence of visual loss was at least 3.9%: 0.4% had bilateral blindness, 1.6% had bilateral visual impairment, 0.7% had unilateral blindness and 1.2% unilateral visual impairment. Cataract was the leading cause for all categories of visual loss except bilateral blindness, for which suspected glaucoma was most frequent. Refractive errors were the second leading cause of bilateral and unilateral visual impairment. Based on one subject (0.4%) in the validation sample who was found to have low vision, we estimated the sensitivity and specificity of E-optotypes for detecting visual loss to be 93% and 99%, respectively. CONCLUSIONS: Cataract and refractive errors were responsible for most of the visual loss in rural Uganda. Snellen's E-optotypes provide a suitable cost-saving tool for conducting population-based eye surveys in sub-Saharan Africa.

Declining HIV-1 incidence and associated prevalence over 10 years in a rural population in south-west Uganda: a cohort study.

BACKGROUND: In Uganda, there have been encouraging reports of reductions in HIV-1 prevalence but not in incidence, which is the most reliable measure of epidemic trends. We describe HIV-1 incidence and prevalence trends in a rural population-based cohort between 1989 and 1999. METHODS: We surveyed the adult population of 15 neighbouring villages for HIV-1 infection using annual censuses, questionnaires, and serological surveys. We report crude annual incidence rates by calendar year and prevalence by survey round. FINDINGS: 6566 HIV-1 seronegative adults were bled two or more times between January, 1990, and December, 1999, contributing 31984 person years at risk (PYAR) and 190 seroconversions. HIV-1 incidence fell from 8.0 to 5.2 per 1000 PYAR between 1990 and 1999 (p=0.002, chi(2) for trend). Significant sex-specific and age-group-specific reductions in incidence were evident. Incidence was 37% lower for 1995-99 than for 1990-94 (p=0.002, t-test). On average, 4642 adult residents had a definite HIV-1 serostatus at each yearly survey round. HIV-1 prevalence fell significantly between the first and tenth annual survey rounds (p=0.03, chi(2) for trend), especially among men aged 20-24 years (6.5% to 2.2%) and 25-29 years (15.2% to 10.9%) and women aged 13-19 years (2.8% to 0.9%) and 20-24 years (19.3% to 10.1%) (all p<0.001, chi(2) for trend). INTERPRETATION: Our findings of a significant drop in adult HIV-1 incidence in rural Ugandans give hope to AIDS control programmes elsewhere in sub-Saharan Africa where rates of HIV-1 infection remain high.

Alcohol and HIV: a study among sexually active adults in rural southwest Uganda.

OBJECTIVE: To investigate the association between alcohol consumption and HIV sero-positivity in a rural Ugandan population. METHODS: The adult population residing in a cluster of 15 neighbouring villages has been kept under epidemiological surveillance for HIV infection using annual censuses and sero-surveys since 1989. At the eighth annual survey all respondents were asked about their history of alcohol consumption, the sale of alcohol in their household, and other socio-demographic information. After informed consent, blood was drawn for HIV serology. RESULTS: Of the total adult population 3279 (60%) were interviewed; 48% were males; 905 (27%) had not started sexual activity and were excluded from further analysis. Of the remaining 2374, 8% were HIV infected, 57% had ever drunk alcohol, and 4% lived in households where alcohol was sold. Living in a household where alcohol was sold was associated with a history of having ever drunk alcohol (OR 2.9, 95% CI : 1.7-4.8). HIV prevalence among adults living in households selling alcohol was 15% compared with 8% among those living in households not selling alcohol (OR 2.0, 95% CI : 1.1-3.6). Individuals who had ever drunk alcohol experienced an HIV prevalence twice that of those who had never drunk, 10% versus 5% (OR 2.0, 95% CI : 1.5-2.8). This association remained after adjusting for potential confounders including sale of alcohol in the household and Muslim religion (OR 1.8, 95% CI : 1.2-2.7). Only age, marital status and having ever drunk alcohol independently predicted HIV sero-positivity in a logistic regression model. CONCLUSIONS: We have demonstrated an association between a history of alcohol consumption and being HIV sero-positive. This unexplored factor may explain in part the observed lower prevalence of HIV infection among Muslims. Public health campaigns need to stress the relationship between HIV and alcohol.

Seven-year trends in HIV-1 infection rates, and changes in sexual behaviour, among adults in rural Uganda.

OBJECTIVE: To assess trends in HIV-1 infection rates and changes in sexual behaviour over 7 years in rural Uganda. METHODS: An adult cohort followed through eight medical-serological annual surveys since 1989-1990. All consenting participants gave a blood sample and were interviewed on sexual behaviour. RESULTS: On average, 65% of residents gave a blood sample at each round. Overall HIV-1 prevalence declined from 8.2% at round 1 to 6.9% at round 8 (P = 0.008). Decline was most evident among men aged 20-24 years (11.7 to 3.6%; P < 0.001) and women aged 13-19 (4.4% to 1.4%; P = 0.003) and 20-24 (20.9% to 13.8%; P = 0.003). However, prevalence increased significantly among women aged 25-34 (13.1% to 16.6%; P = 0.04). Although overall incidence declined from 7.7/1000 person-years (PY) in 1990 to 4.6/1000 PY in 1996, neither this nor the age-sex specific rates changed significantly (P > 0.2). Age-standardized death rates for HIV-negative individuals were 6.5/1000 PY in 1990 and 8.2/1000 PY in 1996; corresponding rates for HIV-positive individuals were 129.7 and 102.7/1000 PY, respectively. There were no significant trends in age-adjusted death rates during follow-up for either group. There was evidence of behaviour change towards increase in condom use in males and females, marriage at later age for girls, later sexual debut for boys and a fall in fertility especially among unmarried teenagers. CONCLUSIONS: This is the first general population cohort study showing overall long-term significant reduction in HIV prevalence and parallel evidence of sexual behaviour change. There are however no significant reductions in either HIV incidence or mortality.

Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners.

OBJECTIVE: To assess the efficacy of transmission of HIV-1 within married couples in rural Uganda according to the sero-status of the partners. DESIGN: Estimation of HIV incidence rates for 2200 adults in a population cohort followed for 7 years comparing male-to-female with female-to-male transmission and sero-discordant with concordant sero-negative couples. METHODS: Each year, adults (over 12 years of age) resident in the study area were linked to their spouses if also censused as resident. The HIV sero-status was determined annually. RESULTS: At baseline 7% of married adults were in sero-discordant marriages and in half of these the man was HIV-positive. Among those with HIV-positive spouses, the age-adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95% confidence interval (CI) 0.9-5.4) whereas, among those with HIV-negative spouses, the incidence in women was less than half that of men (RR = 0.4, 95% CI 0.2-0.8). The age-adjusted incidence among women with HIV-positive spouses was 105.8 times (95% CI 33.6-332.7) that of women with HIV-negative spouses, the equivalent ratio for men being 11.6 (95% CI 5.8-23.4). CONCLUSION: Men are twice as likely as women to bring HIV infection into a marriage, presumably through extra-marital sexual behaviour. Within sero-discordant marriages women become infected twice as fast as men, probably because of increased biological susceptibility. Married adults, particularly women, with HIV-positive spouses are at very high risk of HIV infection. Married couples in this population should be encouraged to attend for HIV counselling together so that sero-discordant couples can be identified and advised accordingly.

Determinants of attendance and patient satisfaction at eye clinics in south-western Uganda.

PURPOSE: To identify the reasons for subjects deciding to attend or not attend local and referral ophthalmology clinics in south-west Uganda, and to establish the levels of satisfaction of clinic attenders with the services they received. METHODS: A population survey identified subjects with ocular conditions who were referred to the local clinic or the district hospital. All non-attenders and a group of attenders were interviewed at home. RESULTS: 31% of those referred did not attend the local clinic. The most common reasons were 'too busy' (29%) or 'unwilling to buy spectacles' (17%). Less than half of attenders were satisfied, mainly because of no perceived clinical improvement or having to buy spectacles. Only 13% of those referred to the district hospital clinic attended. The main reasons for non-attendance were high transport cost and fear of the clinic. CONCLUSION: Attendance and satisfaction with the community ophthalmology service could be improved by more intensive motivation and explanation for patients, and assistance with spectacle and transport costs. The use of aphakic motivators should be tested in this context.

Causes and prevalence of non-vision impairing ocular conditions among a rural adult population in sw Uganda.

Information is scanty about the extent of ocular morbidity in developing countries, particularly for non-vision impairing conditions (NVIC), although these constitute the majority of consultations in eye clinics. We have conducted a survey to determine the prevalence and causes of NVIC in a Ugandan adult population and compared our findings with the work pattern of the district hospital. Adults were screened using Snellen's illiterate E chart and those found with visual impairment (acuity less than 6/18) in either eye were referred to a low-vision clinic, and those with obvious ocular disease or symptoms, but without visual impairment, to an outreach clinic. A total of 2886 (53%) out of 5479 adults were screened. Of these, 257 (8.9%) were referred to the outreach clinic, of whom 173 (67%) attended. Of those attending the low-vision clinic 83% had visual impairment confirmed, and 92% of those attending the outreach clinic were confirmed not to have visual impairment. The four commonest NVIC observed at the outreach clinic were: presbyopia (48%), allergic conjunctivitis (20%), early cataract (9%) and infective conjunctivitis (8%), the same conditions as those most commonly seen at the district hospital. In this community, over 80% of NVIC are caused by four conditions which are potentially either correctable, operable or treatable. Training health workers to recognise and treat these conditions would serve the great majority of eye patients. Hospital activity data can be used cautiously to assess the relative frequency of NVIC in the community.

Mortality associated with HIV-1 infection over five years in a rural Ugandan population: cohort study.

OBJECTIVE: To assess the impact of HIV-1 infection on mortality over five years in a rural Ugandan population. DESIGN: Longitudinal cohort study followed up annually by a house to house census and medical survey. SETTING: Rural population in south west Uganda. SUBJECTS: About 10,000 people from 15 villages who were enrolled in 1989-90 or later. MAIN OUTCOME MEASURES: Number of deaths from all causes, death rates, mortality fraction attributable to HIV-1 infection. RESULTS: Of 9777 people resident in the study area in 1989-90, 8833 (90%) had an unambiguous result on testing for HIV-1 antibody; throughout the period of follow up adult seroprevalence was about 8%. During 35,083 person years of follow up, 459 deaths occurred, 273 in seronegative subjects and 186 in seropositive subjects, corresponding to standardised death rates of 8.1 and 129.3 per 1000 person years. Standardised death rates for adults were 10.4 (95% confidence interval 9.0 to 11.8) and 114.0 (93.2 to 134.8) per 1000 person years respectively. The mortality fraction attributable to HIV-1 infection was 41% for adults and was in excess of 70% for men aged 25-44 and women aged 20-44 years. Median survival from time of enrollment was less than three years in subjects aged 55 years or more who were infected with HIV-1. Life expectancy from birth in the total population resident at any time was estimated to be 42.5 years (41.4 years in men; 43.5 years in women), which compares with 58.3 years (56.5 years in men; 60.5 years in women) in people known to be seronegative. CONCLUSIONS: These data confirm that in a rural African population HIV-1 infection is associated with high death rates and a substantial reduction in life expectancy.

PIP: The impact of HIV-1 infection on mortality in 15 villages in southwest Uganda was assessed in a 5-year (1990-95) longitudinal cohort study with an annual household census and serologic survey. HIV seroprevalence among the 4685 adults in the study area was 8.3%. During 35,083 person-years of follow up, 459 deaths occurred, 186 of which involved HIV-positive persons. Standardized mortality rates among HIV-positive and HIV-negative adults were 10.4 and 114.0 per 1000 person-years, respectively. The mortality fraction attributable to HIV was 41% for all adults and in excess of 70% for men 25-44 years of age and women 20-44 years of age. Median survival time from study enrollment was under 3 years in HIV-infected residents 55 years and older. Life expectancy from birth in the total population in any year of the study was 42.5 years compared with 58.3 years in HIV-negative persons. These findings confirm that HIV-1 is a significant determinant of mortality in rural African populations.

The orphan problem: experience of a sub-Saharan Africa rural population in the AIDS epidemic.

An assessment of the prevalence of orphans and the magnitude of their problems and the extent to which HIV-1 is contributing to this was done in a rural population in South-West Uganda with an HIV-1 seroprevalence of 8% among adults. Slightly over 10% of children aged less than 15 years were reported to have lost one or both parents. Loss of the father alone (6.3%) was more common than loss of the mother alone (2.8%). Generally orphans were living with their surviving parent or other relatives but it was also noted in this study that some children with both parents alive lived with relatives as part of the extended family system. HIV-1 seroprevalence rates were higher among orphans than among non-orphans and were up to 6 times higher in the 0-4 year age group. Seropositivity rates were also higher among surviving parents of orphans than among parents of non-orphans. No significant difference in mortality between orphans and non-orphans was observed. During a 3-year follow-up period a total of 169 children became orphans and 43% of these cases resulted from the death of an HIV-1 positive parent. There was a limited effect on school attendance by orphanhood. The HIV-1 epidemic has substantially increased the number of orphans in this community, a finding which is probably typical of many other sub-Saharan African countries. It appears that these orphans were generally well looked after within the community. This coping capacity may, however become overstretched if the epidemic evolves further.

PIP: During 1989-90 the Medical Research Programme on AIDS enrolled 4975 children younger than 15 living in a cluster of 15 villages in rural Masaka district, southwest Uganda, into a 3-year prospective study. It examined the data to assess the magnitude of the problem of orphans and the extent to which HIV-1 is contributing to their problems. In this area, it is common for children with both parents alive to live with other relatives (e.g., grandparents) to help with domestic work. 518 (10.4%) children had lost 1 or both parents. These orphans were more likely to have lost a father alone than a mother alone (6.3% vs. 2.8%). 67 (13%) of the 518 orphans (i.e., 1% of all children) had lost both parents. Orphans 0-4 years old and surviving parents of orphans were more likely to be HIV-1 infected than their counterparts (5.6% vs. 0.9% for non-orphans 0-4 years old; p = 0.01 and 15.4% vs. 6.2% for parents of non-orphans; p 0.001). During the follow-up period, 83 parents of previous non-orphans died, leaving 169 orphans. 42.6% of the newly registered orphans had an HIV-1 positive parent. 98 deaths occurred among HIV-1 negative children (7 orphans, 91 non-orphans). No significant difference in mortality rates among HIV-1 negative children existed. Yet, in the 0-4 year old age group, orphans had a higher, but insignificantly so, 3-year mortality rate than non-orphans (22.1 vs. 15.6/1000 person-years). School attendance in the previous 6 months was slightly lower among orphans than non-orphans (75.5% vs. 83.6%) but the difference was insignificant (p = 0.3). Census data indicate that orphanhood has increased by at least 50% in the last 20 years, probably due to the AIDS epidemic. These findings suggest that the community tends to care well for orphans, but if the HIV/AIDS epidemic continues this coping mechanism may be become overly burdened.

Incidence of HIV-1 infection in adults and socio-demographic characteristics of seroconverters in a rural population in Uganda: 1990-1994.

BACKGROUND: To evaluate HIV-1 incidence among adults and socio-demographic risk factors in a rural population in Uganda, a prospective cohort study was carried out. METHODS: All consenting adult residents in a cluster of 15 neighbouring villages of the Masaka District of south-west Uganda have been participating in annual socio-demographic and serological surveys since November 1989. Those who had a negative serostatus when they were first tested and had at least one serostatus assessment during the 4 years of follow-up (1990-1994) have been evaluated for HIV-1 seroconversion. Incidence rates have been calculated per 1000 person-years of observation and socio-demographic characteristics assessed for association with recent seroconversion. RESULTS: At the baseline survey, of 4175 adults with assessable serostatus (79% of all censused adults), 342 (8.2%) were seropositive. During 12588.2 person-years of follow-up 89 seroconversions were identified corresponding to an incidence rate of 7.1 (95% CI: 5.6-8.5). Overall rates were highest in females aged 20-24 years (15.2) and in males aged 20-44 years (11.6). There was a significant interaction between age and sex; the ratio of the rate in females to that in males decreased from 3.3:1 to 0.5:1 with increasing age. Rates for males aged > or = 20 years were four times higher than those for younger males. Other significant socio-demographic correlates with risk included not belonging to the majority tribe, non-Muslim religion and length of stay on compound of less than 10 years. Incidence rates did not show any clear trends with time. CONCLUSION: These findings further emphasize the need for targeted interventions.