Influence of attendance at a clinic service for high-risk women on HIV prevention: A longitudinal study in Kampala, Uganda

Background: HIV/AIDS continues to be a major public health threat. Globally, there has been notable progress towards reaching people for HIV testing and treatment, as well as in the development of effective prevention tools. But preventing new HIV infections remains a key challenge, particularly among populations at the most risk including female sex workers and their sexual partners. Reducing HIV transmission in these populations requires combined HIV prevention options not only to be available, but also sufficiently used over time. However, regular attendance at clinic facilities, and use of HIV services by female sex workers is affected by persistent and common barriers including high mobility, stigmatisation, and discrimination in health-care settings. The aim of this thesis is to examine the effect of irregular exposure to a package of HIV prevention interventions among women at high risk of HIV in Uganda. Methods: A cohort of HIV-negative women at high risk of HIV was scheduled to attend dedicated clinic services once every three months within the Good Health for Women Project in Kampala, Uganda. An initial cohort of women was enrolled between April 2008 and May 2009 and followed-up (cohort 1). Alongside cohort 1, a second cohort was enrolled from January 2013, and followed-up (cohort 2). At each scheduled clinic visit, participants were offered a combination HIV prevention package that included risk reduction counselling, STI management, and HIV testing. Based on these data, I analysed (i) trends in HIV incidence following enrolment and the influence of missed scheduled visits on HIV incidence trends. In addition, multiple imputation of time-to-event was used to assess the influence of attrition over time on incidence; (ii) the association of the number of missed scheduled visits with subsequent HIV risk; (iii) the association of the number of missed scheduled visits with subsequent proximate determinants of HIV risk (sexually transmitted infections (STIs), alcohol use, inconsistent condom use with paid sex). The analyses were censored at 29th August 2017. Results: Of the 3084 HIV-negative women enrolled, 2206 (71.5%) had at least one followup visit. HIV incidence declined rapidly following enrolment from 6.1/100 person-years in ≤6 months to 2.0/100 at year 3 in cohort 1 (p-value<0.001), and from 3.8/100 to 1.8/100 in cohort 2 (p-value=0.04). HIV incidence was associated with the prior number of missed scheduled visits (adjusted hazard ratio=1.40; 95%CI 0.93-2.12 for 1-2 missed visits versus none, and 2.00 (95%CI 1.35-2.95) for ≥3 missed visits versus none; p-trend=0.001). Missed visits were associated with increased detection of STIs, and increased reporting of daily 3 alcohol use at the subsequent visit attended, but not with reported consistency of condom use with paid sex. Conclusion: The increased HIV risk when high-risk women interrupted their regular exposure to combination HIV prevention was most likely attributed to untreated STI. But the absence of a concurrent change in pattern of inconsistent condom use with paid sex could additionally suggest influence of contextual factors on HIV risk. HIV programmes need to routinely monitor the individual-level exposure to and use of complementary HIV interventions among high-risk women, as well as actively facilitate their attendance of effective intervention packages at regular intervals. For those unable to regularly attend services at health facilities, HIV programmes must adopt innovative ways to deliver combination intervention packages, incorporating STI management and risk reduction counselling and using mobile clinics, clinic vouchers, or even leveraging technology

Missed Study Visits and Subsequent HIV Incidence Among Women in a Predominantly Sex Worker Cohort Attending a Dedicated Clinic Service in Kampala, Uganda

BACKGROUND: There is limited evidence on the relationship between sustained exposure of female sex workers (FSWs) to targeted HIV programmes and HIV incidence. We investigate the relationship between the number of missed study visits (MSVs) within each episode of 2 consecutively attended visits (MSVs) and subsequent HIV risk in a predominantly FSW cohort. // METHODS: Women at high risk of HIV are invited to attend an ongoing dedicated clinic offering a combination HIV prevention intervention in Kampala, Uganda. Study visits are scheduled once every 3 months. The analysis included HIV-seronegative women with ≥1 follow-up visit from enrollment (between April 2008 and May 2017) to August 2017. Cox regression models were fitted adjusted for characteristics on sociodemographic, reproductive, behavioral, and sexually transmitted infections (through clinical examination and serological testing for syphilis). // FINDINGS: Among 2206 participants, HIV incidence was 3.1/100 (170/5540) person-years [95% confidence interval (CI): 2.6 to 3.5]. Incidence increased from 2.6/100 person-years (95% CI: 2.1 to 3.2) in episodes without a MSV to 3.0/100 (95% CI: 2.2 to 4.1) for 1-2 MSVs and 4.3/100 (95% CI: 3.3 to 5.6) for ≥3 MSVs. Relative to episodes without a MSV, the hazard ratios (adjusted for confounding variables) were 1.40 (95% CI: 0.93 to 2.12) for 1-2 MSVs and 2.00 (95% CI: 1.35 to 2.95) for ≥3 MSVs (P-trend = 0.001). // CONCLUSION: Missing study visits was associated with increased subsequent HIV risk. Although several factors may underlie this association, the finding suggests effectiveness of targeted combination HIV prevention. But exposure to targeted interventions needs to be monitored, facilitated, and sustained in FSWs

From antiretroviral therapy access to provision of third line regimens: evidence of HIV Drug resistance mutations to first and second line regimens among Ugandan adults.

HIV care programs in resource-limited settings have hitherto concentrated on antiretroviral therapy (ART) access, but HIV drug resistance is emerging. In a cross-sectional study of HIV-positive adults on ART for ≥6 months enrolled into a prospective cohort in Uganda, plasma HIV RNA was measured and genotyped if ≥1000 copies/ml. Identified Drug resistance mutations (DRMs) were interpreted using the Stanford database, 2009 WHO list of DRMs and the IAS 2014 update on DRMs, and examined and tabulated by ART drug classes. Between July 2013 and August 2014, 953 individuals were enrolled, 119 (12.5%) had HIV-RNA ≥1000 copies/ml and 110 were successfully genotyped; 74 (67.3%) were on first-line and 36 (32.7%) on second-line ART regimens. The predominant HIV-1 subtypes were D (34.5%), A (33.6%) and Recombinant forms (21.8%). The commonest clinically significant major resistance mutations associated with the highest levels of reduced susceptibility or virological response to the relevant Nucleoside Reverse Transcriptase Inhibitor (NRTI) were; the Non-thymidine analogue mutations (Non-TAMS) M184V-20.7% and K65R-8.0%; and the TAMs M41L and K70R (both 8.0%). The major Non-NRTI (NNRTI) mutations were K103N-19.0%, G190A-7.0% and Y181C-6.0%. A relatively nonpolymorphic accessory mutation A98G-12.0% was also common. Seven of the 36 patients on second line ART had major Protease Inhibitor (PI) associated DRMS including; V82A-7.0%, I54V, M46I and L33I (all 5.0%). Also common were the accessory PI mutations L10I-27%, L10V-12.0% and L10F-5.0% that either reduce PI susceptibility or increase the replication of viruses containing PI-resistance mutations. Of the 7 patients with major PI DRMs, five had high level resistance to ritonavir boosted Lopinavir and Atazanavir, with Darunavir as the only susceptible PI tested. In resource-limited settings, HIV care programs that have previously concentrated on ART access, should now consider availing access to routine HIV viral load monitoring, targeted HIV drug resistance testing and availability of third-line ART regimens

Data resource profile: network for analysing longitudinal population-based HIV/AIDS data on Africa (ALPHA Network)

The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA Network, http://alpha.lshtm.ac.uk/) brings together ten population-based HIV surveillance sites in eastern and southern Africa, and is coordinated by the London School of Hygiene and Tropical Medicine (LSHTM). It was established in 2005 and aims to (i) broaden the evidence base on HIV epidemiology for informing policy, (ii) strengthen the analytical capacity for HIV research, and (iii) foster collaboration between network members. All study sites, some starting in the late 1980s and early 1990s, conduct demographic surveillance in populations that range from approximately 20 to 220 thousand individuals. In addition, they conduct population-based surveys with HIV testing, and verbal autopsy interviews with relatives of deceased residents. ALPHA Network datasets have been used for studying HIV incidence, sexual behaviour and the effects of HIV on mortality, fertility, and household composition. One of the network’s substantive focus areas is the monitoring of AIDS mortality and HIV services coverage in the era of antiretroviral therapy. Service use data are retrospectively recorded in interviews and supplemented by information from record linkage with medical facilities in the surveillance areas. Data access is at the discretion of each of the participating sites, but can be coordinated by the network

How have ART treatment programmes changed the patterns of excess mortality in people living with HIV? Estimates from four countries in East and Southern Africa

Background: Substantial falls in the mortality of people living with HIV (PLWH) have been observed since the introduction of antiretroviral therapy (ART) in sub-Saharan Africa. However, access and uptake of ART have been variable in many countries. We report the excess deaths observed in PLWH before and after the introduction of ART. We use data from five longitudinal studies in Malawi, South Africa, Tanzania, and Uganda, members of the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA). Methods: Individual data from five demographic surveillance sites that conduct HIV testing were used to estimate mortality attributable to HIV, calculated as the difference between the mortality rates in PLWH and HIV-negative people. Excess deaths in PLWH were standardized for age and sex differences and summarized over periods before and after ART became generally available. An exponential regression model was used to explore differences in the impact of ART over the different sites. Results: 127,585 adults across the five sites contributed a total of 487,242 person years. Before the introduction of ART, HIV-attributable mortality ranged from 45 to 88 deaths per 1,000 person years. Following ART availability, this reduced to 14–46 deaths per 1,000 person years. Exponential regression modeling showed a reduction of more than 50% (HR =0.43, 95% CI: 0.32–0.58), compared to the period before ART was available, in mortality at ages 15–54 across all five sites. Discussion: Excess mortality in adults living with HIV has reduced by over 50% in five communities in sub-Saharan Africa since the advent of ART. However, mortality rates in adults living with HIV are still 10 times higher than in HIV-negative people, indicating that substantial improvements can be made to reduce mortality further. This analysis shows differences in the impact across the sites, and contrasts with developed countries where mortality among PLWH on ART can be similar to that of the general population. Further research is urgently needed to establish why the different impacts on mortality were observed and how the care and treatment programmes in these countries can be more effective in reducing mortality further

Trends in age at first sex in Uganda: evidence from Demographic and Health Survey data and longitudinal cohorts in Masaka and Rakai.

OBJECTIVES: To derive the best possible estimates of trends in age at first sex (AFS) among successive cohorts of Ugandan men and women based on all the data available from the Demographic and Health Surveys (DHS) and cohort studies in Masaka and Rakai districts. METHODS: The datasets from the DHS, Masaka cohort and Rakai cohort were analysed separately. Survival analysis methods were used to estimate median AFS for men and women born in the 1950s-1980s and to compute hazard ratios for first sex, comparing later cohorts with earlier cohorts. RESULTS: The DHS and Masaka data showed an increase in AFS in women in the more recent birth cohorts compared with those born before 1970, but this was less apparent in the Rakai data. Successive male cohorts in Masaka appeared first to have an increased AFS which subsequently decreased, a trend that was also apparent (but not significant) in the DHS data. Younger men in Rakai had an earlier AFS than those born before 1980. CONCLUSIONS: Women in Uganda who were born after 1970 have, on average, had sex at a later age than those born earlier. For men, AFS has not changed consistently over the period in question. Differences between Masaka and Rakai may reflect socioeconomic differences. Most of the change in AFS occurred too late to have contributed to the initial decline in the incidence of HIV

A comparative assessment of the quality of age at first sex and age at first marriage reporting in three HIV cohort studies in sub-Saharan Africa

OBJECTIVES: To assess inconsistencies in reported age at first sex (AFS) and age at first marriage (AFM) in three African cohorts, and consider their implications for interpreting trends in sexual and marital debut.METHODS: Data were analysed from population-based cohort studies in Zimbabwe, Uganda and South Africa with 3, 10 and 4 behavioural survey rounds, respectively. Three rounds over a similar time frame were selected from each site for comparative purposes. The consistency of AFS and AFM reports was assessed for each site by comparing responses made by participants in multiple surveys. Respondents were defined as unreliable if less than half of all their age-at-event reports were the same. Kaplan-Meier functions were used to describe the cumulative proportion (1) having had sex and (2) married by age, stratified by sex, birth cohort and site, to compare the influence of reporting inconsistencies on these estimates.RESULTS: Among participants attending all three comparable rounds, the percentage with unreliable AFS reports ranged from 30% among South African women to 56% among Zimbabwean men, with similar patterns observed for AFM. Inclusion of unreliable reports had little effect on estimates of median age-at-event in all sites. There was some evidence from the 1960-9 birth cohort that women in Uganda and both sexes in South Africa reported later AFS as they aged.CONCLUSION: Although reporting quality is unlikely to affect comparisons of AFS and AFM between settings, care should be taken not to overinterpret small changes in reported age-at-event over time within each site

Trends and patterns in marriage and time spent single and sexually active in Sub Saharan Africa: a comparative analysis of six community based cohort studies

OBJECTIVES: To describe trends in age at first sex (AFS), age at first marriage (AFM) and time spent single between events and to compare age-specific trends in marital status in six cohort studies.METHODS: Cohort data from Uganda, Tanzania, South Africa, Zimbabwe and Malawi and Demographic and Health Survey (DHS) data from Uganda, Tanzania and Zimbabwe were analysed. Life table methods were used to calculate median AFS, AFM and time spent single. In each study, two surveys were chosen to compare marital status by age and identify changes over time.RESULTS: Median AFM was much higher in South Africa than in the other sites. Between the other populations there were considerable differences in median AFS and AFM (AFS 17-19 years for men and 16-19 years for women, AFM 21-24 years and 18-19 years, respectively, for the 1970-9 birth cohort). In all surveys, men reported a longer time spent single than women (median 4-7 years for men and 0-2 years for women). Median years spent single for women has increased, apart from in Manicaland. For men in Rakai it has decreased slightly over time but increased in Kisesa and Masaka. The DHS data showed similar trends to those in the cohort data. The age-specific proportion of married individuals has changed little over time.CONCLUSIONS: Median AFS, AFM and time spent single vary considerably among these populations. These three measures are underlying determinants of sexual risk and HIV infection, and they may partially explain the variation in HIV prevalence levels between these populations

Reported number of sexual partners: comparison of data from four African longitudinal studies

Objective: To compare reported numbers of sexual partners in Eastern and Southern Africa. Methods: Sexual partnership data from four longitudinal population-based surveys (1998–2007) in Zimbabwe, Uganda and South Africa were aggregated and overall proportions reporting more than one lifetime sexual partner calculated. A lexis-style table was used to illustrate the average lifetime sexual partners by site, sex, age group and birth cohort. The male-to-female ratio of mean number of partnerships in the last 12 months was calculated by site and survey. For each single year of age, the proportion sexually active in the past year, the mean number of partners in the past year and the proportion with more than one partner in the past year were calculated. Results: Over 90% of men and women between 25 and 45 years of age reported being sexually active during the past 12 months, with most reporting at least one sexual partner. Overall, men reported higher numbers of lifetime sexual partners and partners in the last year than women. The male-to-female ratio of mean partnerships in the last year ranged from 1.41 to 1.86. In southern African cohorts, individuals in later birth cohorts reported fewer sexual partners and a lower proportion reported multiple partnerships compared with earlier birth cohorts, whereas these behavioural changes were not observed in the Ugandan cohorts. Across the four sites, reports of sexual partnerships followed a similar pattern for each sex. Conclusions: The longitudinal results show that reductions in the number of partnerships were more evident in southern Africa than in Uganda. <br/