Inferring HIV-1 transmission networks and sources of epidemic spread in Africa with deep-sequence phylogenetic analysis

To prevent new infections with human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa, UNAIDS recommends targeting interventions to populations that are at high risk of acquiring and passing on the virus. Yet it is often unclear who and where these ‘source’ populations are. Here we demonstrate how viral deep-sequencing can be used to reconstruct HIV-1 transmission networks and to infer the direction of transmission in these networks. We are able to deep-sequence virus from a large population-based sample of infected individuals in Rakai District, Uganda, reconstruct partial transmission networks, and infer the direction of transmission within them at an estimated error rate of 16.3% [8.8–28.3%]. With this error rate, deep-sequence phylogenetics cannot be used against individuals in legal contexts, but is sufficiently low for population-level inferences into the sources of epidemic spread. The technique presents new opportunities for characterizing source populations and for targeting of HIV-1 prevention interventions in Africa

Risky sexual behavior among patients on long-term antiretroviral therapy: a prospective cohort study in urban and rural Uganda

Background: While the effects of initiation of antiretroviral treatment (ART) on risky sexual behavior have been extensively studied, less is known about the long-term changes in risky sexual behavior over time in resource-poor settings. Methods: We conducted a secondary longitudinal analysis of one rural and one urban cohort of patients who initiated ART in Uganda between April 2004 and July 2007 followed up-to 2016. Data on sexual behavior were collected every 6 months for 3.5 years in individuals on ART ≥ 4 years (baseline) when a behavioral questionnaire was introduced. Risky sexual behavior was defined as sexual intercourse with ≥ 2 partners or inconsistent or no condom use in previous 6 months. We report characteristics overall, and by cohort. We used multivariable generalized estimating equations logistic regression to assess the effects of time on ART on risky sexual behavior. Results: Of 1012 participants, 402 (39.8%) were urban and 610 (60.2%) were rural residents. Mean age was 42.8 years (SD 8.5). Mean duration of follow-up was 51.3 months (SD 15.3), but longer for urban than rural participants (64.5 vs 36.4 months). Risky sexual behavior declined from 33.1% at baseline to 9.6% after 3.5 years of follow-up in the rural cohort (p ≤ 0.01 for the test of trend) and was unchanged from 9.7% at baseline to 9.9% after 3.5 years in the urban cohort (p = 0.51). Receiving care at a rural clinic (aOR 4.99, 95% CI 3.64–6.84); male gender (aOR 1.66, 95% CI 1.26–2.19) and being younger (aOR 5.60, 95% CI 3.80–8.25 for 18–34 years and aOR 2.34, 95% CI 1.74–3.14 for 35–44 years) were associated with increased odds of risky sexual behavior. Not being married (aOR 0.25; 95% CI 0.19–0.34), and longer time on ART (aOR 0.71 95% CI 0.67–0.76) were associated with reduced odds of risky sex. Conclusions: We observed a decline in risky sexual behavior in rural people on long-term (≥ 4 years) ART. Rural, male and young individuals had higher odds of self-reported risky sexual behavior. ART programs should continue to emphasize risk reduction practices, especially among people receiving care in rural health facilities, males, younger individuals and those who are married.Other UBCNon UBCReviewedFacult

Prevalence and correlates of non-suicidal self-injury, suicidal ideation, and suicide attempt among children and adolescents: findings from Uganda and Jamaica

Background: Youth non-suicidal self-injury (NSSI) and suicide are major public health concerns, but limited data are available on the prevalence and correlates of these problems in developing countries. The aim of this study is to describe experiences of three suicidal phenomena (NSSI, suicidal ideation [SI], and suicide attempt [SA]) among children and adolescents from two developing countries. We also examine how depression, anxiety, sleep problems, child maltreatment, and other socio-demographic variables associate with the risk of NSSI only, SI only, SA only, and co-occurring NSSI/SI/SA. Methods: We conducted a population-based cross-sectional study of school-based Ugandan and Jamaican children and adolescents. Participants were 11,518 (52.4% female) Ugandan and 7,182 (60.8% female) Jamaican youths aged 9-17 years. Results: The estimated lifetime prevalence of NSSI, SI, and SA was 25.5%, 25.6%, and 12.8% respectively among Ugandan boys and 23.2%, 32.5%, and 15.3% respectively among Ugandan girls. As for the Jamaican sample, the estimated lifetime prevalence of NSSI, SI, and SA was 21%, 27.7%, and 11.9% respectively among boys and 32.6%, 48.6%, and 24.7% respectively among girls. The odds of experiencing SI only, SA only, and co-occurring NSSI/SI/SA were significantly elevated among participants with mild, moderate, and severe depression in both countries. Limitations: The current study relied on retrospective data. Conclusions: This study found that suicidal phenomena are common among youths from Uganda and Jamaica, with rates substantially higher than among youths from high-income countries. The risk of suicidal phenomena was especially high among youths with severe depression

1498. Geographic differences in weight change on dolutegravir: a prospective cohort study

Background: People with HIV (PWH) on integrase inhibitors may be at increased risk of excess weight gain, but it is unclear if this risk is consistent across settings. Our study objective was to compare weight change over 48 weeks among PWH in Uganda and South Africa.Figure 1.Mean weight change (kg) over 48 weeks among DISCO participants overall (A), among men (B), and among women (C). Methods: The Population Effectiveness of Dolutegravir Implementation in Sub-Saharan Africa (DISCO) study is a prospective observational cohort of PWH in routine clinical care at public-sector HIV clinics in Uganda and South Africa. Inclusion criteria were as follows: PWH >18 years old, on NNRTI-based first-line ART for >6 months, and switched to tenofovir disoproxil fumarate, lamivudine, and dolutegravir) by clinic staff. We measured the primary outcomes of weight (in kilograms [kg]) and waist circumference (WC, in centimeters [cm]) at enrollment, 24 weeks, and 48 weeks after switch. The primary outcomes were (1) weight change (kg) and (2) change in WC (cm). We used a linear mixed-effect regression model, adjusted for age, sex, education, duration on ART, and the interaction of study site and visit, to estimate weight. Results: 428 individuals in Uganda and 387 in South Africa had data available. The mean weight change over 48 weeks was 0.6 kg [95% CI: 0.1-1.0] in Uganda compared to 2.9 kg [2.4-3.4] in South Africa (p< 0.001); men had significantly smaller mean weight changes than women did in both countries (Figure 1). After adjustment, PWH in South Africa gained significantly more weight than those in Uganda. In participants with available waist data (277 in Uganda and 402 in South Africa), the mean change in WC was significantly greater among those in South Africa (2.3 cm [1.4-3.2]) than those in Uganda (0.8 cm [0.0-1.5]) (p< 0.017). Conclusion: PWH in South Africa experienced greater weight gain than in Uganda, suggesting substantial heterogeneity in this risk across settings. Strategies to address obesity risk in PWH should account for regionality. Disclosures: W D Francois Venter, MD, FCP, PhD, Gilead Sciences: Grant/Research Support|South African Medical Research Council: Grant/Research Support|Unitaid: Grant/Research Support|USAID: Grant/Research Support|ViiV Healthcare: Grant/Research Support Mark J Siedner, MD, MPH, Viiv Healthcare: Grant/Research Suppor

Population Effectiveness of Dolutegravir Implementation in Uganda - A Prospective Observational Cohort Study (DISCO): 48-week Results.

BACKGROUND: Tenofovir/lamivudine/dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen for people with HIV (PWH), including those who were previously virologically suppressed on non-nucleoside reverse transcriptase inhibitors (NNRTIs). We sought to estimate the real-world effectiveness of the TLD transition in Ugandan public-sector clinics. METHODS: We conducted a prospective cohort study of PWH ≥18 years who were transitioned from NNRTI-based ART to TLD. Study visits were conducted on the day of TLD transition and 24- and 48- weeks later. The primary endpoint was viral suppression (500 copies/mL. RESULTS: We enrolled 500 participants (median age of 47 years; 41% women). At 48-weeks after TLD transition, 94% of participants were in care with a VL 500 copies/mL. No incident resistance to DTG was identified. Few participants (2%, n = 9/500) discontinued TLD due to adverse events. CONCLUSIONS: High rates of viral suppression, high tolerability, and lack of emergent drug resistance support use of TLD as the preferred first-line regimen in the region

Knowledge, attitudes and practices on childhood TB among healthcare workers

BACKGROUND: Increasing childhood TB case detection requires the deployment of diagnostic services at peripheral healthcare level. Capacity and readiness of healthcare workers (HCWs) are key to the delivery of innovative approaches.METHODS: In 2019, HCWs from five district hospitals (DHs) and 20 primary healthcare centres (PHCs) in Cambodia, Cameroon, Cote d´Ivoire, Sierra Leone and Uganda completed a self-administered knowledge-attitudes-practices (KAP) questionnaire on childhood TB. We computed knowledge and attitudes as scores and identified HCW characteristics associated with knowledge scores using linear regression.RESULT: Of 636 eligible HCWs, 497 (78%) participated. Median knowledge scores per country ranged between 7.4 and 12.1 (/18). Median attitude scores ranged between 2.8 and 3.3 (/4). Between 13.3% and 34.4% of HCWs reported diagnosing childhood with (presumptive) TB few times a week. Practising at PHC level, being female, being involved in indirect TB care, having a non-permanent position, having no previous research experience and working in Cambodia, Cameroon, Cote d´Ivoire and Sierra Leone as compared to Uganda were associated with a lower knowledge score.CONCLUSION: HCWs had overall limited knowledge, favourable attitudes and little practice of childhood TB diagnosis. Increasing HCW awareness, capacity and skills, and improving access to effective diagnosis are urgently needed

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

‘People say that we are already dead much as we can still walk’: a qualitative investigation of community and couples’ understanding of HIV serodiscordance in rural Uganda

Background: Stable, co-habiting HIV serodiscordant couples are a key population in terms of heterosexual transmission in sub-Saharan Africa. Despite the wide availability of antiretroviral treatment and HIV educational programs, heterosexual transmission continues to drive the HIV epidemic in Africa. To investigate some of the factors involved in transmission or maintenance of serodiscordant status, we designed a study to examine participants’ understanding of HIV serodiscordance and the implications this posed for their HIV prevention practices. Methods: In-depth interviews were conducted with 28 serodiscordant couples enrolled in a treatment-as-prevention study in Jinja, Uganda. Participants were asked questions regarding sexual behaviour, beliefs in treatment and prevention, participants’ and communities’ understanding and context around HIV serodiscordance. Qualitative framework analysis capturing several main themes was carried out by a team of four members, and was cross-checked for consistency. Results: It was found that most couples had difficulty explaining the phenomenon of serodiscordance and tended to be confused regarding prevention. Many individuals still held beliefs in pseudoscientific explanations for HIV susceptibility such as blood type and blood “strength”. The participants’ trust of treatment and medical services were well established. However, the communities’ views of both serodiscordance and treatment were more pessimistic and wrought with mistrust. Stigmatization of serodiscordance and HIV-positive status were reported frequently. Conclusions: The results indicate that despite years of treatment and prevention methods being available, stigmatization and mistrust persist in the communities of HIV-affected individuals and may directly contribute to new cases and seroconversion. We suggest that to optimize the effects of HIV treatment and prevention, clear education and support of such methods are sorely needed in sub-Saharan African communities.Medicine, Faculty ofOther UBCNon UBCReviewedFacult