AHRI scientists, students and collaborators presented research via workshops and oral and poster abstracts at the recent Conference on Retroviruses and Opportunistic Infections (CROI) 2018 in Boston, Massachusetts.
Read the abstracts below, and follow the links for the webcast or poster for each presentation.
AHRI Faculty Alison Grant was an invited speaker for a workshop on clinical trial design and analysis, titled ‘Pragmatic Trials’.
Pragmatic trials aim to evaluate how an intervention will perform in real-world conditions, contrasting with explanatory trials, which aim to determine whether an intervention can work under experimental conditions. The extent to which a trial is pragmatic can be assessed across multiple domains, including whether the study population is highly selected or has broader inclusion criteria; the flexibility of delivery of the intervention; whether the follow-up schedule reflects routine practice; and whether the primary outcome is relevant to patients. Pragmatic trials are not less rigorous than explanatory trials, and may be logistically more challenging to implement. The research question should determine whether a more explanatory or a more pragmatic design is needed. Tools which help assess where a trial lies on the spectrum from explanatory to pragmatic may help investigators ensure that their trial design aligns with the research question.
Click here for the webcast.
AHRI had three talks in the ‘Surveillance and Epidemiology: new approaches’ oral abstract session at CROI 2018, including presentations dealing with geographical HIV ‘hot-spots’, the sharp decline of male HIV incidence in a rural population in KwaZulu-Natal, and ongoing HIV microepidemics.
Assessing the role of geographical HIV hot-spots in the spread of the epidemic
Diego F. Cuadros, Tiago Graf, Tulio de Oliveira, Till Bärnighausen, Frank Tanser
In the last few years, a radical shift in thinking about geographical targeted interventions has prompted several international stakeholders (UNAIDS, PEPFAR, GFATM) to include geographical prioritization as a key component of their overall HIV intervention strategy. However, there are some critical unexplored issues that need to be addressed to quantify the real impact of geographically targeted interventions on the epidemic. The spatial connectivity of the transmission network of an entire community has never been studied before, and the contribution of geographical clusters of HIV infections, or ‘hot-spots’ on the spread of the infection in the entire population is virtually unknown. To address these issues, a spatially explicit transmission network and the transmission intensity from an HIV hot-spot were analyzed.
We examined a sample of 18,294 individuals located in a hyper-endemic rural community in South Africa, from which 5,624 (4,279 females and 1,345 males) tested positive for HIV. We identified a geographical cluster with high numbers of HIV infections (HIV ‘hot-spot’) using spatial statistical analysis. Additionally, we genetically sequenced and geo-located 1,222 HIV-positive individuals, identified phylogenetic transmission clusters, and estimated the number of transmission links (individuals grouped in these transmission clusters) that arose from the HIV hot-spot.
From the 351 transmission links identified, 254 links (72.4%) included at least one individual located within the HIV hot-spot (Figure 1). The average distance between individuals genetically linked was 6.4 km. Results from microsimulation models indicated that the observed HIV transmission link configuration does not follow a random pattern, and the probability of transmission link formation is negatively affected by the distance between individuals and the HIV hot-spot.
To our knowledge, this is the first time a geographical transmission network of an entire community was studied. We observed intense transmission dynamics between the HIV hot-spot and the rest of the community located outside this high HIV burden area. These results suggest that geographical hot-spots could have a similar role as behavioral core groups in transmission networks of concentrated epidemics. Targeting these geographical core groups, would not only impact HIV incidence within the hot-spot, but could also disrupt the transmission network of the entire community.
Click here for the webcast.
Sharp decline in male HIV incidence in a rural South African population (2004–2015)
Alain Vandormael, Adam N. Akullian, Adrian Dobra, Tulio de Oliveira, Frank Tanser
The extraordinary scale-up of antiretroviral therapy (ART) is expected to reduce the rate of new HIV infections at the population level. In this study, we calculated the incidence of HIV for males and females using data from a complete South African population.
The Africa Health Research Institute (AHRI) maintains an annual HIV surveillance system in the Umkhanyakude district of the KwaZulu-Natal province. Between 2004 and 2015, we followed 6,287 males (aged 15–54 years) and 8,661 females (aged 15–49 years) from their earliest HIV-negative test date until their latest HIV-negative or earliest HIV-positive test date. In addition, we obtained viral load measurements from all HIV-positive participants in 2011, 2012, and 2014 and included ART initiation data from the 17 health-care clinics in the AHRI surveillance area.
The HIV incidence rate declined among males aged 15–25 years between 2012 and 2015, from 1.70 (95% CI: 1.13–2.26) to 0.60 (95% CI: 0.00–1.29) events/100 person-years, as well as for males aged 25–54 years, from 3.28 (95% CI: 1.97–4.55) to 1.87 (95% CI: 0.60–3.56) events/100 person-years. For females aged 15–25 years, however, the HIV incidence rate increased from 6.32 (95% CI: 5.34–7.32) to 6.67 (95% CI: 5.25–8.16) events/100 person-years between 2013 and 2015. Throughout the study period, the HIV incidence rate was flat for females aged 25–49 years, ranging from 4.14 (95% CI: 3.35–5.01) to 5.00 (95% CI: 4.37–5.69) events/100 person-years. ART coverage was significantly higher in woman, increasing from 28.3% to 43.6% between 2010 and 2013, when compared with men, which increased from 26.7% to 32.3%. Among woman aged 15–25 years, the virologic suppression level increased from 20.8% (95% CI: 16.5–25.2%) in 2011 to 40% (95% CI: 34.4-45.7%) in 2014. During this period, the virologic suppression level increased only slightly for men of the same age group, from 15.2% (95% CI: 5.8–24.7%) to 18.5% (95% CI: 7.8–29.2%).
The HIV incidence rate declined for all men aged 15–54 years between 2012 and 2015 but increased among young woman aged 15–25 years. We hypothesize that the more conscientious treatment-and-care behaviors of woman-i.e., higher ART uptake and higher rates of virologic suppression-has begun to protect men from acquiring HIV.
Click here for the webcast.
Ongoing HIV microepidemics in rural South Africa: the need for flexible interventions
Cordelia Coltart, Maryam Shahmanesh, Stephane Hue, Janet Seeley, Till Bärnighausen, Benn Sartorius, Tulio de Oliveira, Thembelihle Zuma, Natsayi Chimbindi, Anne Johnson, Deenan Pillay, Frank Tanser
Using one of Africa’s largest HIV seronegative cohorts in KwaZulu-Natal, South Africa, we recently identified remarkable space-time variations in HIV incidence (2004-14) with the rapid emergence of a rural cluster (incidence >10% per year), near a recent coal mine development. We have undertaken a phylogenetic, epidemiological and social science investigation to understand the drivers, and guide optimal intervention, for this microepidemic.
HIV incidence was measured through population-based annual surveillance. A phylogeny of 2179 HIV-1 subtype C partial pol sequences -1376 local sequences (2010-14, 15% of HIV positive population) and 803 publically available South African control sequences (2000-14) -was reconstructed by maximum likelihood inference. A dated phylogeny was inferred using Beast 2. We geo-located individuals to their residences and conducted a rapid ethnographic assessment of the HIV risk and prevention landscape in adolescents and young adults during 2017.
Phylogenetic reconstruction revealed a distinct monophyletic cluster (75 local sequences). The dated phylogeny suggests this emerged from a common source, with two bursts of infection (2012, 2014) and was expanding at the time of last sampling (2014). There were more males (57 vs. 43%, p<0.01) and higher employment (proportion in full-time employment: 45 vs. 18%, p<0.01) in this cluster compared to the population. Geospatial analyses revealed over 40% resided within a rural area adjacent to a mine. Another 40% of cases were located in the peri-urban area, adjacent to the main highway, previously identified as a high incidence area. The ethnographic survey found that local economic development brought money to this poor rural area, but at the cost of moving homes and bringing young men and truck drivers to the area. Whilst this did not appear to have resulted in visible sex work around the mine area, the residents described a rise in opportunities for transactional sex and access to alcohol and ‘places of risk’ in a nearby urban area.
Our findings highlight the continued emergence of concentrated microepidemics within an existing hyperendemic region, with the potential to fuel ongoing transmission. Rapid socioeconomic changes, such as those induced by mines and other industrial developments, that bring people and money to poor areas may have unintended health consequences. We propose that flexible HIV prevention and sexual health services are required to rapidly respond to such events.
Click here for the webcast.
AHRI’s newest Faculty member, Zaza Ndhlovu (pictured above) presented during the ‘HIV reservoir and viral replication’ session:
CD8+ T cell responses in treated hyperacute HIV infection limit HIV reservoir size
Zaza Ndhlovu, Samuel W. Kazer, Thandeka Nkosi, Funsho Ogunshola, Amber D. Moodley, Krista Dong, Alex K. Shalek, Thumbi Ndung’u, Bruce D. Walker
Early initiation of cART has the potential to enhance protective immunity by preserving CD4+ T cells and limiting T cell exhaustion. However, the quality of HIV-specific CD8+ T responses induced in the context of limited HIV antigen exposure and the impact on the dynamics of HIV reservoir accumulation are underexplored.
Studies were performed in persons identified and treated at the onset of HIV plasma viremia (n=34, 27 Fiebig Stage I, 7 Fiebig stage III/V), and compared to chronic treated persons (n=10). Flow cytometry and transcriptional analyses coupled with HIV DNA measurements were used to longitudinally define the relationships between HIV-specific CD8+ T cells responses, viral persistence and reservoir decay.
More than 90% of individuals initiating treatment in Fiebig I mounted detectable HIV-specific CD8+ T cell responses. The breadth of the initial responses was driven by cumulative HIV plasma viral burden (viremia copy days, VCD), defined as the area under plasma viral load curve. There was a strong positive correlation between VCD and immune responses measured by three different assays namely, activation (CD8+CD38+HLA-DR+) (r=0.08, p=0.0001), frequency of tetramer+ CD8+ T cells (r=0.8, p=0.006) and breadth of HIV-specific CD8+ T cell responses measured by IFN-γ ELISPOT (r=0.5, p=0.02). Tetramer-stained HIV-specific CD8+ T responses of early treated subjects had significantly higher expression of CD127 (p=0.0009) and had a pro-survival transcriptional profile compared to responses from untreated hyperacute HIV infection. The breadth of HIV-specific CD8+ T cells measured by IFN-γ ELISPOT positively correlated with HIV DNA reservoir decay over a one-year period (r=0.8, p=0.04).
These results demonstrate that HIV-specific CD8+ T cell responses generated in early treated persons exhibit enhanced CD127 expression, and the breadth of early responses is associated with reservoir decay. Together these data suggest that early therapy enhances HIV-specific CD8+ T cell function, and provide important parameters by which to evaluate antiviral function induced by prophylactic and therapeutic vaccines.
Click here for the webcast.
Does QI improve PMTCT processes in rural South Africa? A stepped-wedge cluster RCT
Manisha N. Yapa, Jan-Walter De Neve, Terusha Chetty, Carina Herbst, Frank Post, David A. Cooper, Awachana Jiamsakul, Pascal Geldsetzer, Guy Harling, Philippa Matthews, Frank Tanser, Kobus Herbst, Dickman Gareta, Deenan Pillay, Till Bärnighausen
Serosorting for conjugal relationship formation in heterosexual couples, South Africa
Hae-Young Kim, Alain Vandormael, Andrew Tomita, Till Bärnighausen, Frank Tanser
HIV reservoir establishment during hyperacute clade C infection
Guinevere Q. Lee, Kavidha Reddy, Kevin Einkauf, Kamini Gounder, Krista Dong, Bruce D. Walker, Xu G. Yu, Thumbi Ndungú, Mathias Lichterfeld
Hypertension and diabetes control along the HIV care Cascade in South Africa
Jennifer Manne-Goehler, Mark J. Siedner, Livia Montana, Guy Harling, Pascal Geldsetzer, Julia K. Rohr, Xavier Gomez-Olive, Alisha Wade, Thomas Gaziano, Kathleen Kahn, Stephen Tollman, Till Bärnighausen
High percentage of undiagnosed HIV cases in a hyperendemic South African population
Alain Vandormael, Tulio de Oliveira, Frank Tanser, Till Bärnighausen, Joshua T. Herbeck
The effects of HIV treatment on uptake of TB and NCD treatment by household members
Suzue Saito, Andrea Howard, Magdalena Cerda, Frank Tanser, Deenan Pillay, Wafaa M. El-Sadr, Till Bärnighausen
Top image: AHRI Faculty member Zaza Ndhlovu presenting his talk at CROI 2018.