ABSTRACT
Recurrent disease outbreaks caused by a range of emerging and resurging pathogens over the past decade reveal major gaps in public health preparedness, detection, and response systems in Africa. Underlying causes of recurrent disease outbreaks include inadequacies in the detection of new infectious disease outbreaks in the community, in rapid pathogen identification, and in proactive surveillance systems. In sub-Saharan Africa, where 70% of zoonotic outbreaks occur, there remains the perennial risk of outbreaks of new or re-emerging pathogens for which no vaccines or treatments are available. As the Ebola virus disease, COVID-19, and mpox (formerly known as monkeypox) outbreaks highlight, a major paradigm shift is required to establish an effective infrastructure and common frameworks for preparedness and to prompt national and regional public health responses to mitigate the effects of future pandemics in Africa.Copyright © 2022 Elsevier Ltd
ABSTRACT
Background. The relative advantage of each new variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) depends on its inherent transmissibility and capacity to evade pre-existing immunity. Delta and Omicron are variants of concern that have immune-evasive properties and rapidly displaced variants that preceded their emergence. In the United States, SARS-CoV-2 immunity varies considerably by state, which provides a natural experiment to evaluate the effect of population-level immunity on takeover dynamics of new variants. We hypothesized that if immune evasion was a major driver of fitness compared with previously prevalent variants, Delta and Omicron would become the dominant variants faster in states with higher immunity. Methods. We evaluated changes in variant proportion per week from the first detection of Delta or Omicron in a state until they consistently represented >90% of all sequenced genomes. We used logistic growth curves to characterize the dynamics of variant takeover, evaluating three outcomes: 1) takeover rate, defined as the maximum slope of the logistic curve;2) takeover date, i.e., the estimated date at which variant proportion reached 50% in a state;and 3) time from emergence to dominance, the time taken for variant proportion to increase from 10% to 50%. Next, we estimated the relative proportion of each state that was immune from a combination of infection and full vaccination (for Delta) or boosting (for Omicron) prior to variant takeover. For each outcome, we fit linear regression models to estimate the relationship between population immunity and Delta or Omicron takeover. Results. We found no statistically significant association between takeover rate of Delta or Omicron and immunity (Fig. 1A, B). In contrast, we observed a later takeover date (p< 0.001) and slower time from emergence to dominance (p=0.046) for Omicron in more immune states (Fig. 1D, F). There was a similar but not statistically significant trend for Delta in delayed takeover date (Fig. 1C). genomes in different states with 95% confidence intervals. States are identified by standard two-letter abbreviations;states in the same census geographic region are plotted with the same color. Left panel: Delta, Right panel: Omicron. Immunity is estimated by the combined proportion of the state's population with SARS-CoV-2 infection prior to detection of the new variant in the state and either fully vaccinated (for Delta) or boosted (for Omicron) two weeks prior to takeover. Pearson correlation coefficient (R) and p-value test results are shown for each plot.
ABSTRACT
Background: In 2018, Uganda began programmatically switching individuals with HIV-1 RNA <1,000 copies/mL on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART to a fixed-dose regimen of tenofovir/lamivudine/dolutegravir (TLD). Our objective was to estimate the population effectiveness of the TLD transition in public-sector clinics in Uganda. Methods: We conducted a prospective cohort study that enrolled adults ≥18 years who were switched from NNRTI-based first-line ART to TLD at public-sector clinics in Uganda. We observed participants at 3 study visits over 1 year. We obtained blood specimens at each visit and conducted HIV-1 RNA viral load (VL) testing using Cepheid Xpert assays. We fit multivariable logistic regression models to assess predictors of our composite outcome of interest of viral suppression (<50 copies/mL) with retention in care 1 year after switch to TLD. Results: We enrolled 500 participants with a median age of 47 years (IQR 40-53);41% were women. The most common regimen prior to switch was lamivudine/tenofovir/efavirenz (44%), and median duration on ART prior to switch was 8.8 years (IQR 5.7-12.2). Over 95% (n=475/499) were virally suppressed (<50 copies/mL) at the time of switch to TLD. The final visit for all participants occurred a median of 54 weeks (IQR 49-67) after enrollment, with some participants affected by delays due to COVID-19 mitigation measures. One participant self-elected to disenroll. Only 3% (n=13/499) of participants discontinued TLD due to side effects or clinician discretion. We observed 1% mortality (n=6/499), 2% (n=10/499) lost to follow-up, and 5% (n=23/499) with HIV-1 RNA ≥50 copies/mL at 1 year, with a median VL of 252 copies/mL (IQR 81-78,200 copies/mL). Overall, 92% (n=459/499) were virally suppressed and in care at 1 year. An HIV-1 RNA ≥50 copies/mL at the time of switch to TLD, male gender, and any self-reported ART adherence <90% were all significant negative predictors of the composite outcome of retention in care with a suppressed VL (Table). Conclusion: Rates of viral suppression with retention in care >90% after 1 year on TLD, as well as a 2% TLD discontinuation rate, affirm World Health Organization guidelines for the regional transition to TLD. Nonetheless, an 8% failure rate in HIV-endemic countries corresponds to a large population of individuals. Long-term surveillance of this population, strategies to combat imperfect adherence, and continued attention to treatment options after failure on TLD may be needed.
ABSTRACT
Background: The fixed-dose combination of tenofovir (TDF), lamivudine (3TC), and dolutegravir (TLD) is now preferred first-line antiretroviral therapy (ART) for most adults with HIV in Sub-Saharan Africa. Yet, concerns remain about durability of TLD with high circulating resistance to 3TC and TDF and metabolic abnormalities observed in clinical trials. Limited programmatic data are available to describe the success of the TLD transition in the region. Methods: We established the DISCO cohort to quantify viral suppression and regimen tolerability during the TLD transition. We prospectively enrolled adults from public clinics in Uganda and South Africa who had been on non-nucleoside reverse transcriptase inhibitor-based ART for ≥6 months and were programmatically switched to TLD. We obtained demographics, medical history data, and plasma specimens at enrollment and week 24. We conducted retrospective HIV-1 RNA viral load (VL) testing using the Cepheid GeneXpert platform. Though both sites were interrupted by COVID-19, here we report complete week 24 results for the Uganda cohort. Results: We enrolled 500 participants (41% female) in Uganda. Median age was 47 years (IQR 40-53). Median ART duration was 8.8 years (IQR 5.7-12.2). The most common regimens prior to TLD switch were 3TC/TDF/efavirenz (44%) and 3TC/zidovudine/nevirapine (39%). Retrospective VL testing demonstrated that 95% (475/499) had VL <50 copies/mL, 4% (19/499) had VL 50-1,000 copies/ mL, and 1% (5/499) had VL >1,000 copies/mL at enrollment. 90% (448/500) completed week 24 visits, with 50 additional visits delayed during COVID-19, 1 disenrollment, and 1 death. By week 24, 1% (6/448) discontinued TLD due to side effects or clinician discretion. At week 24, 96% (432/448) had VL <50 copies/mL, 3% (12/448) had VL 50-1,000 copies/mL, and 1% (4/448) had VL >1,000 copies/mL. Of those with week 24 VL >50 copies/mL, 31% (5/16) had detectable VL >50 copies/mL at enrollment, versus 3% (15/431) in those with suppressed VL at week 24 (χ2 p-value<0.001). Conclusion: The great majority of participants transitioned to TLD with an undetectable VL. Overall, we documented 86% suppression at week 24 after TLD switch in the midst of the COVID-19 pandemic and 96% suppression in those completing a week 24 visit. These data support early tolerability and efficacy of TLD transition in the public sector. However, detectable VL at switch predicted detectable VL at 24 weeks. Vigilance and programmatic monitoring are needed to ensure long-term durability of TLD.