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
SUMMARY: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles <10 µm that can remain suspended for hours before being inhaled. Because particulate filtering facepiece respirators ('respirators'; e.g. N95 masks) are more effective than surgical masks against bio-aerosols, many international organisations now recommend that health workers (HWs) wear a respirator when caring for individuals who may have COVID-19. In South Africa (SA), however, surgical masks are still recommended for the routine care of individuals with possible or confirmed COVID-19, with respirators reserved for so-called aerosol-generating procedures. In contrast, SA guidelines do recommend respirators for routine care of individuals with possible or confirmed tuberculosis (TB), which is also transmitted via aerosol. In health facilities in SA, distinguishing between TB and COVID-19 is challenging without examination and investigation, both of which may expose HWs to potentially infectious individuals. Symptom-based triage has limited utility in defining risk. Indeed, significant proportions of individuals with COVID-19 and/or pulmonary TB may not have symptoms and/or test negative. The prevalence of undiagnosed respiratory disease is therefore likely significant in many general clinical areas (e.g. waiting areas). Moreover, a proportion of HWs are HIV-positive and are at increased risk of severe COVID-19 and death. RECOMMENDATIONS: Sustained improvements in infection prevention and control (IPC) require reorganisation of systems to prioritise HW and patient safety. While this will take time, it is unacceptable to leave HWs exposed until such changes are made. We propose that the SA health system adopts a target of 'zero harm', aiming to eliminate transmission of respiratory pathogens to all individuals in every healthcare setting. Accordingly, we recommend: the use of respirators by all staff (clinical and non-clinical) during activities that involve contact or sharing air in indoor spaces with individuals who: (i) have not yet been clinically evaluated; or (ii) are thought or known to have TB and/or COVID-19 or other potentially harmful respiratory infections;the use of respirators that meet national and international manufacturing standards;evaluation of all respirators, at the least, by qualitative fit testing; andthe use of respirators as part of a 'package of care' in line with international IPC recommendations. We recognise that this will be challenging, not least due to global and national shortages of personal protective equipment (PPE). SA national policy around respiratory protective equipment enables a robust framework for manufacture and quality control and has been supported by local manufacturers and the Department of Trade, Industry and Competition. Respirator manufacturers should explore adaptations to improve comfort and reduce barriers to communication. Structural changes are needed urgently to improve the safety of health facilities: persistent advocacy and research around potential systems change remain essential.
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.
ABSTRACT
Background: New SARS-CoV-2 variants with mutations in the spike glycoprotein have arisen independently at multiple locations and may have functional significance. The combination of mutations in the 501Y.V2 variant first detected in South Africa include the N501Y, K417N, and E484K mutations in the receptor binding domain (RBD) as well as mutations in the N-terminal domain (NTD). Here we address whether the 501Y.V2 variant could escape the neutralizing antibody response elicited by natural infection with earlier variants. Methods: We were the first to outgrow two variants of 501Y.V2 from South Africa, designated 501Y.V2.HV001 and 501Y.V2.HVdF002. We examined the neutralizing effect of convalescent plasma collected from adults hospitalized with COVID-19 using a microneutralization assay with live (authentic) virus. Whole genome sequencing of the infecting virus of the plasma donors confirmed the absence of the spike mutations which characterize 501Y.V2. We infected with 501Y.V2.HV001 and 501Y.V2.HVdF002 and compared plasma neutralization to first wave virus which contained the D614G mutation but no RBD or NTD mutations. Results: We observed a reduction in antibody activity ranging from 6-fold to knockout for the 501Y.V2 (B.1.351) relative to the B.1.1 variant derived from the first wave of the pandemic in South Africa. Conclusion: This observation indicates that 501Y.V2 may escape the neutralizing antibody response elicited by prior natural infection. It raises a concern of potential reduced protection against re-infection and by vaccines designed to target the spike protein of earlier SARS-CoV-2 variants.