Our study tested the safety and efficacy of different antiviral combination regimens in Egyptian adults with moderate COVID-19 infection. The results demonstrated favorable efficacy outcomes for all the treatment arms, where they displayed significantly decreased days of hospitalization by 31, 29, and 29 days, respectively, compared to arm 1 (p p = 0.007)]. Additionally, after regression analysis and adjustment for all other factors, all arms displayed a lower and statistically significant proportion of patients with progressive CT scans by 61%, 62%, and 85%, respectively, compared to arm 1 (p = 0.023, p = 0.010, and p p = 0.021).
It is urgently needed to employ early-stage interventions to prevent the infection from worsening and having long-term effects. This is especially important since vaccine hesitation among Egyptians persists despite the country’s efforts to make vaccinations accessible, inexpensive, and appealing to the population19. Testing various available antivirals in the Egyptian market is thus relevant and worthy of exploration to prevent disease progression and decrease the death toll. This includes drugs with known antiviral effects or therapy against RNA virus families such as COVID-19, with well-established safety profiles. The ones recruited in our study, SOF/LED and sovodak, are known antivirals with marked availability in the Egyptian pharmaceutical markets19 making them easily accessible instead of highly expensive, newly developed drugs.
HCV drugs have been of interest to test as treatments for COVID-19. For instance, sofosbuvir and daclatasvir are FDA-approved for the treatment of chronic HCV. SARS-CoV-2 possesses similar mechanisms of RNA replication as observed in other RNA viruses; subsequently, sofosbuvir and daclatasvir combined were hypothesized to demonstrate efficacy in inhibiting SARS-CoV-2 replication according to in vitro and in silico research12,20. Other repurposed combination HCV antivirals include sofosbuvir/ledipasvir (SOF/LED) and protease inhibitors, which have also been tested against COVID-19 in multiple studies9,12,13,20,21. These different combinations and approaches drove our study to compare the most effective ones in the unique Egyptian population.
Sovodak (sofosbuvir/daclatasvir) has been tested in multiple clinical trials for its effect on clinical recovery. A recent meta-analysis of three Iranian trials showed that it improved the time to clinical recovery [HR = 2.04 (95% CI = 1.25–3.32), p = 0.004] and exhibited lower days of hospitalization compared to the control group [MD = − 0.56 (95% CI = − 0.86 to − 0.26)]12. This is comparable to our results where the proportion of patients with total clinical recovery was significantly higher in the sovodak arm compared to the standard of care (p = 0.009), and the median days of hospitalization days were also lower in the sovodak arm (p
A multicenter, randomized controlled clinical trial in adults with moderate or severe COVID-19 admitted to four university hospitals in Iran randomized patients into a treatment arm receiving sofosbuvir and daclatasvir plus standard care, or a control arm receiving standard care alone. The clinical recovery within 14 days was achieved by 88% in the treatment arm versus 67% in the control arm (P = 0.076), where they also showed a significantly shorter median duration of hospitalization [6 days (IQR 4–8)] than the control group [8 days (IQR 5–13)] (p = 0.029)22. Furthermore, Abbass et al. compared sofosbuvir/daclatasvir to the standard of care, with all patients receiving additional therapies, such as HCQ and ivermectin, according to the treating physician’s clinical judgment. Patients receiving sofosbuvir/daclatasvir showed significant clinical improvement compared to standard of care on both day 7 (p = 0.041) and day 10 (p = 0.040), while no significant differences in mortality were observed (p = 0.329)23. Our finding similarly showed the median days of hospitalization were significantly different in arm 1 (control) versus arm 2 (sofosbuvir/ daclatasvir plus ivermectin) [(median: 12 days, IQR: 9–41 in arm1) versus (median: 10 days, IQR: 7–11 days in arm 2), p p value
Khalili et al. compared SOF/LED to the standard of care (HCQ and atazanavir/ritonavir). They found no significant differences in the incidence of clinical improvement (p = 0.65), length of hospital stay (p = 0.98), or 14 day mortality (p = 0.60) between the groups. However, the SOF/LED arm had a shorter time to clinical improvement (2 [1–3.75]) than the control group (4 [2–5, p = 0.02)14. In contrast, our findings for arm 3, which utilized SOF/LED with HCQ, showed significant and shorter median days of hospitalization compared to arm 1(p = 0.025). Additionally, there was no difference between both arms in terms of time to clinical improvement. These disparities could be attributed to the difference in study design; ours is a retrospective cohort compared to Khalili’s randomized controlled trial design. Moreover, we used SOF/LED in combination with HCQ, while their method included atazanavir/ritonavir. Finally, their patient count was 42 versus 75 in our study, all of which may account for differences in results and significance.
COVID-19 has been identified to cause alterations in lab measures, including increased neutrophil count and platelet-lymphocyte ratio, which are linked to a worse clinical outcome24. Additionally, it is considered a risk factor for elevations in urea, creatinine, D-dimer, ALT, and AST levels3. Thus, monitoring these parameters can be used as an indicator of the efficacy of our tested treatment regimens, where we found multiple results in favor of these repurposed antiviral combinations versus the standard of care. For instance, arm 2 displayed significantly lower ferritin levels throughout all the lab measures compared to arm 1, arm 3 showed lower lymphocytes compared to arm 1, and arm 4 showed significantly lower creatinine levels than arm 1 in both 1st and 3rd measures, and lower CRP in 3rd measures. Furthermore, the tested treatments did not lead to any significant increases in renal or hepatic lab test results, thus indicating the tolerability of these combined treatments. In real-world clinical practice, not all lab measures are ideal, however, these results demonstrate promising efficacy and safety outcomes for these treatment regimens in COVID-19 patients.
Similar contexts testing the efficacy of age and other variables on mortality have been present in other studies. For instance, a recent study of multiple antiviral regimens including remdesivir and favipiravir showed that age was significantly correlated with the overall fatal cases (p p > 0.001)25. This is similar to our findings where age if increased by 1 year, will significantly increase the death risk by 8% (p = 0.021). However, their population mainly consisted of severe COVID-19 cases, which could justify the need for different forms of antivirals, especially remdesivir, which is the first FDA-approved treatment for COVID-19 use in emergency cases26.
Our work is distinctive in that it provides a thorough assessment of whether or not progressive changes in CT scans occur with various antiviral treatment regimens. The evaluation of radiographic disease progression has gotten comparatively less attention than clinical outcomes, such as time to clinical improvement or mortality, which have been the main focus of previous research. Our results demonstrated that all arms displayed lower and statistically significant odds of progressive CT scan compared to arm 1 (p = 0.023, p = 0.010, p p 27, which have a major impact on patient management and long-term results. Incorporating this radiographic objective can aid healthcare professionals in making the best treatment decisions for patients with moderate COVID-19.
Though the aim was to test new treatment combinations, we noticed that arm 1 comprising HCQ plus ivermectin, displayed a significant and shorter number of days till clinical improvement compared to arm 4 (p = 0.007). Additionally, it demonstrated the highest percentage of complete normalization of vital signs (p = 0.023). This shows that despite the many other benefits of novel combinations, the standard of care remains a very good option for moderate COVID-19 patients.
Limitations and strengths
Our study has some potential limitations. For instance, due to the retrospective nature, we couldn’t identify or present treatment-related side effects in the safety outcomes as they are better monitored in an RCT study. Additionally, our study’s end date was in 2022, after which new antivirals as molnupiravir or remdesivir have been added to the national guidelines. Furthermore, the single-center design and relatively small sample sizes are limitations that should be considered when interpreting the findings. Finally, the baseline differences in some groups (like the relatively younger age in arm 4), limit the conclusions that can be drawn from our study.
On the other hand, the strengths of this study include the comprehensive assessment of both safety and efficacy endpoints, as well as the inclusion of a well-defined reference group for comparison. Moreover, these repurposed antiviral combination regimens’ relative safety and efficacy outcomes demonstrate successful and potential drug candidates that can be utilized for COVID-19 treatment and its emerging variants. Additionally, our study is unique in identifying CT improvement associated with the anti-HCV antiviral regimen which can help guide future case-specific treatment approaches.
