Ukwuru Therapeutics is an Ukwuru science research journal. It spans all therapeutics research conducted by Ukwuru Science Study Group (USSG), Independent Researchers (IR), and Companies.
Ukw Thera. 2024; 24(10): 1-13. Published Online 2024 October 16
UkwSciID: USThera4
DORAVIRINE IS SUPERIOR TO OTHER NNRTIS IN SAFETY BUT EQUIVALENT IN EFFICACY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Edmund Ikpechi Ukwuru, and Ejiro Akpevba
1
2
Ukwuru, E.I. and Akpevba, E. (2024). Doravirine is Superior to other NNRTIs in Safety but Equivalent in Efficacy: A Systematic Review and Meta-Analysis. Ukwuru Therapeutics, 24(10): 1-13.
Abstract
Background
Treatment of HIV-1 infection relies on HAART. Doravirine is a non-nucleoside reverse transcriptase inhibitor a component of HAART regimen used in the management of HIV-1. Its efficacy and safety in comparison to existing medications is examined in this systematic review and meta-analysis.
Method
A total of 45 studies were identified from Google Scholar (34), PubMed (3), Clinicaltrials.gov (8), using systematic techniques in line with the PRISMA checklist. Ten (10) studies were included in the meta-analysis. RevMan v 5.4.1 was used to carry out the odds ration and fixed effects meta-analysis.
Findings
There was no statistically significant relationship between Doravirine and efficacy; however, Doravirine was statistically associated with safety (p<.00001).
Conclusion
Both Doravirine and other NNRTIs can achieve efficacy, but Doravirine is safer for reducing or preventing adverse events.
Recommendations
Care providers can administer either Doravirine or other NNRTIs, but Doravirine should always be preferred over other NNRTIs.
Keywords: Doravirine, HIV-1, NNRTIs, Efficacy, Safety
Introduction
Human immunodeficiency virus (HIV) has made its mark as a severe pandemic. Vitoria et al. (2021) noted that efforts to combat the disease have been relentless; and this has ensured a gradual halt in the transmission, spread, and progression of the disease. Gunthard et al. (2016) stated the role of policies and medicines that were developed to prevent infection and progression. Therefore, Highly Active Antiretroviral Therapy (HAART) emerged as a suitable policy to ensure that people who are infected can receive treatment. Vitoria et al. (2019) pointed out the constituents of HAART; they included, Non-nucleoside-analog reverse transcriptase inhibitors (NARTIs), integrase inhibitors, protease inhibitors, fusion inhibitors, coreceptor antagonists and non-nucleoside reverse transcriptase inhibitors (NNRTI). Thus, HAART recommends that triple combination therapy involving at most two drugs from a specific group should be used for treatment. In order instances, quadruple therapy have been considered by Feng et al. (2019), it was found that a significant difference was not obtained when compared to triple combination therapy. Meaning that triple combination therapy was just as ideal as a quadruple therapy.
The efficacy of any medicine or therapy is of significance. However, it is often complexed by the number of pills to be administered, the duration of treatment, and the financial burden. For example, HAART recommends the administration of two Nucleoside inhibitors and a single protease inhibitor. Hence, Barrett et al. (2018) and Heath et al. (2021) have argued the need for a single combination therapy that can reduce the pill burden. Also, suggestions to develop nano-particle-dependent immunoengineered medication that can increase the bioavalability have been considered (Bowen et al., 2020; Sailaja et al., 2021). Studies by Umotoy and de Taeye, (2021) have suggested the development of antibody-dependent therapy to mitigate the issue of pill burden. A narrative review carried out by Vilaluz and Grantner, (2022) recognized the introduction of new antiretroviral medicines in 2018. These included a dual combination therapy; Fostemsavir and Ibalizuman-uiyk: dolutegravir and lamivudine; and a triple combination therapy; bictegravir, tenofovir alafenamide, and emtricitabine. In light of these new arrivals, Deeks et al. (2021) states that factors such as combination therapy and bioavailability contribute to the efficacy of medicines. Also, adherence to duration of the prescription is essential, and this should be encouraged by reducing the number of doses or the pill burden.
Doravirine is a NNRTI; HAART recommends the integration of at least one NNRTI. Hence, in majority of cases, Doravirine is often included in the triple combination therapy for people living with HVI. This is evident in randomized controlled trials such as Johnson et al., (2019); Talwani and Temesgen, (2020); Orkin et al. (2021); Molina et al. (2021). In these various studies, the efficacy of Doravirine was considered more superior to other NNRTIs. Hence, we carried out this systematic review and meta-analysis to determine the efficacy and safety of Doravirine.
Method
PICO research framework was used to frame the research question of this study. Hence, we looked for studies in which the population was individuals above the age of 18 years who were receiving HAART therapy that involved Doravirine. We employed the PRISMA flowchart to support the process of study search.
Search Strategy
The study search lasted for a total of 15 days. This was because we narrowed down the year of publication to include RCTs that were published after 2018 when the new set of antiretroviral therapies were approved by the US Food and Drug Administration. We identified our keywords and developed our search string. Two of the authors were involved in the study search and screening. The eligibility assessment was used to determine the studies that would be included in the meta-analysis (figure I).
Figure I: PRISMA checklist
In total two hundred and twenty studies were identified from research databases, before the removal of duplicates.
Critical Appraisal
Critical Appraisal Skills Program (CASP) tool was used to analyse the methodological quality.
Data Extraction and Data Analysis
The data was extracted in line with the PICO framework. After that, the meta-analysis was conducted using odds ration and fixed effects analysis. Confidence interval was set to 95%, and significance was tested at <.00001.
Results
Description of Included Studies
Ten studies were included in the meta-analysis; Cahn et al. (2021); Gatell et al. (2018); Johnson et al. (2019); Mills et al. (2024), Molina et al. (2020); Molina et al. (2021); Molina et al. (2024); Orkin et al. (2019); Orkin et al. (2021); Orkin et al. (2024). Two of these studies lasted for a period of 24 weeks Johnson et al. (2019) and Molina et al. (2021): five studies ran for a duration of 48 weeks; Johnson et al. (2019); Mills et al. (2024), Molina et al. (2021); Molina et al. (2024); Orkin et al. (2019). Three of the studies ran for 96 weeks; Gatell et al. (2018); Molina et al. (2020); Orkin et al. (2021). Cahn et al. (2021) and Orkin et al. (2024) were conducted for 192 weeks. There were always more males in the studies than females (Table IA and IB).
Table IA: Characteristics of included Studies
AE = Adverse Events; TTR = time in the therapeutic range; INR = International Normalized Range;
Time in the therapeutic range (TTR) (2.0-3.0) INR (2.0-3.0) range in at least 2 consecutive measurements.
Table IB: Characteristics of included Studies; cure rate and adverse events
The Effectiveness of Doravirine
There is no statistically significant difference (p=0.87) between the efficacy of Doravirine and other NNRTIs. This implies that administering Doravirine or other NNRTIs such as efavirenze and bictegravir can result in the same levels of efficacy (viremia <50 copies per ml). Similarly, switching patients to doravirine resulted in the same levels of efficacy as seen with Molina et al. (2021) and Orkin et al. (2024). Likewise, the duration of doravirine administration resulted in similar levels of efficacy. Implying that a minimum of 24 weeks of administering doravirine was likely to result in the same outcomes as 192 weeks. Also, other NNRTIs were likely to achieve similar levels of efficacy with doravirine as they moved towards longer durations (Figure IIA).
Figure IIA: There is no statistically significant difference between the efficacy of doravirine and other NNRTIs
Figure IIA I2 value was 0% for all weeks but week 48 were it was 42%. The difference was not statistically significant at any point, further consolidating the claim for movement of the plots towards the line of no effect. The meta-analysis is statistically insignificant (p=0.79), evidenced by the black diamond at the base making contact with the line of no effect.
The homogeneity of the studies is very high, evident from obtaining an I2 value of 0%; however, it did not result in a statistically significant difference (p=0.50); a reflection of the fact that other NNRTIs are just as effective as Doravirine. The homogeneity is depicted in figure 3; all the studies are within the limits of the confidence interval with the exception of Molina et al. (2024) which has made contact with the confidence interval because all doravirine recipients expressed viremia less than 50 copies per ml (figure IIB).
Figure IIB: Funnel plots for the efficacy of doravirine
The largest studies are distributed at the top, and the rest of the studies are distributed towards the base. Only one study (Molina et al., 2021; red square at the top right) made contact with the confidence interval.
Safety
The meta-analysis was statistically significant in favour of other NNRTIs; meaning that other NNRTIs were more likely to result in an adverse event compared to doravirine. The implication is that despite having an equivalence in efficacy, the safety levels of doravirine renders it as a more preferred option for achieving non-incidental or reduced incidence of adverse events among patients.
Figure IIIA: Doravirine results in higher levels of safety than other NNRTIs
Figure IIIA: the pooled prevalence is 1290/3501 for doravirine while other NNRTIs is 770/2734. The level of heterogeneity is significantly high (p<0.00001) as evidenced by the I2 value (97.3%). The meta-analysis is statistically significant (p<0.00001)
The heterogeneity of studies is depicted in figure IIIB. One study made contact with the confidence interval, and two other studies can be seen outside the funnel plot.
Figure IIIB: Funnel plots of the safety of doravirine
Figure IIIB: The statistically insignificant studies from weeks 48 and weeks 96 can be seen outside the funnel plots or in contact with the confidence interval.
Discussion
Our finding shows that there is no statistically significant association between efficacy and doravirine or other NNRTIs, implying that a HIV-1 patient can achieve viremia <50 copies per ml when administered a HAART regimen that does or does not include doravirine. Our findings are different from the findings of Zhang et al. (2022) in which doravirine had better virologic suppression than other NNRTIs. The difference is that Zhang et al. (2022) included more studies and it was a network meta-analysis; in contrast to the linear meta-analysis carried out in this study in which 9 studies that addressed only Doravirine were included in the meta-analysis. Even in the study by Zhang et al. (2022) the evidence suggests that the margin between Doravirine and other NNRTIs is not large, and as evidenced in this study, the longer the treatment, the more propensity for other NNRTIs to achieve viremia levels <50 copies per ml.
Our findings also reveal that other NNRTIs are more likely to result in adverse events. Zhang et al. (2022) also revealed that other NNRTIs were more likely to result in adverse events such as severe adverse events, and drug related adverse events. In this study, we focused on drug related adverse events, and they were statistically associated with other NNRTIs than with doravirine. Lanzafame et al. (2019) argued that the side effects of Efavirenz makes it a less suitable comparator for Doravirine in the DRIVE-AHEAD trials, and recommended using a newer NNRTI as a comparator to Doravirine. In this meta-analysis, the evidence shows that there were differences in safety with respect to the duration of treatment. For example, Doravirine was safe for use at four weeks and 96 weeks; however, at 48 weeks and 192 weeks, this was not the case. Meaning that Efavirenz as a comparator was not entirely a poor option.
Conclusion
The efficacy of doravirine is not significantly different from that of other NNRTIs. Health professionals can consider administering other NNRTIs in the absence of Doravirine. Also, it is not imperative to emphasise on administering doravirine rather than other NNRTIs, except when the safety of doravirine is a preferred option. Patients can be switched from other NNRTIs to doravirine and the same improvements can be achieved. Preferrable, switching to doravirine should be considered before week 96. However, in the event that this is not possible, our findings suggest that patients should receive doravirine for another 96 days.
Limitations
We recognise that there are limitations associated with drawing evidence from different study location. However, doravirine is not limited to any specific location, therefore comparing the use of doravirine in different locations was suitable for obtaining a more holistic finding. Similarly, we pooled a large sample population that increased the reliability of the findings; this means that our findings can be generalized. Hence, we conclude that other NNRTIs are just as effective as doravirine but doravirine is a safer option.
References
Barrett, S.E., Teller, R.S., Forster, S.P., Li, L., Mackey, A.M., Skomski, D., Yang, Z., Fillgrove, K.L., Doto, G.J., Wood, S.L., Lebron, J., Grobbler, A.J., Sanchez, R.I., Liu, Z., Lu, B., Niu, T., Sun, L. and Gindy, M.E. (2018). Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. Antimicrobial Agents and Chemotherapy, https://journals.asm.org/doi/full/10.1128/AAC.01058-18
Bowen, A., Sweeney, E.E. and Fernandes, R. (2020). Nanoparticle-Based Immunoengineered Approaches for Combating HIV. Frontiers in Immunology, 11:789. doi: 10.3389/fimmu.2020.00789
Cahn, P., Molina, J-M., Lombaard, J., Squires, K., Kumar, S., Wan, H., Teal, V., Asante-Appiah, E., Sklar, P., Martin, E.A., Lahoulou, R. and 626. (2021). The Efficacy and Safety of Maintenance with Doravirine Plus Two NRTIs after Initial Suppression in Adults with HIV-1 in the DRIVE-FORWARD Clinical Trial: Results from the Study Extension through 192 Weeks. Open Forum Infectious Diseases, 8(1): e S417.
Deeks, S.G., Archin, N., Cannon, P., Collins, S., Jones, R.B., de Jong, M.A.W.P., Lambotte, O., Lamplough, R., Ndung’u, T., Sugarman, J., Tiemessen, C.T., Vendekerckhove, L., Lewin, S.R. and the international AIDS Society (IAS) Global Scientific Strategy Working Group. (2021). Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021. Nat Med, 27, 2085–2098 (2021). https://doi.org/10.1038/s41591-021-01590-5
Feng, Zhou, A., Zou, H., Ingle, S., May, M.T., Cai, W., Cheng, C-Y., Yang, Z. and Tang, J. (2019)Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials. BMJ, 2019; 366 doi: https://doi.org/10.1136/bmj.l4179
Gatell, J.M. Morales-Ramirez, J.O., Hagins, D.P., Thompson, M., Arasteh, K., Hoffman, C., Raffi, F., Osiyemi, O., Dretler, R., Harvey, C., Xu, X., Plettenberg, A., Smith, D.E., Portilla, J., Rugina, S., Kumar, S., Frobose, C., Wan, H., Rodgers, A., Hwang, C. and Teppler, H. (2018). Doravirine dose Selection and 96-Week Safety and Efficacy versus Efavirenz in Antiretroviral Therapy-Naive Adults with HIV-1 Infection in a Phase IIb Trial. Antiviral therapy, 24(6):425-435. doi:10.3851/IMP3323
Gunthard, H.F., Saag, M.S., Benson, C.A., del Rio, C., Eron, J.J., Gallant, J.E., Hoy, J.F., Mugavero, M.J., Sax, P.E., Thompson, M.A., Gandhi, R.T., Landovitz, R.J., Smith, D.M., Jacobsen, D.M. and Volberding, P.A. (2016). Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA, 316(2), 191–210. https://doi.org/10.1001/jama.2016.8900
Heath, K., Levi, J. and Andrew, H. (2021). The Joint United Nations Programme on HIV/AIDS 95–95–95 targets: worldwide clinical and cost benefits of generic manufacture. AIDS, 35(2): S197 – S203 doi: 10.1097/QAD.0000000000002983
Johnson, M., Kumar, P., Molina, J. M., Rizzardini, G., Cahn, P., Bickel, M., Mallolas, J., Zhou, Y., Morais, C., Kumar, S., Sklar, P., Hanna, G. J., Hwang, C., Greaves, W., & DRIVE-SHIFT Study Group (2019). Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. Journal of acquired immune deficiency syndromes, (1999), 81(4), 463–472. https://doi.org/10.1097/QAI.0000000000002056
Lanzafame, M., Lattuada, E. and Vento S. (2019). DRIVE-AHEAD Trial’s Results and the Need for a More Appropriate Comparator Drug. Clinical Infectious Diseases, 69(10, 15):1832, https://doi.org/10.1093/cid/ciz227
Mills, A.M., Rizzardini, G., Ramgopal, M.N., Osiyemi, O.O., Bogner, J.R., Hagins, D.P., Paredes, R., Reynes, J., Rockstroh, J.K., Carr, A., Su, F-H., Klopfer, S.O., Eves, K., Plank, R.M., Correll, T. And Fox, M.C. (2024). Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial. The Lancet, 11(6): E357-E368.
Molina, J. M., Squires, K., Sax, P. E., Cahn, P., Lombaard, J., DeJesus, E., Lai, M. T., Rodgers, A., Lupinacci, L., Kumar, S., Sklar, P., Hanna, G. J., Hwang, C., Martin, E. A., & DRIVE-FORWARD trial group (2020). Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. The lancet. HIV, 7(1), e16–e26. https://doi.org/10.1016/S2352-3018(19)30336-4
Molina, J. M., Yazdanpanah, Y., Afani Saud, A., Bettacchi, C., Chahin Anania, C., DeJesus, E., Olsen Klopfer, S., Grandhi, A., Eves, K., Robertson, M. N., Correll, T., Hwang, C., Hanna, G. J., & Sklar, P. (2021). Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. The lancet. HIV, 8(6), e324–e333. https://doi.org/10.1016/S2352-3018(21)00021-7
Molina, J-M., Rizzardini, G., Orrell, C., Afani, A., Calmy, A., Oka, S., Hinestrosa, F., Kumar, P., Tebas, P., Walmsley, S., Grandhi, A., Klopfer, S., Gendrano, I., Eves, K., Correll, T.A., Fox, M.C. and Kim. J. (2024). Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial. The Lancet HIV, 11(6): E369-E379.
Molina, J-M., Yazdanpanah, Y., Saud, A.A., Bettacchi, C., Anania, C.C., DeJesus, E., Klopfer, S.O., Grandhi, A., Eves, K., Robertson, M.N., Correll, T., Hwang, C., Hanna, G.J. and Sklar, P. (2021). Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. The Lancet HIV,8(6): e324-e333.
Orkin, C., Molina, J-M., Cahn, P., Lombaard, J., Suppararpinyo, K., Kumar, S., Campbell, H., Wan, H., Teal, V., Xu, Z.J., Asante-Appiah, E., Sklar, P., Teppler, H., Lahoulou, R., and DRIVE-FORWARD and DRIVE-AHEAD collaborators. (2024). Safety and efficacy of doravirine as first-line therapy in adults with HIV-1: week 192 results from the open-label extensions of the DRIVE-FORWARD and DRIVE-AHEAD phase 3 trials. The Lancet HIV, 11(2): e75-e85
Orkin, C., Squires, K. E., Molina, J. M., Sax, P. E., Sussmann, O., Lin, G., Kumar, S., Hanna, G. J., Hwang, C., Martin, E., & Teppler, H. (2021). Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73(1), 33–42. https://doi.org/10.1093/cid/ciaa822
Orkin, C., Squires, K. E., Molina, J. M., Sax, P. E., Wong, W. W., Sussmann, O., Kaplan, R., Lupinacci, L., Rodgers, A., Xu, X., Lin, G., Kumar, S., Sklar, P., Nguyen, B. Y., Hanna, G. J., Hwang, C., Martin, E. A., & DRIVE-AHEAD Study Group (2019). Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 68(4), 535–544. https://doi.org/10.1093/cid/ciy540
Sailaja, I., Baghel, M. K. and Shaker, I.A. (2021). Nanotechnology Based Drug Delivery for HIV-AIDS Treatment. In (Ed.), AIDS Updates - Recent Advances and New Perspectives. IntechOpen. https://doi.org/10.5772/intechopen.97736
Talwani, R., & Temesgen, Z. (2020). Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Drugs of today (Barcelona, Spain : 1998), 56(2), 113–124. https://doi.org/10.1358/dot.2020.56.2.3109966
Umotoy, J.C. and de Taeye, S.W. (2021). Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure. Frontiers in Immunology, 12:708806. doi: 10.3389/fimmu.2021.708806
Villaluz, I. and Grantner, G.R. (2020). Newly Approved HIV Medications. US Pharmacist, US Pharm, 45(10):17-25.
Vitoria, M., Rangaraj, A., Ford, N. and Doherty, M. (2019). Current and future priorities for the development of optimal HIV drugs. Current Opinion in HIV and AIDS, 14(2): 143-149 doi: 10.1097/COH.0000000000000527
Zhang K, Zhang Y, Zhou J, Xu L, Zhou C, Chen G and Huang X (2022) Comparison of the Efficacy and Safety of a Doravirine-Based, Three-Drug Regimen in Treatment-Naïve HIV-1 Positive Adults: A Bayesian Network Meta-Analysis. Front. Pharmacol. 13:676831. doi: 10.3389/fphar.2022.676831
Acknowledgements
We acknowledge the efforts of Ukwuru Science Management team and Ukwuru Science Study Group in bringing this study to reality.
Funding
Funding was provided by Ukwuru Science.
Author Information
Edmund Ikpechi, Ukwuru is the research director at Ukwuru Science Lagos. He works with a number of private organisations and individuals, consulting on public health and biomedical science research. He is also a Management Consultant and holds a Honorary Doctor of Business Administration (DBA) for his expertise in business practices.
Ejiro Akpevba is a researcher affiliated with Department of Optometry, University of Benin.
Corresponding Author
Edmund Ikpechi, Ukwuru
Competing Interests
There are no competing interests for this study.
Rights
The publication is open for public use; credits must be provided by acknowledging the authors of the study.
Cite as
Ukwuru, E.I. and Akpevba, E. (2024). Doravirine is Superior to other NNRTIs in Safety but Equivalent in Efficacy: A Systematic Review and Meta-Analysis. Ukwuru Therapeutics, 24(10): 1-13..
Received: 1 August 2024
Accepted: 1 October 2024
Published: 10 October, 2024
Keywords: Doravirine, HIV-1, NNRTIs, Efficacy, Safety