A push for 90-90-90: Initial treatment with INSTI-based regimens against HIV-1 infection

In recent years, the global scenario of HIV infection has dramatically changed with the widespread implementation of antiretroviral treatment (ART) and the aim to reach the goals of the UNAIDS initiative “90-90-90: Treatment for all” (www.unaids.org/en/resources/909090) by 2030. Furthermore, ground-breaking scientific evidence has revolutionized the life of people living with HIV/AIDS (PLWH). Undetectable equals untransmittable (U=U) is one of the most important messages since the rise of HIV epidemic with the power to reduce the stigma related to infectiveness [[1]Eisinger R.W. Dieffenbach C.W. Fauci A.S. HIV viral load and transmissibility of HIV infection: undetectable equals Untransmittable.JAMA. 2019; 321: 451-452Crossref PubMed Scopus (176) Google Scholar]. Among the potential strategies to be implemented to end HIV epidemics, treatment as prevention is the one with the strong scientific evidence [[2]Rodger A.J. Cambiano V. Bruun T. PARTNER Study Group et al.Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive PARTNER taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study.Lancet. 2019; 393: 2428-2438Summary Full Text Full Text PDF PubMed Scopus (239) Google Scholar]. In their work Zhu J et al have formalized a model assessing the potential impact of integrase strand-transfer inhibitor (INSTI)-containing regimens in reducing onward HIV transmissions in British Columbia [[3]Zhu J. Rozada I. David J. et al.The potential impact of initiating antiretroviral therapy with integrase inhibitors on HIV transmission risk in British Columbia, Canada.EClinicalMedicine. 2019; 13: 101-111Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. By applying two previously described models of HIV transmission [4Wilson D.P. Law M.G. Grulich A.E. Cooper D.A. Kaldor J.M. Relation between HIV viral load and infectiousness: a model-based analysis.Lancet. 2008; 372: 314-320Summary Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 5Fraser C. Hollingsworth T.D. Chapman R. de Wolf F. Hanage W.P. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis.Proc Natl Acad Sci U S A. 2007; 104: 17441-17446Crossref PubMed Scopus (269) Google Scholar], which are based on HIV-RNA viral load and the natural history of HIV infection (early vs chronic vs late), the authors demonstrated how the use of INSTI-based regimens in naïve patients could potentially reduce the risk of HIV transmission when compared to non INSTI-based regimens in their cohort. In particular, a HIV transmission risk reduction of 25%, according to the model by Fraser C et al, has been estimated for gay, bisexual and other men who have sex with men (gbMSM) starting an INSTI-based regimen with a viral load ≥5log10 copies/mL irrespectively of HIV stage [[5]Fraser C. Hollingsworth T.D. Chapman R. de Wolf F. Hanage W.P. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis.Proc Natl Acad Sci U S A. 2007; 104: 17441-17446Crossref PubMed Scopus (269) Google Scholar]. Authors concluded that INSTI-based regimens have the potential to avert onward HIV transmission by achieving a fast virologic suppression, in particular among gbMSM with pre-treatment high viral load. Although these data are sound, some potential pitfalls should be acknowledged to correctly interpret the findings reported by Zhu J et al. Firstly, the time span covered by the study is between 2011 and 2016 and only 376/1459 (25.8%) of the patients in the cohort started the treatment with and INSTI-based regimen. These findings are partially overcome by the widespread use of INSTIs in recent years due to the high efficacy, improved safety profile and, more recently, dolutegravir-based antiretroviral drug regimens implementation strategies in resource limited setting. Secondly, 46% of the patients started antiretroviral treatment with <350 CD4 cells/mm3, reflecting the prescription recommendations followed until 2015, when the INSIGHT START trial demonstrated the incontrovertible beneficial effects of starting ART irrespectively of the CD4 cells count [[6]Lundgren J.D. Babiker A.G. Gordin F. et al.Initiation of antiretroviral therapy in early asymptomatic HIV infection.N Engl J Med. 2015; 373 (INSIGHT START Study Group): 795-807Crossref PubMed Scopus (1) Google Scholar]. In other words, the findings of the authors should be considered as confirmatory and add a strong scientific evidence to a change in the prescribing behaviour occurring in everyday clinical practice. Moreover, the study relies on the assumption that there are no changes in the behaviours of a newly infected PLWH. However, it could not be excluded that changes in the sexual behaviours after the diagnosis - due to extensive counselling and a novel risk perception - could impact on the risk of HIV transmission [[7]Steward W.T. Remien R.H. Higgins J.A. et al.Behavior change following diagnosis with acute/early HIV infection-a move to serosorting with other HIV-infected individuals. The NIMH multisite acute HIV infection study: III.AIDS Behav. 2009; 13: 1054-1060Crossref PubMed Scopus (81) Google Scholar]. The authors focus their attention on a high-risk gbMSM population who show the highest number of previous condomless sexual intercourses. In this population, the use of INSTIs is advisable not only to reduce HIV risk by dropping the time of HIV-RNA detectability (defined as HIV-RNA >200 cp/mL), but also by reducing the risk of potential drug–drug interaction with chem-sex compounds [[8]Bracchi M. Stuart D. Castles R. Khoo S. Back D. Boffito M. Increasing use of 'party drugs' in people living with HIV on antiretrovirals: a concern for patient safety.AIDS. 2015; 29: 1585-1592Crossref PubMed Scopus (56) Google Scholar]. The burden of drugs resistance to antiretrovirals is still the main cause of virologic failure, at least in developed countries. The impact of INSTI drug resistance within the first-line treatment is still very limited [[9]Demarest J. Underwood M. St Clair M. Dorey D. Brown D. Zolopa A. Dolutegravir-based regimens are active in integrase Strand transfer inhibitor-naive patients with nucleoside reverse transcriptase inhibitor resistance.AIDS Res Hum Retroviruses. 2018; 34: 343-346Crossref PubMed Scopus (14) Google Scholar], thus this pharmacological class is potentially useful in all HIV-1-infected individuals who start their first ART. When we think about the potential window of HIV transmission opportunities after the engagement in care of PLWH, it's important to consider the timespan between HIV diagnosis and ART initiation. In fact, the potential advantage of HIV-RNA rapid reduction obtained with INSTI-based regimens should be considered additive to the “same day strategy” which is potentially practicable with high genetic barrier INSTIs, such as dolutegravir and bictegravir. The “same day strategy” has been demonstrated to increase the linkage to care of PLWH by reducing the stigma and the fear related to the infectiveness [[10]Pilcher C.D. Ospina-Norvell C. Dasgupta A. et al.The effect of same-day observed initiation of antiretroviral therapy on HIV viral load and treatment outcomes in a US public health setting.J Acquir Immune Defic Syndr. 2017; 74: 44-51Crossref PubMed Scopus (104) Google Scholar]. Ending HIV epidemic is an ambitious goal and no single intervention by itself is able to interrupt the transmission chain. Conversely, a multilevel intervention strategy relying on prevention strategies (i.e. U=U and pre-exposure prophylaxis implementation) combined with universal ART coverage with highly effective, well tolerated new drugs, such as INSTIs in resource limited setting, would be able to close the gap within 2030, making 90-90-90 not just a dream but a matter of fact. SR received research grants to his Institution from ViiV Healthcare, Gilead Sciences and Janssen, outside the submitted work; he was also a paid consultant for ViiV Healthcare, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen and Mylan. AG was a paid consultant for Mylan. This manuscript is dedicated to the memory of Professor Andrea De Luca: a great friend, physician, mentor, and scientist. The potential impact of initiating antiretroviral therapy with integrase inhibitors on HIV transmission risk in British Columbia, CanadaInitiating ART on INSTI-based regimens has the potential to reduce HIV transmission risk among individuals with high baseline viral load levels, especially among those with high levels of sexual activity. Full-Text PDF Open Access

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