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This year’s international AIDS Society 2021 conference should be exciting for multiple reasons – especially in that we hope that this will be the last virtual IAS meeting. One of the key issues to be discussed at this meeting will be how we have coped with the crisis of COVID-19. The pandemic has had huge impacts on HIV, some of which have been immediate and some of which will be felt in the coming years.
People at risk for HIV have largely had access to pre-exposure prophylaxis (PrEP) since it became available, though arguably the uptake has been lower than desired. The pandemic, however, has meant inconsistencies in things like prescriptions and point-of-care visits, which may mean decreased adherence. Incidence rates have been stable for a prolonged period owing to unrestricted access to PrEP, so hampering access may mean an uptick in new cases. And while not necessarily representative of broader trends, data to be presented from Vancouver, Canada-based researchers suggest the lockdown has created an opportunity for growth in HIV transmission in key populations.
Healthcare workers around the world have been strained in the last year responding to the pandemic, but that strain has been pronounced in the area of infectious diseases where the need for “all hands-on deck” to manage an acute healthcare crisis took attention, focus and resources away from managing a perennial health issue which is HIV.
As we emerge from the pandemic and resume normal life, we have to take stock that the rate of recovery from the pandemic will not be uniform throughout the world because of reasons such as differences in vaccine supply, allocation, and deployment across countries. As such, resuming treatment and healthcare delivery in HIV will look different dependent where you are in the world. Investigators from Australia will present data on what recommencing HIV PrEP will look like “down under”.
Another consideration is vaccine hesitancy and if vaccine hesitancy will differ in the HIV population compared to the seronegative population. Much misinformation has been circulating to promote vaccine hesitancy to decrease the uptake of COVID-19 vaccines.
Injectable vs. oral agents in PrEP
The superior efficacy of injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in men who have sex with men and in transgender women in HPTN083, and in HPTN084, the companion study for cisgender women, was big news in the last year. For instance, HPTNO84 reported that CAB was 89% (95% CI 68-96%) more effective than oral FTC/TDF in preventing HIV acquisition.
The trials demonstrated superiority of injectable agents over oral agents in preventing HIV infection. The superiority was driven by sub optimal adherence in the group taking pills vs excellent adherence in the group receiving injections. Long-acting injectable PrEP achieved superior results over oral PrEP in these trials because patients in the trials did not take their pills. Clearly, the outcomes from these trials underline that there are adherence challenges to oral regimens. In fact, numerous abstracts from this year’s IAS meeting reinforce the preference of various populations to use long-acting injectable PrEP.
But we should not conclude that oral regimens are necessarily inferior with respect to the degree of protection from HIV infection that they offer. Improvements in adherence as a reflection, perhaps of patient preference, is a driving force behind the use of long-acting injectable agents such as PrEP.
Infections and resistance with injectable cabotegravir (CAB)
While long-acting cabotegravir combined with TDF/FTC was effective in affording protection against HIV, there were 5 cases of patients who developed integrase resistance out of 12 new infections. Among these 12 incident infections in the CAB arm: 5 had no recent CAB dosing; 3 occurred in the oral lead-in phase (1 had no CAB detected); and 4 occurred despite on-time CAB injections and targeted CAB concentrations. Five of the infections in the CAB arm had integrase resistance associated mutations (RAMs; Q148R or Q148K with accessory mutations, or R263K).
One question that has been raised since the trial data have become available is what concentration of the drug is necessary to provide complete protection from HIV infection. The development of integrase inhibitor resistance may mean that integrase strand transfer inhibitors are no longer available as a reliable class of agents for our patients.
More about this topic will be unpacked at IAS 2021.
Leading agents in the fight against HIV
We anticipate hearing about new agents in the fight against HIV. One of these is the first nucleoside reverse transcriptase translocation inhibitor, islatravir. It is attractive as an option in PrEP therapy because it offers a long half life and potentially less frequent dosing, but data also demonstrated efficacy as an HIV treatment. Data at this year’s conference will look at islatravir-based regimens, such as metabolic and bone outcomes of treatment with islatravir and doravirine after 96 weeks. In addition, data on the safety of the therapy in treating HIV positive patients who are treatment-naive will be presented.
Another exciting, novel therapy that we can look forward to hearing about is the capsid inhibitor lenacapavir, a long-acting therapy administered subcutaneously every 6 months. Early evidence suggests this long-acting therapy may represent a first-in-class agent, leading the way for an eighth class of ART agents that will present new options for heavily-treated patients.
Data from the CALIBRATE study, a phase 2 induction-maintenance study, to be presented at this year’s meeting, will assess the impact of the therapy in treatment-naïve patients. The long-acting injectable therapies have all required an oral lead-in dosing of approximately a month to ensure there is no allergic response, followed by oral lenacapavir plus emtricitabine (F)/tenofovir alafenamide (TAF), with a 1-time dose of lenacapavir on day 15. In the maintenance phase, subcutaneous lenacapavir is initiated at week 28, as well as oral daily TAF following discontinuation of F/TAF. Participants are slated to be followed at least 18 months.
Addressing weight gain with HIV treatment
One class of agents that has become a mainstay for managing treatment-naïve HIV patients are integrase strand transfer inhibitors (INSTIs). One observation with the use of this class has been weight gain. While weight gain had been viewed in people living with HIV (PLWH) as a return to health, there is now some concern in the treatment community around the development of comorbidities associated with this weight gain.
Data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) demonstrate weight gain in INSTI-based ART regimens in treatment-naïve patients and in those who were switched to INSTI-based ARV regimens. That study revealed patients treated with INSTI-based ART regimens gained weight compared to those treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Some agents produced greater weight gain than others, with dolutegravir producing the most, followed by raltegravir, and then elvitegravir.
Analyses have identified particular risk factors for a weight gain of greater than 10% body weight at two years including female sex, decreased baseline CD4 T-lymphocyte count, and starting an INSTI-based regimen.
Still another investigation that employed an INSTI-based regimen identified dolutegravir as having greater increases in weight gain compared with elvitegravir and an NNRTI-based regimen. The findings from the NA-ACCORD study and other investigations should perhaps give clinicians pause when considering which INSTI-based regimen to select for their HIV patients.
There have been other studies that have demonstrated greater weight gain in those on tenofovir alafenamide compared with tenofovir DF, such as ADVANCE and NAMSAL.[14,15] It is really, however, the biological impact of weight gain that is paramount, and a recent study by the NA-ACCORD research group demonstrated a greater risk of diabetes mellitus associated with weight gain resulting from INST-based regimens.
This year’s IAS meeting will include abstracts that add to the accumulating evidence of weight gain as an adverse event linked to INSTI as well as the roles of NRTI agents in initiation and switch settings and will ask questions about whether this weight gain is clinically significant for our patients.[17,18]
Moving forward, in addition to monitoring our patients’ viral load, it may become incumbent upon us, as treating clinicians, to monitor patient weight, blood sugar, lipids, and C-Reactive Protein in our patients as we learn more about the characterization of metabolic changes conferred by INSTI-based regimens and their NRTI accompanying agents.
HIV Prevention with Dolutegravir in Women
One HIV treatment option that is gaining traction in areas of the world like sub-Saharan Africa is dolutegravir. It offers advantages as an antiretroviral therapy (ART) like enhanced viral suppression, decreased risks of drug-drug interactions, as well as a reduced risk of the threat of drug resistant mutations. One of the concerns around dolutegravir use in women is the risk of teratogenicity in pregnant women in the first trimester, specifically the development of neural tube defects (NTDs) in the fetus, when women take dolutegravir during the periconception period. The Tsepamo study, published in 2018, found the prevalence of NTDs with dolutegravir to be 0.94% vs. 0.12% with non-dolutegravir ART, with NTDs occurring in about 1 in every 100 births amongst women in Botswana.
As a result, all female patients of childbearing age who use dolutegravir have been offered informed consent prior to taking dolutegravir. Since the publication of the 2018 paper, lower rates of congenital defects have been reported with dolutegravir, as evidenced by data from the ongoing Tsepamo study, presented at the 2020 IAS meeting by Rebecca Zash and co-investigators. Zash and et al reported NTDs among infants born to women on dolutegravir at conception was about 2 per 1000 births.
At this year’s meeting, we expect to hear promising data from investigators in Zimbabwe who will report on the rising use of dolutegravir in women of childbearing age. Data such as these are leading to greenlighting the expanded use of dolutegravir as an effective, and safe, option in ART regimens.
Créditos: Comité científico Covid