The LATTE Phase IIb trial. Long-acting HIV treatment with injections: is this revolutionary approach an effective alternative to daily oral doses?

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Christelle  The LATTE Phase IIb trial. Long-acting HIV treatment with injections: is this revolutionary approach an effective alternative to daily oral doses? Christelle

Christelle Dassi, PhD, CRP CRA Academy Montreal

Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) represent a spectrum of conditions caused by infection with HIV. In 2016, about 36.7 million people were living with HIV and the disease resulted in 1 million deaths (1). Most of those infected live in sub-Saharan Africa. Typically, after the initial infection, there is a prolonged period with no symptoms (2). As the infection progresses, it interferes with the immune system, increasing the risk of common infections like tuberculosis as well as other opportunistic infections. These late symptoms of the infection are referred to as AIDS (2).

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HIV is spread primarily by unprotected sex, contaminated blood transfusions, hypodermic needles, and from mother to child during pregnancy, delivery or breastfeeding. Methods of prevention include safe sex, needle exchange programs and antiretroviral (ARV) treatment of the infected person, as well as both the mother and child in the case of baby prevention (3). In the absence of an effective cure and vaccine, the World Health Organization (WHO) recommends earlier ARV treatments, which help slow the course of the disease and could lead to a near-normal life expectancy (3).

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Since the disease discovery in 1981 (4), more and more effort has been devoted to research in order to achieve more effective treatments. So far, highly active antiretroviral therapies (HAART) are used to slow disease progression (5). Other supporting therapies include preventive and active treatments of opportunistic infections. Current HAART regimens combine at least three medications belonging to at least two types of ART agents (6). Initial treatments are typically composed of a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analog reverse transcriptase inhibitors (NRTIs) (7). Typical NRTIs include: zidovudine (AZT), tenofovir (TDF), lamivudine (3TC) and emtricitabine (FTC) (7). Combinations containing protease inhibitors (PI) are also used if this regimen loses effectiveness (6). The desired outcome of treatment is to obtain a long-term plasma HIV-RNA count below 50 copies per mL. This assessment is recommended after the first 4 weeks of treatment, then every 3 to 6 months once the cell count falls below 50 copies per mL (8).

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The treatment effectiveness depends largely on patient adherence to medical regimen (8). In many cases, treatment non-adherence is due to poor access to medical care, inadequate social support, mental illness and drug abuse. Along with adverse effects, the complexity of treatment regimens including the large numbers of pills taken and high dosing frequency may also reduce adherence (9-11). Consequently, researchers are trying hard to find new therapies that could reduce the regimen complexity, with the goal of improving treatment adherence and effectiveness.

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Long-acting antiretroviral injections

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Since the introduction of combination antiretroviral therapy (cART), the lifespan of people living with HIV/AIDS has been remarkably prolonged and has been associated with a significant reduction in HIV-related morbidity and mortality. Although available cART regimens do not provide a cure for HIV, they have transformed HIV infection into a chronic disease requiring lifelong daily oral treatment (12). Importantly, as with patients taking oral medication for chronic diseases, non-adherence is common. Non-adherence rates are estimated to be around 50-70% of cases, which remains an important challenge in HIV treatment.

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At present, with the exception of the rarely-prescribed enfuvirtide, all available antiretrovirals (ARVs) are administered orally. However, long-acting formulations for both the prevention and treatment of HIV infection are under development, and routine injection visits can potentially replace daily pill taking (12). Long-acting injectable ARVs provide a more convenient approach to manage HIV infection that avoids daily oral dosing and the need to keep, store, and transport medications.

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Rilpivirine and cabotegravir are characterized by different mechanisms of action against HIV and favorable drug interaction profiles, providing a rationale for co-administration. The high potency and low daily dosing requirements of oral cabotegravir and rilpivirine facilitate long-acting formulation development (14-17). Several Phase II studies are currently underway to evaluate the co-administration of rilpivirine and cabotegravir intramuscularly to HIV-infected individuals with an undetectable viral load.

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The LATTE Phase IIb trial

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In this framework, long-acting ARV injections would be an effective alternative to daily oral doses of the same medication in treating HIV, as suggested by Margolis and colleagues based on their Phase IIb trial LATTE (Long Acting Antiretroviral Treatment Enabling) (18). This trial was a randomized, open-label study aiming to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability and safety of two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine.

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Cabotegravir and rilpivirine, two ARV drugs which have been used in oral forms and have been recently developed as long-acting injectable formulations, were evaluated for maintenance of HIV-1 viral suppression through 96 weeks. In this study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily for 20 weeks. After this 20-week induction period, patients with viral suppression, corresponding to a plasma HIV-1 RNA count below 50 copies per mL, were randomly assigned to 3 different groups of treatment: intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or at 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections), or continued oral cabotegravir plus abacavir–lamivudine (18). The study showed that both injected combinations were well accepted and tolerated, and as effective as daily 3-drug oral therapy at maintaining HIV-1 viral suppression over 96 weeks. A few adverse events were also noted, with the most frequent being pain where the intramuscular injection had been administered. In most cases, however, this reaction lasted only 3 days, and the pain was mild.

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Summary

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Positive findings from the above study may reinforce the notion that long-acting ARV injections could be a potential replacement for daily oral medications in HIV treatment. This promising therapy may help facilitate adherence in patients by simplifying the medication regimens while improving treatment effectiveness. Nevertheless, in some cases, long-acting regimens are less likely to replace oral cARTs. For example, with patients who are stable on cART and typically see their treating physicians only twice yearly, the new regimen will create an undesirable requirement of increasing the number of visits to the clinic for monthly or bimonthly injections.

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In conclusion, long-acting antiretroviral formulations provide additional treatment options for people living with HIV. These promising therapies could offer advantages to select populations who find difficulty in adhering to daily oral therapy.

 

References

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