Highlights

Apretude (cabotegravir [CAB]) is a new drug for pre-exposure prophylaxis (PrEP) of human immunodeficiency virus (HIV-1) infection to reduce the risk of sexually transmitted HIV infection among adults and adolescents (weighing at least 35 kg) at risk.

Before starting Apretude, testing should be done to make sure there is no HIV infection.

Intramuscularly administered Apretude is first given once a month for two consecutive months and then once every two months.

The theoretical level of protection against HIV provided by Apretude is close to absolute. However, this does not mean that 100% protection is unconditionally guaranteed. The risk of HIV infection depends on behavioral, biological, or epidemiological factors, such as sex without a condom, a history of sexually transmitted infections (STIs), having sexual partners with unknown HIV viremic status, sexual activity in a region with high HIV prevalence, and resistance to cabotegravir.

Despite the availability of highly effective strategies to prevent HIV infection, the number of new infections worldwide exceeds 5,000 per day.

The protective efficacy of Truvada (emtricitabine + tenofovir disoproxil fumarate [FTC/TDF]) by Gilead Sciences, the drug that pioneered the PrEP approach, depends directly on compliance (patient adherence to therapy). With no regard for Truvada’s 99% efficacy, it’s easy to forget to take a pill and then regret bitterly. That’s why a PrEP regimen of just six injections of Apretude a year looks much preferable to daily Truvada.

Apretude is more than appropriate for people with chaotic lifestyles or who are addicted to alcohol or drugs. Again, a small amount of injectable is easier to hide from prying eyes in conditions of still reprehensible attitudes towards HIV: stigmatization, discrimination and persecution are especially expressed in countries with poor, underdeveloped, dogmatic and stubbornly inert populations, although there are no objective prerequisites for this.

Apretude will definitely be in demand among gay, bisexual, and transgender people who want to protect themselves because new HIV infections occur mostly as a result of sexual contact between men. [1] [2] [3]

Apretude is approved by the U.S. Food and Drug Administration (FDA).

Apretude was developed by ViiV Healthcare, three-quarters owned by GlaxoSmithKline; the remainder is divided between Pfizer and Japan’s Shionogi & Co.

Apretude’s list price is $3,700 per dose, the equivalent of $22,200 for a one-year course.

Apretude (cabotegravir).

 

Apretude: Cabotegravir’s Mechanism of Action

Cabotegravir (CAB, GSK1265744) is an integrase strand transfer inhibitor (INSTI) that is a structural analog of dolutegravir (DTG).

In Apretude, cabotegravir is implemented in a long-acting formulation.

The know-how of long-acting cabotegravir refers to a nanosuspension of crystalline active substances of submicron size (200 nm), forming a kind of depot with a drug reservoir and controlled dissolution in the surrounding interstitial fluid. Due to the very low dissolution rate of such particles, they are released very slowly (the half-life is 40–80 days for this cabotegravir formulation), thus providing a prolonged therapeutic effect.

The corresponding NanoCrystal technology was developed by Elan Drug Technologies, a business unit of Elan Corporation. In May 2011, Alkermes bought Elan Drug Technologies for $960 million.

Many drugs based on NanoCrystal technology have been launched. For example, in July 2009, Janssen, part of Johnson & Johnson, offered Invega Sustenna/Xeplion (paliperidone), an atypical antipsychotic of prolonged action to treat schizophrenia by intramuscular injection once a month. In May 2015, an improved version appeared in the form of Invega Trinza/Trevicta (paliperidone), prescribed once every three months. In September 2021, Invega Hafyera (paliperidone) came out, with injections once every six months.

 

Apretude: Cabotegravir’s Efficacy in Protecting Against HIV Infection

Protecting Men From HIV Infection

The HPTN 083 (NCT02720094) phase IIb/III (randomized, double-blind, active-drug comparison, multicenter, international) clinical trial enrolled adult volunteers (n=4566) without HIV infection: cisgender men and transgender women who have sex with men.

Participants had to be at high risk of HIV infection, as evidenced by at least one of the following criteria recorded within 6 months prior to inclusion in the study:

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  • anal intercourse without a condom in a receptive role (other than condomless anal intercourse within a monogamous HIV seronegative concordant relationship)
  • more than 5 sexual partners (regardless of condom use and HIV serostatus)
  • use of any stimulant drug
  • either rectal or urethral gonorrhea or chlamydia, or an episode of syphilis infection
  • SexPro score of less than or equal to 16.

Subjects were given either Apretude once every eight weeks intramuscularly or Truvada daily orally. Apretude administration was preceded by an introductory phase to assess drug tolerability: oral cabotegravir daily for up to five weeks.

The primary endpoint was the number of confirmed HIV infections over the entire observation period, which lasted a maximum of 3 years.

After a median follow-up of 1.4 years (interquartile range [IQR] 0.8–1.9), there were 52 cases of HIV infection, of which 13 were in the Apretude group and 39 in the Truvada group. Apretude was 66% (95% CI: 38–82) more effective than Truvada: hazard ratio [HR] 0.34 [95% CI: 0.18–0.62]; p<0.001).

After retrospective analysis of the data, it turned out that the number of HIV infections was lower in Apretude group: one subject had already been infected before the study began. The HIV incidence rate was 0.37% (n=12/3205) and 1.22% (n=39/3187) in Apretude and Truvada groups, respectively. Thus, Apretude provided 69% more protection against HIV than Truvada: HR 0.31 (95% CI: 0.16–0.58); p=0.0003.

The analysis also found that the cumulative number of HIV infections in Apretude group was 16. Of these, 4 occurred before inclusion in the study, 5 occurred due to a prolonged interruption in the use of injectable cabotegravir, 3 occurred before the start of injectable cabotegravir, and the remaining 4 occurred among participants who received all necessary injectable doses to ensure proper plasma concentrations of the drug. Thus, based on 4 cases of breakthrough HIV infection that occurred despite therapy, the level of protection against HIV with Apretude was close to absolute (99.88%).

HIV infection occurred more frequently in the subgroups of people aged 30 years and younger, as well as among men rather than transgender women.

What is remarkable is that the subjects in Truvada group were characterized by a high degree of adherence to pre-exposure HIV prophylaxis (87% of people had the drug detected in their blood, and 75% had a concentration consistent with strict adherence to taking it every day), but the experimental cabotegravir still showed clear superiority in protection against human immunodeficiency virus infection.

The failure of protection against HIV infection in Apretude group is explained in two ways. First, the low plasma concentration of the drug between the initial injections and its reduced concentration in rectal tissue, as well as rectal inflammation caused by any sexually transmitted infection. Second, resistance of HIV strains to cabotegravir.

 

Protecting Women from HIV Infection

The HPTN 084 (NCT03164564) phase IIb/III (randomized, double-blind, active-drug comparison, multicenter, international) clinical trial enrolled sexually active adults (at least two days with vaginal intercourse in the 30 days before screening) that cisgender women (n=3224) without HIV infection and at high risk for infection.

The study invited volunteers living in sub-Saharan African countries (Botswana, Kenya, Malawi, South Africa, Swaziland, Uganda, Zimbabwe). Such a choice of residents is not accidental: HIV infection in these countries has become endemic — more than two-thirds of all HIV-positive people in the world live in these territories. For example, in South Africa, at least 20% of the adult population is HIV-infected, while in Swaziland and Botswana, literally every third person has HIV.

Such a high proportion of HIV-positive people can be explained by many factors. First, behavioral patterns and cultural traditions suggest liberal attitudes toward multiple sexual partners and premarital and extramarital sex. Second, a lack of awareness and education. Third, financial resources for HIV prevention commodities are scarce. Fourth, ongoing military conflicts and frequent natural disasters push young women into prostitution to improve their economic status, as well as to increase access to basic resources such as safe travel, food, and shelter.

The PrEP scheme in HPTN 084 was similar to that in HPTN 083.

There were 40 cases of HIV infection at the end of follow-up: 4 in Apretude group and 36 in Truvada group. Long-acting cabotegravir was 88% more effective than Truvada: HR 0.12 (95% CI: 0.05–0.31); p<0.0001.

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After retrospective analysis of the data, it turned out that the number of HIV infections was lower in Apretude group: one subject had already been infected before the study began. The HIV incidence rate was 0.15% and 1.85% in Apretude and Truvada groups, respectively. Thus, Apretude provided 90% more protection against HIV than Truvada: HR 0.10 (95% CI: 0.04–0.27); p<0.0001.

Infection with HIV was more frequent in subgroups of people aged 25 years or younger, and among those with a body mass index (BMI) below 30 kg/m2.

 

Apretude: Cabotegravir Safety to Protect Against HIV Infection

Apretude’s prescribing information contains a black box warning about the risk of developing drug resistance if the medicine is used by people who are already infected with HIV. And therefore, it is recommended to be tested for HIV infection before each dose of Apretude.

The safety and tolerability profile of Apretude was characterized by acceptability. The most common adverse events were injection site-specific reactions (pain/tenderness, nodules, induration, swelling, bruising, erythema, pruritus), which were experienced by 82% and 38% of subjects in HPTN 083 and HPTN 084.

 

Extras

Apretude (cabotegravir). Prescribing information. [PDF]

Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021 Aug 12;385(7):595-608. [source] [PDF]

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Julia Mardi

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Julia strives to recognize in advance in which direction the pharmaceutical industry is moving. Her professional interests include gene therapy, immune checkpoint inhibitors, molecular biology, and drug repurposing.

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