A BRIEF HISTORY OF HIV THERAPY, AND NEW DRUGS FOR HIV, 2020-21

 A BRIEF HISTORY OF HIV THERAPY, AND NEW DRUGS FOR HIV, 2020-21

Ronald P. Hattis, MD, MPH

Prepared for Beyond AIDS Foundation as a resource to providers, updated 5/20/21

In 1987, AZT (now rarely used), a nucleoside reverse transriptase inhibitor (NRTI) originally studied as a possible anti-cancer remedy, became the first antiviral drug approved for AIDS by the FDA. Monotherapy helped temporarily, but typically resulted in the development of viral resistance. As more NRTIs were developed and over the next few years, combinations of two of them were found to be more effective than monotherapy, but still not adequate as a total regimen for treatment because of some eventual resistance and progression of disease. (Later, however, some duo combinations were found to be useful for pre-exposure prophylaxis or PrEP, see below).

Starting in 1996 (when protease inhibitors became available) and until very recently, the standard of care for “highly effective anti-retroviral therapy” (HAART) for HIV has been a combination of three drugs in one or more pills. These have included 2 NRTIs, or in the most highly recommended combinations of recent years, one NRTI plus the highly effective and chemically similar nucleotide reverse transcriptase inhibitor tenofovir disoproxil, approved in 2001.  An alternative form of tenofovir, alefenamide instead of disoproxil, was approved 15 years later and is discussed below. The term N(t)RTI is now sometimes used to refer jointly to the nucleosides and nucleotides.  Regimens that include N(t)RTIs all utilize either emtracitabine or the similar (and generically available) lamivudine, as these are considered to be the least toxic in the group. Those regimens that still include 2 N(t)RTIs combine one of these with either of those two forms of tenofovir, or with a less commonly used alternative, abacavir.

The third drug is selected from a separate class of antivirals. There are now several antiviral drug classes effective against HIV, but based on effectiveness and safety, one has become the class of choice to give with 2 N(t)RTIs as a complete regimen for treating HIV (and especially for starting treatment), This preferred class is the integrase strand transfer inhibitors, known for short as integrase inhibitors or INSTIs. Recently developed INSTIs (dolutegravir, bictegravir, and cabotegravir) have shown great effectiveness and negligible viral resistance, raising the prospect that they might be effective with only one other drug for treatment. This has already been approved for dolutegravir plus one NRTI, lamivudine. Cabotegravir has been approved in a long activing injection with one other drug, and has been proposed for use alone for PrEP, see below. This has influenced three of the new developments below. Unfortunately, INSTI drugs, and particularly dolutegravir and bictegravir, have been associated with weight gain.

Two drugs, ritonavir and cobicistat, are used solely as "boosters" to raise the level of another drug. All of the protease inhibitors are now given with a "booster," as is one of the INSTIs, elvitegravir.

In 2001, tenofovir disoproxil plus an NRTI, emtracitabine, were approved as the first drug combination (Truvada) for pre-exposure prophylaxis (PrEP). Unfortunately, tenofovir disoproxil has some mild toxicity to bone and kidney, which is a concern in particular when treating persons who are well and not infected. Fortunately, a pro-drug alternative lacking those bone and kidney side effects, tenofovir alefenamide, has been developed by the same company, and has been implemented both for treatment and for PrEP. That is one of the new developments discussed below. However, a countervailing consideration is that tenofovir disoproxil actually has some beneficial effects on lipids, which are reversed by switching to the alefenamide preparation. Also, tenofovir alefenamide has been associated with more weight gain than the disoproxil. So treatment choices should be individualized in patients with hyperlipidemia or obesity, and strong bones and kidneys.

1. Dovato (dolutegravir with lamivudine), was approved 4//8/19 as the first 2-drug combination sufficient for a complete treatment regimen. HHS treatment guidelines suggest that this be an approved starting regimen, except for patients with pre-treatment HIV RNA >500,000 copies/mL, or who are known to have active hepatitis B virus (HBV) coinfection; or who will initiate ART before results of HIV genotype testing for reverse transcriptase or HBV testing are available  (https://www.fda.gov/news-events/press-announcements/fda-approves-first-two-drug-complete-regimen-hiv-infected-patients-who-have-never-received; https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf)

2. Descovy (tenofovir alefenamide, the pro-drug of tenofovir not considered to be toxic to bone and kidneys but see above re lipids and weight gain, plus emtracitabine) was approved in 4/16 as part of treatment regimens, and 10/19 as the second combination for PrEP, a safer alternative to Truvada. Unfortunately, it has not been studied or approved for cis females exposed to sex by males. (https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic) 

3. Cabotegravir is a new integrase transfer strand inhibitor, given by injection. When combined with a long-activing injectable form of rilpivirine (a member of the non-nuclease reverse transcriptase inhibitors, one of the other drug classes, and previously approved for daily oral use), it has proven effective. This combination was approved by FDA as Cabenuva on January 21, 2021, as a complete 2-drug treatment regimen.  It is administered monthly, with the starting dose 50% higher than subsequent doses. Meanwhile, cabotegravir alone is being studied and is expected to be approved as the first single-drug and first injectable PrEP.  In a small study with females in sub-Saharan Africa, it was more effective than Truvada as PrEP. Cabotegravir for this use was given a "breakthrough therapy designation" by FDA in November 2020, meaning that the agency will collaborate closely with the manufacturer in hopes of reaching approval in the near future.  (https://www.who.int/news/item/09-11-2020-trial-results-reveal-that-long-acting-injectable-cabotegravir-as-prep-is-highly-effective-in-preventing-hiv-acquisition-in-women; https://jamanetwork.com/journals/jama/article-abstract/2771873) 

In addition, two entirely new types of drugs discussed below have recently been developed for patients with strains of HIV highly resistant to usual medications.

4. Trogarzo (ibalizumab-uiyk) is a new type of HIV drug for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV). It was approved by the FDA on 3/6/18. It must be administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. It is the first CD4-directed post-attachment HIV-1 inhibitor, and binds to CD4+ receptors on host cells, blocking the HIV virus from infecting the cells. Additional drugs requiring IV infusion are in the pipeline. (https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-treatment-patients-who-have-limited-treatment-options; https://www.prnewswire.com/news-releases/theratechnologies-announces-fda-approval-of-breakthrough-therapy-trogarzo-ibalizumab-uiyk-injection-the-first-hiv-1-inhibitor-and-long-acting-monoclonal-antibody-for-multidrug-resistant-hiv-1-300609280.html)

5. Rukobia (Fostemsavir) is a new fusion/entry inhibitor for treatment-experienced adults with failing HIV-1 therapy. It was approved by the FDA on 7/2/20, and is taken orally twice a day.  (https://www.usnews.com/news/health-news/articles/2020-07-07/rukobia-approved-for-patients-with-multidrug-resistant-hiv)

As of 2021, there is a robust pipeline of new drugs in development, some of which are in clinical trials. Both oral and injectable new medications will tend to have long half-lives and not require daily dosage.