A BRIEF HISTORY OF HIV THERAPY,
AND NEW DRUGS FOR HIV, 2020
Ronald P. Hattis, MD, MPH
Prepared for Beyond AIDS Foundation, 12/13/20
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 or them were found to be more effective than monotherapy, but still not adequate as a total regimen for treatment (but later found to be useful for PrEP, see below).
Since 1996 (when protease inhibitors became available), 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 include 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 (which was approved in 2001). (The term N(t)RTI is now sometimes used to refer jointly to the nucleosides and nucleotides.)
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, the one that has become the class of choice to give with N(t)RTIs as a complete regimen for treating HIV (and especially for starting treatment) is the integrase strand transfer inhibitors or INSTIs. Recently developed INSTIs (dolutegravir and the not-yet-approved cabotegravir) have shown great effectiveness and negligible viral resistance, raising the question of whether they might be effective with only one other drug for treatment, or alone for PrEP. This has influenced two of the new developments below.
In 2001, tenofovir disoproxil plus an NRTI, emtracitabine, were approved as the first drug (Truvada) for pre-exposure prophylaxis (PrEP). Unfortunately, tenofovir disoproxil has some toxicity to bone and kidney, which is a concern in particular when treating persons who are well and not infected. Fortunately, a safer pro-drug alternative, 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.
- 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)
- Descovy (tenofovir alefenamide, the pro-drug of tenofovir less toxic to bone and kidneys, plus emtracitabine) was approved in 2016 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 (those with natural vaginas).(https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic)
- Cabotegravir is a new integrase transfer strand inhibitor, not yet approved, given by injection every 8 weeks. When combined with long-activing rilpivirine (a non-nuclease reverse transcriptase inhibitor from one of the other drug classes), it is showing promising results as a complete 2-drug regimen. Meanwhile, cabotegravir alone is being studied as the first single-drug PrEP. So far, it has only been studied as PrEP in a small number of females in sub-Saharan Africa, but was more effective than Truvada. IAS-USA recommends (10/14/20 in JAMA) that upon approval, these uses of cabotegravir become recommended options.
In addition, two entirely new types of drugs discussed below have been developed for patients with strains of HIV highly resistant to usual medications.
- 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. (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)
- Rukobia (Fostemsavir) is a new fusion/entry inhibitor for treatment-experienced adults with failing HIV-1 therapy. It was approved by the FDA in July of this year, 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)