Modern Antiretroviral Therapy is Less Toxic, but Not Free from Side Effects

By: Ranier Simons, ADAP Blog Guest Contributor

Antiretroviral therapy (ART) has indisputably improved the medical outcomes of people living with HIV/AIDS (PLWHA). ART increases life expectancy, prevents people with an HIV-positive diagnosis from reaching an AIDS diagnosis, brings many patients back from AIDS into healthier CD4 counts, and even renders many undetectable. Today’s current lines of defense are also increasingly less toxic than earlier drugs. 

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AZT, the first antiretroviral (ARV) used alone against HIV, was so toxic that it caused a faster health decline than HIV would have in people left untreated. The side effects, including damage to bone marrow, made people feel worse than they did without it. Although ART has evolved significantly, it is not perfect. Current ARVs have fewer serious or unbearable adverse issues; however, many PLWHA still deal with side effects.

Some side effects are short term lasting only a few days or weeks. Conversely, some can be much more long-term. It is important to remember that the side effects of one medication can vary from person to person in type, severity, and number. Additionally, some drugs take months to years to develop side effects. PLWHA are living longer and thus are on ART for more extended periods. Researchers are concerned about the potential cumulative toxicity that can develop from long-term use.[1] 

Diarrhea, depression, other mood changes, and hypertension are three common side effects of ART.[2] Diarrhea is one of the most prevailing side effects and causes some people to stop taking their medications. Commonly, it is a side effect of protease inhibitors like ritonavir which may damage the intestinal lining.[3] Immodium (loperamide) is a common over-the-counter remedy used to help PLWHA deal with diarrhea. There are frequently prescribed solutions such as Mytesi (Crofelemer) as well. Derived from the red sap of the Croton lechleri plant, it is just the second botanical prescription drug approved by the U.S. Food & Drug Administration (FDA).[2] Unfortunately, while effective, some State AIDS Drug Assistance Program (ADAP) drug formularies do not offer it.

Depression in PLWHA can have many causes. For some, it can be the psychological result of dealing with having the disease. It can also be caused by the penetration of HIV across the blood-brain barrier and infection of the central nervous system.[4] However, it can also be a side effect of some ARVs. In fact, many list depression or strange dreams as a side effect.[4] Efavirenz, which is in drugs like Atripla, is known for causing nightmares, vivid dreams, or depression.[5] While being a comorbidity among PLWH, hypertension is also shown to be a side effect of some ARVs. Studies show that the chronic inflammation associated with HIV and ART is a significant factor in the high prevalence of PLWHA with high blood pressure.[2]

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A side effect of ART not well-known by many is Diabetes. Some older nucleoside reverse transcriptase inhibitors and older protease inhibitors that are no longer used as much, such as zidovudine and lopinavir, respectively, cause pancreatic damage.[2,6] Newer treatments, such as integrase inhibitors like dolutegravir and bictegravir, have been correlated with weight gain.[6] Unhealthy weight gain increases the risk of developing Diabetes as well. Integrase inhibitors have been shown to lead to faster viral suppression than some other ARVs.[6] Thus, eating well and exercising when using them is essential to mitigate any possible weight gain.

Fortunately, with the breadth of current options available, PLWHA are not stuck dealing with lifestyle challenges or unpleasant and possibly severe side effects to maintain viral suppression. Suffering from adverse effects results in poor medication adherence or complete abandonment. PLWHA are encouraged to communicate with their care team when a medication switch may be necessary. Sometimes PLWHA feel as if too many medications are becoming toxic in their body. In this case, their physician may be able to switch them from a three-drug regimen to a one or two-drug regimen.[7] 

Some ARVs have to be taken with food or even specific types of food. When that becomes a problem, there are options for those who have specific dietary restrictions by choice or necessity. HIV-positive pregnant women must beware of birth defects some ARVs can cause. For them, dolutegravir-based regimens are recommended.[7] PLWHA at risk of kidney problems are directed not to use regimens like Stribild and Truvada, which contain tenofovir disopoxil fumarate (TDF), which can cause them harm.[7] Regimens containing tenofovir alafenamide (TAF), such as Biktarvy or Descovy, better serve that population.[7] Even novel options exist for those who do not wish to take pills. The FDA approved Cabenuva, a two-shot injectable regimen containing rilpivirine and cabotegravir, in 2021. The two injections are administered in a doctor’s office every two months.[7]

All drugs cause side effects, even essential established medications like aspirin. Although newer ARVs don’t have the number or severity of side effects as ones from the past, it is misleading to describe newer regimens as “free from side effects.” Knowledge of possible side effects of regimens enables PLWHA and their doctors to make informed decisions about their care. Moreover, awareness empowers patients to distinguish between side effects and adverse outcomes caused by other issues. Being educated is empowering as well as informs realistic expectations.

[1] Chawla, A., Wang, C., Patton, C., Murray, M., Punekar, Y., de Ruiter, A., & Steinhart, C. (2018). A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population. Infectious diseases and therapy, 7(2), 183–195. https://doi.org/10.1007/s40121-018-0201-6

[2] Yahoo News. (2023, July 3). 2023 Treatment Guide: Dealing With HIV Med Side Effects? Retrieved from https://news.yahoo.com/2023-treatment-guide-dealing-hiv-134944629.html?soc_src=social-sh&soc_trk=tw&tsrc=twtr

[3] MacArthur, R. D., & DuPont, H. L. (2012). Etiology and pharmacologic management of noninfectious diarrhea in HIV-infected individuals in the highly active antiretroviral therapy era. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 55(6), 860–867. https://doi.org/10.1093/cid/cis544

[4] Rapid Response Service. (2009, March). HIV medication and depression. Retrieved from https://www.ohtn.on.ca/rapid-response-hiv-medication-and-depression/

[5] Cairns, G.(2012, October). Efavirenz and the brain: are we nearer to solving a mysterious side-effect?.Retrieved from https://www.aidsmap.com/news/oct-2012/efavirenz-and-brain-are-we-nearer-solving-mysterious-side-effect

[6] Haynes, R. (2021, January).Type 2 diabetes and HIV. Retrieved from https://www.aidsmap.com/about-hiv/type-2-diabetes-and-hiv#:~:text=Some%20anti%2DHIV%20medications%20may,taken%20them%20in%20the%20past

[7] Yahoo News. (2023, June 29). 2023 Treatment Guide: Is it Time to Change Your HIV Regimen? Retrieved from https://www.yahoo.com/entertainment/2023-treatment-guide-time-change-203031820.html?soc_src=social-sh&soc_trk=tw&tsrc=twtr

Disclaimer: Guest blogs do not necessarily reflect the views of the ADAP Advocacy Association, but rather they provide a neutral platform whereby the author serves to promote open, honest discussion about public health-related issues and updates.