What Are the Two Most Common Adverse Effects of Antiretroviral Drugs?

October 9, 2025 •

6 min read

Over 39 million people globally are living with HIV, and antiretroviral therapy (ART) has transformed the virus into a manageable chronic condition, but a key concern for patients is what are the two most common adverse effects of antiretroviral drugs. The most frequently reported issues are short-term gastrointestinal problems and central nervous system effects, particularly during the initial phase of treatment.

Quick Summary

The most frequent adverse effects of antiretroviral drugs are gastrointestinal issues like nausea, vomiting, and diarrhea, along with central nervous system effects such as fatigue, headache, and insomnia. Many of these side effects often improve over time.

Key Points

Gastrointestinal issues are the most common side effect: Nausea, vomiting, and diarrhea are frequently reported, particularly during the first few weeks or months of starting a new ART regimen.
Central Nervous System (CNS) effects are also highly common: Patients often experience fatigue, headaches, insomnia, and mood changes, with symptoms sometimes linked to specific drugs like older efavirenz or newer dolutegravir.
Newer ART regimens have a much-improved safety profile: Modern drugs are significantly better tolerated than older versions, with a lower incidence of side effects, including lipodystrophy, kidney, and liver issues.
Many short-term side effects resolve over time: The body often adjusts to the medication, and many common initial side effects will diminish within a few weeks or months.
Effective management is key to long-term adherence: Working closely with a healthcare provider to manage symptoms through lifestyle changes, supportive medicines, or regimen adjustments is critical for treatment success.
Open communication with your doctor is vital: Report any and all side effects to your provider. They can help determine if symptoms are medication-related and how best to address them.

Understanding Antiretroviral Therapy (ART)

Antiretroviral therapy (ART) involves taking a combination of medicines to manage Human Immunodeficiency Virus (HIV). ART works by preventing the virus from replicating, which reduces the viral load in the body to undetectable levels. This allows the immune system to recover, keeping the person healthy and preventing the transmission of HIV. While newer ART regimens are generally much better tolerated than older versions, side effects can still occur and may vary depending on the specific drugs in a person's regimen. The successful long-term management of HIV depends heavily on adherence to the treatment plan, making it crucial for patients and their healthcare providers to effectively manage any adverse effects.

The Most Common Adverse Effect: Gastrointestinal Issues

For many patients, gastrointestinal (GI) side effects are the most commonly experienced adverse effects, particularly when first starting a new regimen. These issues are often transient, improving within a few weeks or months as the body adjusts to the medication.

Common Gastrointestinal Symptoms

Nausea and vomiting: A frequent side effect that can impact quality of life and medication adherence. It is particularly common with older protease inhibitors but can occur with newer classes as well.
Diarrhea: This can be a persistent and bothersome side effect, with some drugs like nelfinavir specifically noted for causing it. Persistent diarrhea can also impact the absorption of nutrients and the medications themselves.
Abdominal pain and bloating: These symptoms often accompany nausea and diarrhea.

Managing Gastrointestinal Side Effects

Dietary adjustments: Eating smaller, more frequent meals throughout the day instead of three large ones can help. Avoiding spicy or fatty foods may also relieve nausea.
Timing of doses: Taking medication with or without food as recommended can be important.
Supportive medication: Over-the-counter or prescription medications, such as antiemetics for nausea or anti-diarrhea agents like loperamide, can be effective.
Hydration: Drinking plenty of fluids is important, especially for patients experiencing diarrhea or vomiting, to prevent dehydration.

The Other Common Adverse Effect: Central Nervous System (CNS) Effects

Another class of adverse effects frequently reported by patients involves the central nervous system. These can include a range of cognitive and psychological symptoms that may impact daily functioning and sleep.

Common CNS Symptoms

Fatigue: A general feeling of tiredness or lack of energy is a common complaint, particularly with some older drugs like zidovudine.
Headache: Headaches are a very common and often mild side effect experienced with many different ART regimens.
Insomnia and abnormal dreams: Trouble sleeping or experiencing vivid, disturbing dreams can occur, particularly with older NNRTIs like efavirenz, but also with newer integrase inhibitors like dolutegravir.
Mood changes: Some patients report experiencing depression, anxiety, or other mood swings. Efavirenz is historically linked to neuropsychiatric issues, but some modern drugs can also cause them.
Dizziness: Feeling lightheaded or dizzy is a reported effect, especially during the initial weeks of therapy.

Managing CNS Side Effects

Adjusting medication timing: Taking medications that cause sleep issues, like dolutegravir, in the morning instead of at night can be beneficial.
Supportive care: Strategies such as maintaining a consistent sleep schedule, engaging in exercise, and managing stress can help.
Switching therapy: If CNS effects are severe or persistent, a provider might recommend switching to an alternative regimen with a lower risk of these side effects.

Comparison of Adverse Effects in Older vs. Newer Antiretroviral Regimens

The landscape of HIV treatment has evolved significantly, with newer drugs generally offering a better safety profile and fewer serious side effects compared to older agents. The following table highlights some key differences in side effect profiles across different ART regimens:


Feature	Older Regimens (e.g., Stavudine, Efavirenz, older PIs)	Newer Regimens (e.g., INSTI-based, TAF-containing)
Gastrointestinal Effects	High incidence, often dose-dependent. Older PIs (like ritonavir) and NRTIs caused significant nausea and diarrhea.	Generally much lower incidence, with many regimens being well-tolerated.
CNS Effects	Efavirenz was particularly notorious for severe neuropsychiatric side effects, including vivid dreams, depression, and hallucinations.	While some newer drugs like dolutegravir can cause insomnia or mood changes, the effects are generally milder and less frequent.
Lipodystrophy	Strongly associated with older NRTIs like stavudine and zidovudine, causing fat loss (lipoatrophy). Protease inhibitors were linked to fat accumulation (lipohypertrophy).	This syndrome is rare with modern first-line therapy.
Renal and Bone Toxicity	Tenofovir disoproxil fumarate (TDF) was associated with a risk of renal toxicity and reduced bone mineral density, especially over long-term use.	Tenofovir alafenamide (TAF) is a newer formulation with significantly improved renal and bone safety profiles. Cobicistat can cause a harmless rise in creatinine.
Hepatotoxicity	Some drugs like nevirapine and older ritonavir-boosted PIs had higher risks of liver toxicity, particularly in patients with co-infections like hepatitis.	Newer drugs generally have lower hepatotoxicity risk, but liver enzyme monitoring is still standard.

Less Common but Important Side Effects

Beyond the most common GI and CNS issues, other side effects warrant careful monitoring, even if they are less frequent with current treatments.

Metabolic Changes and Lipodystrophy

Metabolic changes, including altered blood lipids (hyperlipidemia) and glucose intolerance, can occur with ART. While older drugs were a major culprit for lipodystrophy—noticeable changes in body fat distribution—the risk is substantially lower with current regimens. However, long-term monitoring for metabolic health remains important, particularly for cardiovascular risk factors.

Nephrotoxicity (Kidney Toxicity)

Kidney damage is a known risk, particularly with certain drugs like tenofovir disoproxil fumarate (TDF). While the newer formulation, tenofovir alafenamide (TAF), offers a much-improved safety profile, kidney function is still regularly monitored, especially in patients with pre-existing risk factors.

Hepatotoxicity (Liver Toxicity)

Liver injury is another serious but less common adverse effect, more frequently associated with older NNRTIs like nevirapine and certain PIs. The risk is higher in individuals with co-infection with hepatitis B or C. Liver function is regularly monitored to catch potential issues early.

Hypersensitivity Reactions

Some medications, most notably abacavir, can cause a serious and potentially life-threatening hypersensitivity reaction in individuals with a specific genetic marker (HLA-B*5701). Pre-treatment genetic screening for this marker is standard practice to prevent this reaction.

Managing and Preventing Side Effects

The effective management of ART side effects is a collaboration between the patient and their healthcare provider.

Open communication: Patients should always discuss any symptoms with their provider, no matter how minor they seem. Reporting side effects early can lead to effective management strategies or regimen adjustments before they compromise adherence.
Regular monitoring: Routine blood tests, urinalysis, and checkups are crucial for detecting silent side effects like metabolic changes or early kidney/liver issues.
Lifestyle modifications: A healthy diet and regular exercise can help mitigate metabolic side effects like weight gain and high cholesterol.
Medication adherence: Never stop or reduce your medication dose without consulting a healthcare provider. This can lead to viral rebound and the development of drug resistance.
Regimen switching: For persistent or severe side effects, switching to a different combination of drugs may be necessary. Given the availability of many different ART options, this is often a viable solution.

For more detailed information on ART and its management, authoritative sources such as the NIH's Clinicalinfo offer comprehensive guidance.

Conclusion

What are the two most common adverse effects of antiretroviral drugs? The evidence points to gastrointestinal disturbances (nausea, diarrhea) and central nervous system effects (headache, fatigue, insomnia) as the most frequent complaints, especially when initiating treatment. While other, more severe side effects have been associated with older regimens, the modern era of ART has seen a marked improvement in tolerability, and many initial side effects are transient. The key to successful long-term ART lies in proactive communication with healthcare providers, regular monitoring, and unwavering adherence, ensuring that the transformative benefits of treatment are not jeopardized by manageable adverse effects.

Frequently Asked Questions

No, side effects vary depending on the specific drug or combination of drugs used. Different drug classes have different side effect profiles, and individual reactions can also differ.

For nausea, try eating smaller, more frequent meals, avoiding spicy or fatty foods, and taking the medication with or without food as prescribed. If it persists, talk to your doctor about anti-nausea medications.

Yes, fatigue and headaches are very common initial side effects as your body adjusts to the medication. These symptoms often improve over time. However, if they are severe or persistent, you should discuss them with your provider.

If your medication is causing sleep problems, ask your doctor if it can be taken in the morning. Practicing good sleep hygiene, such as avoiding caffeine and electronics before bed, can also help.

Lipodystrophy is a fat redistribution syndrome historically associated with older ART drugs. While it caused significant fat loss or gain in the past, it is now rare with modern, first-line regimens.

You should never stop taking your medication without consulting a doctor. Stopping treatment can cause the virus to rebound, lead to drug resistance, and limit future treatment options.

Yes, regular blood and urine tests are performed to monitor for potential issues like liver enzyme elevations or kidney function changes. This allows for early detection and management.