What Are the Side Effects of HIV Medications?

HIV drugs can cause a number of serious side effects, but the risk of disease progression and transmission is greatly reduced by sticking to a drug regimen.

Treatment for HIV (human immunodeficiency virus) infections has advanced mightily in the decades since the global pandemic in the 1980s, but there is still no cure. That means people with the infection must stay on antiviral therapy for their entire lives to stave off AIDS (acquired immune deficiency syndrome). AIDS is the condition in which the HIV overwhelms the body’s immune system, leaving the infected person vulnerable to opportunistic bacteria, fungi, and cancers that eventually kill them.

There is no evidence people infected with HIV can currently be cured. In general, those who are treated for years and are repeatedly found to have no virus in their blood by standard viral load assays will experience a prompt rebound in the amount of virus when therapy is discontinued. Consequently, the decision to start therapy must balance the risks versus the benefits of treatment. The risks of therapy include the short- and long-term side effects of the drugs, described in subsequent sections, as well as the possibility that the virus will become resistant to the therapy, which can limit options for future treatment. The risks of both of these problems are quite small with the treatment options currently available.

Still, it’s important to know the potential side effects of all the drugs you take, as well as potential drug interactions. All of the NNRTIs (nonnucleoside analogue reverse transcriptase inhibitors), for example, are associated with important drug-drug interactions so they must be used with caution in patients on other medications. The following is a list of the standard treatment medication classes used in managing HIV:

• nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs)
• nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs)
• protease inhibitors
• fusion inhibitors
• CCR5 antagonists
• integrase strand transfer inhibitors, and
• entry inhibitors

This article will discuss some of the most common and most dangerous side effects in each drug class. This is by no means a comprehensive list. People should read the package information and discuss with their doctor or pharmacist each drug they are prescribed.

Most NRTIs can cause mild nausea and loose stools. In general, these symptoms resolve with time.

ZDV (zidovudine) has been associated with decreased production of blood cells by the bone marrow, most often causing anemia, and occasionally hyperpigmentation (most often of the nails).

D4T (stavudine) can damage nerves and cause peripheral neuropathy, a neurological condition with numbness and/or tingling of the feet and hands, and inflammation of the pancreas (pancreatitis) that causes nausea, vomiting, and mid/upper abdominal pain.

DDI (didanosine) also causes pancreatitis and, to a lesser extent, peripheral neuropathy. Peripheral neuropathy can become permanent and painful, and pancreatitis can be life-threatening if therapy is not discontinued. The drug ddC also is associated with peripheral neuropathy, as well as oral ulcers.

ABC (abacavir) can cause a hypersensitivity reaction during the first two to six weeks of therapy in approximately 5% of individuals. The hypersensitivity reaction most often causes fever and other symptoms, such as muscle aches, nausea, diarrhea, rash, or cough. The symptoms generally get worse with each dose of ABC and, if suspected, therapy must be discontinued and never restarted for fear of developing a life-threatening reaction. There is now a simple blood test (HLA-B*5701) that can be performed to determine whether a patient is at risk for developing the hypersensitivity reaction. If the test is positive, the patient should never receive this medication. There is also conflicting data stating that abacavir may or may not be associated with increased risk of cardiovascular events.

TDF (tenofovir) is generally well tolerated although there may be rare kidney damage and may have a greater impact on reducing bone density than other agents. Both of these problems appear to be attenuated with the new formulation of tenofovir called TAF.

FTC (emtricitabine)is also well tolerated except for the occasional development of hyperpigmentation, most often on the palms and soles. This hyperpigmentation occurs more frequently in people of color.

Although all NRTIs can be associated with lactic acidosis (a serious condition in which lactic acid accumulates in the blood), it may occur more often with some drugs, such as D4T. Although this complication of treatment is rare, it can be severe and life-threatening. Early symptoms of lactic acidosis are nausea, fatigue, and sometimes shortness of breath. Lactic acidosis needs to be watched for and, if suspected, requires that therapy be discontinued until symptoms and laboratory test abnormalities resolve.

There has been a great deal of attention given to the more recently identified problem of "lipodystrophy." Individuals suffering from this syndrome can be categorized as having lipohypertrophy (fat accumulation) syndromes, such as the "buffalo hump" on the back of the neck, breast enlargement, or increased abdominal girth. Others primarily suffer from lipoatrophy with fat loss under the skin with complaints of prominent veins on the arms and legs, sunken cheeks, and decreased gluteal (buttock) size. These syndromes appear to be related to multiple factors, including, but not limited to, drug therapy. The NRTIs appear to be most closely linked to lipoatrophy, in particular D4T and to a lesser extent ZDV. In fact, some studies have suggested slow accumulation of fat in those who modify the NRTI component of their regimen. Some NRTIs also have been linked to elevation in lipid (fat) levels in the blood. While switching therapy is always a consideration in those experiencing potential drug-related toxicity, this should only be done under the careful supervision of an experienced HIV provider.

The most common side effect associated with NNRTIs is a rash, typically occurring during the first weeks of therapy. This is most common in individuals treated with NVP (nevirapine). In this case, the overall risk of rash is reduced if therapy is started as a single 200 mg NVP pill once per day during the first two weeks before increasing to the full dose of 200 mg twice per day. If the rash is mild, therapy usually can be continued if antihistamines are given, and if the rash resolves, treatment with the NNRTI can be continued. If the rash is severe, associated with liver inflammation or blisters, changes in the mouth or around the eyes, or with high fevers, therapy with the NNRTI usually needs to be discontinued. Decisions regarding continuing or stopping treatment need to be made with the primary care professional. In some patients, NVP can cause a severe allergic reaction characterized by fever, rash, and severe liver inflammation. Recent data suggests that the groups at the greatest risk for the severe reaction are those with stronger immune systems, such as HIV-uninfected people given this treatment after an exposure to HIV, women with CD4+ T cells >250 cells per mm3, and men with CD4+ T cells >400 cells per mm3. There is also likely to be increased risk in pregnant women and individuals with other underlying liver diseases. Consequently, NVP probably should not be used in any of these groups, or if used, used with caution. In addition, whenever NVP is started, liver tests that are markers for liver inflammation should be monitored at regular intervals during the first several months of treatment.

Side effects associated with EFV (efavirenz) are mostly dizziness, confusion, fatigue, and vivid dreams. These tend to be most prominent during the first weeks of therapy and then often decrease in severity. It is generally recommended that EFV be taken at bedtime so that the patient is asleep during the time dizziness and confusion may be most severe. It is also noteworthy that there may be an increased risk of depression associated with the use of this drug, and it should be used with caution in those with poorly managed depression. Rash and liver inflammation can occur with both EFV and DLV (delavirdine), and these drugs may also be linked to abnormalities of lipids in the blood.

The most common side effect reported with the most recently approved NNRTI, ETR (etravirine), is rash and it was generally mild and rarely required that medications needed to be stopped. Side effects appear to be uncommon with RPV (rilpivirine) with some uncertainty as to whether it is associated with various neurologic symptoms.

All of the NNRTIs are associated with important drug-drug interactions so they must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

There are currently nine approved PIs that all have distinct toxicities. The most common side effects associated with these drugs are nausea and diarrhea, which occur more often with some PIs than others. For example, diarrhea is more common with NFV (nelfinavir) than other PIs but can occur with any and all drugs in this class. Many of the drugs in this class also increase blood lipid levels, some more than others with ATV (atazanavir) and DRV (darunavir) appearing to have less effect on lipids than other drugs in the class. Other unique toxicities associated with various PIs are kidney stones, kidney damage, and increases in blood bilirubin levels and potentially jaundice with IDV (indinavir) and ATV. Some of these drugs also have been associated with elevations in blood sugar levels and bleeding in hemophiliacs. Finally, little is known regarding the role these drugs may play in the development of lipodystrophy. There is also some data suggesting that LPV/RTV (lopinavir/ritonavir) and DRV may be associated with an increased risk of cardiovascular events.

Most PIs are associated with important drug-drug interactions so they must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

The only drug in this class is T-20 (enfuvirtide), which is administered as a twice-daily subcutaneous injection. The most common side effects are redness and pain at the site of injection. Rarely, infection can occur at the injection site. There also are reports of generalized allergic reactions.

Although there were some early concerns of liver inflammation for drugs in this class, MVC (maraviroc) appeared to be well tolerated in clinical trials without any specific toxicities attributable to the drug. However, it is a new drug in a new class and the first to actually target the cell. For these reasons, longer follow-up from clinical trials and those followed in the clinic will be very important for assessing the overall safety of the drug. There are important drug-drug interactions with MVC, so it too must be used with caution in patients on other medications.

RAL (raltegravir) has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems and of increasing depression that needs to be watched for when starting this or any new medications. EVG (elvitegravir) appears to be well tolerated when used as the fixed-dose combination of Stribild or Genvoya, with the anticipated effect on measures of kidney function and bone mineral density with Stribild and COBI component (cobicistat) of the regimen being associated with drug-drug interactions. DTG (dolutegravir) has been associated with mild headache, insomnia, and nausea in some patients and like COBI is associated with mild early decrease in measures of renal function that actually do not reflect true kidney damage.