What are side effects of HIV therapy?
There are many potential side effects associated with antiviral therapies. The most common ones for each class of drug are summarized in readily available product information. Some specific toxicities are summarized by class below.
Most NRTIs can cause mild nausea and loose stools. In general, these symptoms resolve with time.
ZDV 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 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 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 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 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 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. 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 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, 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, is rash and it was generally mild and rarely required that medications needed to be stopped. Side effects appear to be uncommon with RPV 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 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 and DRV 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 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 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, 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 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.
Integrase strand transfer inhibitors
RAL 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 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 of the regimen being associated with drug-drug interactions. DTG 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.
Monitoring antiviral therapy
The goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing important side effects or selecting for drug-resistant virus. Currently, the best marker of a drug's activity is a decrease in the viral load.
Ideally, prior to initiating treatment, the viral load and the CD4 cell count should be checked and the viral load test then repeated after approximately four weeks of treatment. If the patient is beginning a regimen that includes two to three drugs for which the patient's virus does not appear to be resistant, it is expected that the amount of virus should decrease by at least a hundredfold during this interval. The ultimate goal is for the viral load to decrease to undetectable levels which should occur by approximately 12-24 weeks. There are some individuals that despite taking all of their medications correctly will suppress their viral load to less than 200 copies/mL but not consistently undetectable levels. It is not completely known how to optimally manage this situation but many experts would continue to monitor on current therapy as long as viral load remains below 200 copies/mL. Those who are not having an appropriate response to therapy need to be questioned to make sure that they are taking their medications correctly, and if not, why. If the viral load is not going to undetectable levels and the patient is taking the medications correctly, then it is likely that there is a resistant virus to some of the medications. Drug-resistance testing then should be performed and the patient managed as described in the next section. Once the patient's viral load is suppressed, they can often have viral load and CD4 cell counts performed less frequently (for example, every three to four months and in select cases every six months or possibly even less).