Drug Side Effects
This chart should only be used as a guide to help identify possible drug-related side effects. Some of these side effects have been reported in medical literature, others are anecdotal. Not everyone taking a drug will experience side effects. Most side effects show up in only a small percentage of those using a drug. Many people experience no obvious side effects, while others experience several from the same drug.
The manufacturer's labels included with most prescriptions list how often different side effects have been seen in clinical trial participants. Side effects may be affected by interactions with other drugs (See the Drug Interactions Chart). A more extensive version of this chart, including laboratory abnormalities, is available by calling the Project Inform Treatment Hotline at 800-822-7422.
It's important to recognize that no drug should be evaluated solely based on the number or type of side effects listed. Some drugs may have a high number of side effects which are minor but affect a large percentage of users, others may have few or infrequent, but serious side effects. There is seldom any way to predict what side effects will occur for an individual. Many responses listed as drug side effects also occur as a consequence of HIV disease. It is often difficult to tell whether the disease or the drug is responsible. Sometimes, even the anticipation of a particular side effect can influence how often it is reported; people receiving a placebo (harmless substances disguised to look and taste like a drug) often report the same side effects as those receiving the real drug.
This guide should primarily be used to help identify the possible causes of effects noted when using a drug. Often, the best way to determine whether a drug is the cause is to temporarily stop using the drug. However, this approach itself can have harmful consequences, such as encouraging faster development of drug resistance. In many instances, therefore, it may be useful to try to overcome a side effect rather than withdraw the use of a drug, especially when there are few good alternatives to the drug in question. Suspected side effects, and compensating strategies, should always be discussed with your physician.
Click here to see the table.
Click here to see the table.
Therapy: Side Effects UpdateReprinted from
PI Perspective #25, September 1998.
Some of the enthusiasm over protease inhibitors has been dampened by reports of a redistribution of body fat (lipodystrophy) that has been observed in some people who have been on long-term protease inhibitor therapy. There is considerable debate over whether this phenomenon is directly caused by the protease inhibitors or whether it is caused by rapid and sustained decreases in viral load (HIV RNA levels) and not unique to a particular class of therapy.
Some researchers report observations of lipodystrophy in the pre-protease era, when people were treated with two-drug nucleoside analogue combinations. Further, there is controversy over the incidence of this phenomenon. Some researchers contend that they have rarely, if ever, seen lipodystrophy among their patients while others report they see it frequently. Notably, an Australian group reports an incidence rate of almost 65%, although their figures are based on self-reporting by the patients. The cause of lipodystrophy is still unknown. Information on treating lipodystrophy is sorely lacking and as yet, there isn't a standardized definition for the condition.
The most commonly accepted descriptions of lipodystrophy may include:
From the limited information that is currently available it appears that people experiencing lipodystrophy are not commonly experiencing decreases or increases in their overall body weight. Individual and anecdotal reports from some patients and physicians, however, claim overall weight loss. For the most part, the distribution of weight is changing -- perhaps moving away from arms and legs and into the gut area. In effect, it appears to be a change in the way and places the body stores fat. The difference between this phenomenon and normal changes in body fat distribution is that lipodystrophy results in the fat being found under the abdominal muscles and not directly under the skin where fat usually builds up. Additionally, this fatty buildup is solid and can't be pinched like a beer belly. Furthermore, both women and men have reported increased breast size in addition to the other changes in body composition.
Other side effects, which may be associated with lipodystrophy or independently associated with protease inhibitor therapy, are metabolic changes. These include elevated triglyceride and cholesterol levels (increases in LDL [bad cholesterol] and decreases in HDL [good cholesterol]), onset of diabetes or insulin resistance, and elevated blood pressure. One recent study indicated that the risk of elevated triglyceride levels was nearly 20 times greater in patients using ritonavir, compared to some other protease inhibitors. High triglcyeride levels might be predictive of an increased risk of pancreatitis, while excessive cholesterol levels might be associated with greater risk of heart disease. Other less common, non-metabolic side effects include increased bleeding in people with hemophilia, loss of body hair and ingrown toe nails. These changes usually occur despite effective control of HIV replication, a more robust immune system and otherwise generally improved health.
There are several theories on the cause of lipodystrophy and the metabolic changes. The Australian group has proposed that the protease inhibitors may bind to a human protein, a lipid binding protein, which is structurally similar to the HIV protease enzyme. The role of this protein is to gather up and destroy lipids (fatty substances). They speculate that because the protease inhibitors may be partially blocking the function of this protein, they may change the lipid concentrations in blood as well as the death of certain fatty cells resulting in an accumulation of fat under the abdominal muscle. Furthermore, this protein transports essential materials to the same liver enzyme (known as cytochrome P450 3A4) that is used by the protease inhibitors to be broken down. Since the protease inhibitors block this liver enzyme, it may further worsen the situation. This theory may partially explain why some people developed lipodystrophy before the advent of protease inhibitors as there are other drugs which potently block this liver enzyme, including the antifungal drug ketoconazole (Nizoral®).
One of the potential effects of these metabolic changes is heart disease. One recent report showed three cases of narrowing of the coronary arteries, which prevents an adequate supply of blood to the heart and can result in damage to the heart muscle. All three cases involved men who were 40 years of age or younger and who were being treated with a protease inhibitor containing regimen. Two of the men subsequently had heart attacks.
A study comparing cholesterol levels between people on protease inhibitors and those who were not showed that people on protease inhibitors were significantly more likely to have considerably higher cholesterol levels. This study involved almost 200 people with approximately half of the participants taking at least one protease inhibitor. Interestingly 66% of people on the ritonavir (Norvir®) and saquinavir (Invirase® or Fortovase®) combination had cholesterol levels high enough to require treatment according to the standards by the US National Cholesterol Intervention Program (NCEP) guidelines. However, only 32% of people on indinavir (Crixivan®) and 39% on nelfinavir (Viracept®) met the NCEP guidelines. Surprisingly, some of the participants used gemfibrozil (Lopid®) and or atorvastatin (Lipitor®) to reduce triglyceride and cholesterol levels and had only moderate success despite the fact that these are considered the most active drugs to control elevated triglyceride and cholesterol levels. This suggests that whatever the protease inhibitors are doing, they may also be interfering with the activity of drugs used to treat high cholesterol levels. A small number of people who discontinued protease inhibitor therapy had significant improvements in triglyceride and cholesterol levels. This study raises concerns about the long-term use of protease inhibitors and creates new questions about the wisdom of treating people with very early stage HIV disease.
Another study compared 131 people who were taking protease inhibitors to 25 people receiving non-nucleoside reverse transcriptase inhibitors (NNRTIs) to determine if there were differences in metabolic changes between the groups. The participants were matched based on weight, age, sex, race and time since HIV diagnosis. Eighteen percent of the people taking a protease inhibitor complained of lipodystrophy compared to none among people receiving the NNRTIs. Additionally, the group receiving protease inhibitors had higher cholesterol and triglyceride levels. Again, people receiving the ritonavir and saquinavir dual protease inhibitor combination were significantly more likely to have elevated cholesterol and triglycerides compared to people receiving only one protease inhibitor. However, this data must be seen as somewhat questionable because the patients were not matched for equivalent viral loads (HIV RNA levels) and the group receiving protease inhibitors had much lower HIV levels. Since one major theory attributes lipodystrophy to high levels of viral suppression, it may be unfair to compare the outcomes in these two study groups.
A number of studies looking at body composition were presented at the recent conference in Geneva. One included 455 men (74% were on protease inhibitors) and 63 women (44% were on protease inhibitors) who were considered to be "weight stable" and had CD4+ cell counts below 200. The study examined body weight and composition measures in this group from 1996 to 1997 and compared them with people who were HIV-negative. Overall, both men and women with HIV had significantly lower weight, body cell mass and total body fat compared to their HIV-negative counterparts. There were no differences between the variation from the HIV-negative group based on gender.
Another study of 21 HIV-infected people (13 men and 8 women) and HIV-negative controls looked at sensitive measures of body composition (whole body magnetic resonance imaging [MRI]and DEXA). Of the 21 HIV+ people studied, 5 men and 3 women reported symptoms of lipodystrophy. Of those with truncal obesity, three were not taking a protease inhibitor containing regimen and one was not taking any anti-HIV medication. The researcher, Dr. Donald Kotler, a leader in the field of HIV-related wasting syndrome, concluded that truncal obesity occurs in both men and women at similar rates, and that this type of change in body composition is not only observed among people receiving protease inhibitors and/or anti-HIV therapy.
In another study by Dr. Kotler's team, body composition information was collected from people since 1996 and compared to information gathered prior to the wide-scale use and availability of protease inhibitors. This study confirmed that losses of weight, body cell mass and fat, and changes in body fat distribution are characteristic features of HIV infection, and not strictly related to the use of protease-inhibitor containing regimens. The occurrence of truncal obesity preceded the protease inhibitor era. Results were similar in both men and women and in volunteers taking or not taking protease inhibitors.
A study looking at body shape changes in women taking protease inhibitors showed that 16% of women (19 of 118) noticed body changes after starting therapy with a protease inhibitor. Of the 19 women who had noted body composition changes, 8 were taking indinavir, 10 had switched from indinavir to another protease inhibitor, and 1 had never taken indinavir. The average time these women were taking protease inhibitors was 1.1 years, their average CD4+ cell counts were 333 and 11/18 had viral load levels under 500 copies HIV RNA. Of these 19 women, many reported increases in breast size (71%), increase in abdominal size (71%) and peripheral (arm and leg) wasting (47%). Both the average total body fat and superficial fat were 38%, which indicates a high body fat content. Many of the women also had lipid abnormalities that correlated to the body changes, including low HDL in 13/17 women, high LDL in 8/17 women and high total cholesterol and triglycerides in 7/17 and 6/17 women respectively. Similar changes were also reported in men, but increases in breast size and other changes can result in other problems for women, such as severe back pain. These body image changes can have a significant psychological impact on an individual, and any women or men experiencing such changes should speak with their health care provider.
There is still no strategy proven effective to combat metabolic changes and lipodystrophy. There have been mixed reports of using anti-lipidemic medications such as clofibrate (Atromid®) and gemfibrozil (Lopid®) to lower triglyceride levels. Similarly there have been mixed results with using the "statin" inhibitors such as cerivastatin (Baycol®), fluvastatin (Lescol®), atorvastatin (Lipitor®), lovastatin (Mevacor®), pravastatin (Pravachol®) and simvastatin (Zocor®). People who are considering starting a `statin' inhibitor who are using a protease inhibitor should discuss potential interactions between these two classes of drugs with their healthcare provider and pharmacist. These drugs are both processed through the same liver enzyme and there is a strong potential for interaction. There have been some anecdotal reports of success using human growth hormone to reduce the buffalo hump and the fatty deposit around the abdomen. However, these have involved a very small number of people and larger studies are needed to determine whether this is a useful therapeutic approach. In some severe cases of buffalo hump, people have had liposuction to remove the excess fatty buildup. This is usually only considered when the fatty buildup causes pain or hinders mobility. It is not yet clear whether liposuction results in a permanent solution or whether the hump will simple reoccur over time. In any case, patients should be advised that liposuction can sometimes have serious complications, and few if any practitioners have much experience using it for this purpose.
This article was provided by Project Inform. Visit Project Inform's website to find out more about their activities, publications and services.